wk
`Encyclopedia of
`Nutritional Supplements
`The Essential Guidefor Improving
`Your Health Naturally
`
`Michael T. Murray, N.D.
`
`
`
`PRIMA PUBLISHING
`
`
`
`Sandoz Inc. IPR2016-00318
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`Sandoz V. Eli Lilly, Exhibit 1087-0001
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`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1087-0001
`
`

`
`Copyright © 1996 by Michael T. Murray
`
`All rights reserved. No part of this book may be reproduced or transmitted in any form or by any means,
`electronic or mechanical, including photocopying, recording, or by any information storage or retrieval
`system, without written permission from Random House, lnc., except for the inclusion of brief quotations
`in a review.
`
`Published by Prima Publishing, Roseville, California. Member of the Crown "Publishing Group, a division
`of Random House, Inc., New York.
`
`PRIMA PUBLISHING and colophon are trademarks of Random House, Inc., registered with the United
`States Patent and Trademark Office.
`
`Warning—Disclaimer
`Prima Publishing has designed this book to provide information in regard to the subject matter covered.
`It is sold with the understanding that the publisher and the author are not liable for the misconception or
`misuse of information provided. Every effort has been made to make this book as complete and as accu-
`rate as possible. The purpose of this book is to educate. The author and Prima Publishing shall have
`neither liability nor responsibility to any person or entity with respect to any loss, damage, or injury
`caused or alleged to be caused directly or indirectly by the information contained in this book. The
`information presented herein is in no way intended as a substitute for medical counseling.
`
`Library of Congress Cataloging-in-Publication Data
`
`Murray, Michael T.
`Encyclopedia of nutritional supplements 2 the essential guide for improving your health naturally /
`Michael T. Murray.
`p.
`cm.
`Includes index.
`ISBN 0-7615-0410-9
`
`'
`
`02 03 04 DD 181716
`Printed in the United States of America
`First Edition
`
`Visit us online at www.primapublisl1ing.com
`
`/lo. 3003 R 1%‘?
`
`
`
`1. Vitamins in human nutrition——Encyclopedias. 2. Minerals in human nutrition~—~Encyclopedias.
`s 3. Dietary supp1ements—~Encyc1opedias.
`I. Title.
`QP771.M87 1996
`6l2.3'9-—dc20
`
`96-3804
`CH’
`
`Sandoz Inc. IPR2016-00318
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`Sandoz V. Eli Lilly, Exhibit 1087-0002
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1087-0002
`
`

`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1087-0003
`
`

`
`SOME PRACTICAL RECOMMENDATIONS
`
`Recommended Vitamin Intake in International Units (I.U.), Milligrams (mg-)r
`or Micrograms lincg.)
`
`
`
`
`Vitamin Comments Rangefor Adults
`
`
`
`Vitamin A (retinol)
`
`5,0 0 1_[)_
`0
`
`Vitamin A (from beta-carotene)
`Vitamin D
`
`5,000—25,000 I.U.
`100.400 LU,
`
`Vitamin E (d—alpha tocopherol)
`,
`Vitamin K (phytonadione)
`Vitamin C (ascorbic acid)
`
`100-800 I.U.
`
`60—300 mcg.
`100~l,000 mg.
`
`Women of child-bearing age
`should not take more than 2,500
`l.U. of retinol daily due to the
`possible risk of birth defects if
`they become pregnant.
`
`Elderly people in nursing homes
`living in northern latitudes
`should supplement at the high
`range.
`
`It may be I’f101‘e C0St effeCtiVe *0
`take Vitamin E separately.
`
`It may be easier to take vitamin C
`separately rather than in a mul-
`tiple formula.
`
`ants, I
`‘eader
`11-jent
`; Sup_
`
`5‘
`
`‘
`
`10-100 mg.
`Vitamin B1 (thiamin)
`10-50 mg,
`Vitamin B2 (riboflavin)
`10—1o0 mg.
`Niacin
`10.30 mg.
`Niacinamide
`25-100 mg.
`Vitamin B6 (pyridoxine)
`100-300 mcg.
`Biotin
`25-100 mg,
`Pantothenic acid
`400 mcg_
`Folic acid
`40° ‘mg’
`Vita”.“i“ B12
`all of
`10.100 mg_
`Choline
`3ple_
`10-100 mg
`Inositol
`fime,
`ts as ~”-%_”
`defi-
`1
`“Ore
`3 But
`isms
`‘3 to
`ium
`
`Free radicals have also been shown to be responsible for the initiation of many dis-
`eases, including the two biggest killers of Americans--heart disease and cancer.
`Antioxidants, in contrast, are compounds that help protect against free-radiCa1
`damage. Antioxidant nutrients like beta-carotene, selenium, Vitamin E , and Vitamin
`C are very important in protecting against the development Of heart disease, Caneer,
`and other chronic degenerative diseases. In addition, antioxidants are also thought to
`slow down the aging process.
`.
`.
`_
`_
`Based on extensive data, it appears that a combination of antioxidants will provide
`greater antioxidant protection than any single nutritional antioxidant. Therefore, in
`addition to recommending that individuals consume a diet rich in plant foods, espe-
`cially fruits and vegetables, I suggest using a combination of antioxidant nutrients
`rather than high dosages of any single antioxidant. Mixtures of antioxidant nutrients
`
`rud-
`and
`139'
`
`11
`
`Sandoz V. Eli Lilly, Exhibit 1087-0004
`
`Sandoz Inc. IPR2016-00318
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1087-0004
`
`

`
`
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`
`Folic Acid
`
`either pan-
`
`acid mms_
`C acid and
`
`Folic acid, also known as folate, folacin, and pteroylmonoglutamate, functions
`together with vitamin B12 in many body processes. It is critical to cellular division
`because it is necessary in DNA synthesis. Without folic acid, cells do not divide prop~
`erly. Folic acid is critical to the development of the nervous system of the fetus. Defi~
`ciency of folic acid during pregnancy has been linked to several birth defects,
`including neural tube defects like spina bifida. Folic acid deficiency is also linked to
`depression, atherosclerosis, and osteoporosis.
`
`Food Sources
`
`Folic acid received its name from the Latin word folium, which means ”foliage,” be
`cause it is found in high concentrations in green leafy vegetables like kale, spinach,
`beet greens, and chard. Other good sources of folic acid include legumes, asparagus,
`broccoli, cabbage, oranges, root vegetables, and whole grains (see Table 14.1)
`
`TABLE 14.1 Folic Acid Content of Selected Foods, in Micrograms per 31/2-oz. (100-g.) Serving
`
`
`
` Yeast, brewer's
`
`..
`
`Blackeye peas
`Rice germ
`Soy flour
`Wheat germ
`Liver, beef
`Soy beans
`Wheat bran
`Kidney beans
`Mung beans
`Lima beans
`Navy beans
`Garbanzos
`Asparagus
`
`2,022
`440
`430
`425
`305
`295
`225
`195
`180
`145
`130
`125
`125
`110
`
`Lentils
`Walnuts
`Spinach, fresh
`Kale
`Filbert nuts
`Beet 8: mustard greens
`Peanuts, roasted
`Peanut butter
`Broccoli
`Barley
`Split peas
`Whole~wheat cereal
`Brussels sprouts
`Almonds
`
`.
`
`105
`77
`75
`70
`65
`60
`56
`56
`53
`50
`50
`49
`49
`45
`
`Whole—wheat flour
`Oatmeal
`Cabbage
`Dried figs
`Avocado
`Green beans
`Corn
`Coconut, fresh
`Pecans
`Mushrooms
`Dates
`Blackberries
`Orange
`
`38
`33
`32
`32
`30
`28
`28
`28
`27
`25
`25
`14
`5
`
`1 1 9
`
`
`
`Sandoz Inc. IPR2016-00318
`
`Sandoz V. Eli Lilly, Exhibit 1087-0005
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1087-0005
`
`

`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1087-0006
`
`

`
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`F O L I C A C I D
`
`Micrograms
`
`Group
`YOUNG Auuus AND Aouus
`150
`Males 11-14 years
`200
`Males 15+ years
`150
`Females 11-14 years
`180
`Females 15+ years
`400
`Pregnant females
`280
`Lactating females
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`,
`
`Beneficial Effects
`.
`Folic acid, vitamin B12, and a form of the amino acid methionine known as SAM
`(S—adenosyl—methionine; see Chapter 45) function as ”methyl donors.” They carry
`and donate methyl molecules to facilitate reactions, including the manufact-ure of
`DNA and brain neurotransmitters.
`Much of the benefit of folic acid (along with vitamin B6 and B12) supplementation
`is a result of reducing body concentrations of homocysteine, an intermediate in the
`conversion of the amino acid methionine to cysteine. If a person is relatively deficient
`in folic acid, he or she experiences an increase in homocysteine. This compound has
`been implicated in a variety of conditions, including atherosclerosis and osteoporo-
`sis. Homocysteine most likely promotes atherosclerosis by directly damaging the
`artery and reducing the integrity of the vessel wall. In osteoporosis, elevated homo-
`cysteine levelswlead to a defective bone matrix by interfering with the formation of
`proper collagen (the main protein in bone).
`
`Available Forms
`
`---....
`
`"‘*'-~
`
`V
`
`.
`
`Folic acid is available as folic acid (folate) and folinic acid (5-methyl-tetra~hydrofo1ate).
`In order to utilize folic acid, the body must convert it first to tetrahydrofolate and then
`add a methyl group to form 5—methyl-tetra~hydrofolate (folinic acid). Therefore, sup-
`plying the body with folinic acid bypasses these steps. Folinic acid is the most active
`form of folic acid and is more efficient at raising body stores than folic acid.‘
`
`Principal Uses
`
`Folic acid deficiency or supplementation is a factor in the following health conditions:
`0 Acne
`.
`
`~—-—~——-
`
`0 AIDS
`
`0 Anemia
`
`l2l
`
`
`
`Sandoz Inc. IPR2016-00318
`
`Sandoz V. Eli Lilly, Exhibit 1087-0007
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1087-0007
`
`

`
`VITAMINS
`
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`0 Atherosclerosis
`° Cancer
`0 Candidiasis
`0 Canker sores (recurrent)
`0 Cataract
`
`0 Celiac disease
`
`0 Cerebrovascular insufficiency
`0 Cervical dysplasia
`0 Constipation
`0 Crohn’s disease
`0 Diarrhea
`
`0 Epilepsy
`0 Fatigue
`0 Gout
`
`0 Hepatitis
`
`Infertility
`0
`0 Osteoporosis
`0 Neural tube defects
`0 Parkinson's disease
`0 Periodontal disease
`0 Restless legs syndrome
`0 Seborrheic dermatitis
`- Senility
`0 Ulcerative colitis
`E‘Fa‘ 8‘z:.-0 SD539. U):
`
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`
`Prevention of Neural Tube Defects
`Neural tube defects refer to a developmental failure affecting the spinal cord or brain
`in the embryonic stageoffetal development. Veryearlyin fetal development, there is
`a ridge ofnerve tissue along theback ofthe embryo. As the fetus develops, this ridge
`becomes the spinal cord, body nerves, and brain. Atthe same time, the bones that
`make up the back gradually surround the spinal cord on all sides. If any part of the
`development process goes awry, many defects can occur. The worst is total lack of
`brain (anencephaly). The most common is spina bifida,\_a defect in which the verte-
`brae do not form a complete ring to protect the spinal cord. In the United States, ap-
`proximately one to two babies per 1,000 births have a neural tube defect. Folic acid
`
`122
`
`
`
`Sandoz Inc. IPR2016-00318
`
`Sandoz v. Eli Lilly, Exhibit 1087-0008
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1087-0008
`
`

`
`
`
`
`
`FOLIC ACID
`
`supplementation (400 micrograms per day) in early pregnancy is projected to reduce
`the incidence of neural tube defects by 48 percent to 80 percent.
`The discovery that folic acid can prevent spina bifida and other neural tube de-
`fects has been referred to as one of the greatest discoveries of the last part of the
`twentieth century. Numerous studies have now demonstrated the benefit of folic
`acid supplementation beginning either preconception or very early on in the preg—
`nancy and continued througliout.“ The evidence became so overwhelming that the
`FDA finally had to reverse its previous position, acknowledge the association be—
`tween folic and neural tube defects, and allow folic acid supplements and high folic
`acid-containing foods. Now the FDA claims that ”Daily consumption of folic acid by
`women of childbearing age may reduce the risk of neural tube defects.”
`Concerning this discovery of the link between folic acid deficiency and neural
`tube defects, I have noticed how long it took for obstetricians and other medical doc-
`tors to begin making the recommendation of folic acid supplementation to pregnant
`women. Once it became ”accepted medical practice,” however, obstetricians felt they
`had to do everything possible to make sure that their patients were taking folic
`acid——presumably to prevent a malpractice suit being filed in the event that a child
`happened to be born with a neural tube defect.
`Although obstetricians and other medical doctors claim the protective effect of
`folic acid was not known until 1992 (when the U.S. Public Health Service issued a
`recommendation that all U.S. women of childbearing age capable of becoming preg-
`nant should consume 4OO micrograms of folic acid), the fact of the matter is that folic
`acid deficiency has been linked to neural tube defects for over 30 years. The first
`double-blind studies showing a protective effect of folic acid supplementation were
`performed in the early 1980s.“ It makes one wonder how long it will take the med-
`ical profession to accept other links of nutritional supplementation in the treatment
`and prevention of disease.
`
`1ci~
`: of
`on.
`
`Atherosclerosis
`
`Elevated homocysteine levels are an independent risk factor for developing a heart
`attack, stroke, or peripheral vascular disease. Elevations in homocysteine are found
`in approximately 20 to 40 percent of patients with heart disease?” It is estimated
`that folic acid supplementation (400 micrograms daily) alone would reduce the num-
`ber of heart attacks suffered by Americans each year by 10 percent. Although folic
`acid supplementation (l to 2.5 milligrams daily) on its own lowers homocysteine lev-
`els in many cases, given the importance of vitamin B12 and B6 to proper homocys-
`teine metabolism it simply makes more sense to use all three together.““3
`
`Osteoporosis
`
`Increased homocysteine concentrations in the blood have been demonstrated in
`postmenopausal women and probably play a role in osteoporosis by interfering with
`collagen cross-linking, leading to a defective bone matrix.“"5 Since osteoporosis is
`a loss of both the organic and inorganic phases of bone, the homocysteine theory
`
`123
`
`
`
`Sandoz Inc. IPR2016-00318
`
`Sandoz V. Eli Lilly, Exhibit 1087-0009
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1087-0009
`
`

`
`
`
`VITAMINS
`
`has much validity because it is one of the few that addresses both factors. Folic acid
`supplementation reduces homocysteine levels in postmenopausal women even
`though none of the women were deficient in folic acid by standard laboratory criteria.
`
`Cervical Dysplasia
`Cervical dysplasia is an abnormal condition of the cells of the cervix. It is generally
`regarded as a precancerous lesion and has risk factors similar to those of cervical can-
`cer. It is quite probable that many abnormal Pap smears reflect folate deficiency .
`rather than true dysplasia, especially in women who are pregnant or taking oral con-
`traceptives, because estrogens antagonize folic acid.“'‘9 Although macrocytic ane-
`mia is the most commonly recognized sign of folic acid deficiency, abnormalities in
`the cervical cells are seen many weeks ear1ier.“’I‘7
`Some researchers hypothesize that oral contraceptives interfere with folate metabo-
`lism and, although serum levels may be increased, tissue levels of the cervix may be
`
`dysplasia), while serum levels may be normal or even increased.” Oral contraceptives
`probably stimulate the synthesis ofa molecule that inhibits folate uptake by cells.
`In clinical studies, folic acid supplementation (10 milligrams per day) results in
`improvement or normalization of Pap smears in patients with cervical dysplasia.“"2°
`The rate of normalization for women with untreated cervical dysplasia is typically
`1.3 percent for mild and 0 percent for moderate dysplasia. When patients were
`treated with folic acid, the regression-to~normal rate was observed to be 20 percent in
`one study” and 100 percent in another”. Furthermore, the progression rate of cervi-
`cal dysplasia in untreated patients is typically 16 percent at 4 months (a figure
`
`untreated women ranges from 86 months for patients with very mild dysplasia to 12
`months for patients with severe dysplasia, and ‘improvement is very uncommon.
`Therefore, I would suggest instituting a trial of folate supplementation (along with
`other considerations discussed) in mild-to-moderate dysplasia, with a follow-up Pap
`smear and coloscopy at 3 months. Vitamin B12 supplementation should always ac-
`company folate supplementation.
`
`Depression
`Many psychiatric patients exhibit folic acid deficiency.2“23 Correction of an underly-
`ing folate acid deficiency has brought about remarkable reversal of mental and psy-
`chological symptoms in some patients, especially elderly patients suffering from
`impaired mental function.2"24“23 Folic acid exerts a mild antidepressant effect,“ pre-
`sumably via its function as a methyl donor and increasing the brain content of sero-
`tonin, SAM (S~adenosyl-methionine), and BH4 (tetrahydrobiopterin). I discuss SAM
`in greater detail in Chapter 45. BH4 functions as an essential coenzyme in the activa-
`124
`
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`
`Sandoz Inc. IPR2016-00318
`
`Sandoz v. Eli Lilly, Exhibit 1087-0010
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1087-0010
`
`

`
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`tion of enzymes that manufacture monoamine neurotransmitters like serotonin and
`dopamine from their corresponding amino acids. Patients with recurrent depression
`have reduced BH4 synthesis, probably as a result of low folic acid or SAM levels. Bl-I4
`supplementation produces dramatic results in these patients.29'~°’° Unfortunately, BH4
`is not currently available commercially. However, since folic acid, vitamin B12, and
`vitamin C stimulate Bl-I4 synthesis, it is possible that increasing these vitamin levels
`in the brain may stimulate both BH4 formation and the synthesis of monoamines like
`serotonin.“
`Folic acid supplementation increases methylation reactions in the brain, leading to
`an increase in the serotonin content of the brain. The serotonin~elevating effects are
`undoubtedly responsible for much of the antidepressive effects of folic acid and
`other methyl donors.32‘34 Typically, the dosages used in the clinical studies where
`folic acid has been used as an antidepressant have been very1\igh—15 milligrams to
`50 milligrams. Dosages of folate this high require a doctor's prescription. High-dose
`folic acid therapy is safe (except in patients with epilepsy) and can be as effective as
`antidepressant drugs.“ However, there are other natural measures in this book that
`yield even better results (SAM).
`
`Dosage Ranges
`These are the condition-based dosages I recommend:
`0 For general health and the prevention of atherosclerosis and osteoporosis, 400 mi-
`crograms daily
`0 For the treatment of cervical dysplasia and depression, 10 milligrams daily.
`....,....-re....‘....~a_~.».._~..............................-.,....................................,v‘...........A...........,..........,.....~...t....A..,.....Mum-.... «..—....».~....,..v-... um.‘..,..V.....»_~4.«..~.1«.....4....4..,....-..-...n.....—.«.».»..~.....~»..........»_-.1
`Since the FDA restricts the amount of folic acid available in nutritional supple~
`ments to 400 micrograms, ask your doctor for a prescription when higher
`levels are required.
`ax.........«.....«....u~.....<......_.(.‘.....¢...................~.......y.m....Nuts...»..\,...aw..............................«.....w..4...~.-.~.....~...«...»...,...¢...-...M..--..»........a........-.-..~v,4~..«.~..4«..x;.ua».u.\...«.«..~.».-a.4w..«.«uv.v.»......t....;..\..
`
`Safety Issues
`
`Folic acid supplementation should always include vitamin B12 supplementation
`(400 to 1,000 micrograms daily) because folic acid supplementation can mask an
`underlying vitamin B12 deficiency. The danger is that while the folic acid reverses
`the macrocytic anemia, it does not prevent or reverse the neurological symptoms of a
`Vitamin B12 deficiency. Nerve damage can result that does not respond to vitamin B12
`supplementation.
`Folic acid is well—tolerated. In high dosages (e.g., 5 to 10 milligrams) it may cause
`increased flatulence, nausea, and loss of appetite. High dosage folic acid supplemen-
`tation should be used with extreme caution in epileptics because occasionally it may
`increase seizure activity.
`
`125
`
`
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`Sandoz Inc. IPR2016-00318
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`Sandoz V. Eli Lilly, Exhibit 1087-0011
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1087-0011
`
`

`
`
`
`VITAMINS
`
`Interactions
`
`Folic acid works together with vitamin B12, SAM, vitamin B6, and choline. Oral pan-
`creatic extracts may reduce folic acid absorption, so they should be administered
`away from folate supplementation.”
`Estrogens, alcohol, various chemotherapy drugs (especially methotrexate), sul~
`fasalazine (a drug used in the treatment of Crohn’s disease and ulcerative colitis),
`barbiturates, and anticonvulsant drugs all interfere with folic acid absorption or
`function.
`
`126
`
`Sandoz Inc. IPR2016-00318
`
`Sandoz v. Eli Lilly, Exhibit 1087-0012
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1087-0012
`
`

`
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`
`
`Vitamin B12, or cobalamin, was isolated from a liver extract in 1948 and identified as
`the nutritional factor in liver that prevented pernicious anemia, a deadly type of ane-
`mia characterized by large, immature red blood cells. Vitamin B12 is a bright red -crys-
`talline compound because of its high content of cobalt. Vitamin B12 works with folic
`acid in many body processes, including the synthesis of DNA, red blood cells, and
`the insulation sheath (the myelin sheath) that surrounds nerve cells and speeds the
`conduction of the signals along nerve cells. In order to absorb the small amounts of
`vitamin B12 found in food, the stomach secretes intrinsic factor, a special digestive se-
`cretion that increases the absorption of vitamin B12 in the small intestine.
`
`Food Sources
`Vitamin B12 is found in significant quantities only in animals foods. The richest
`sources are liver and kidney, followed by eggs, fish, cheese, and meat (see Table 15.1).
`Strict vegetarians (vegans) ‘are often told that fermented foods like tempeh are ex-
`cellent sources of vitamin B12. However, in addition to tremendous variation of B12
`
`TABLE 15.1 Vitamin Bu Content of Selected Foods, in Micrograms
`per 3 ‘./2-oz. (100-g.) Serving
`
`‘
`
`Blue cheese
`4.0
`Salmon, flesh
`104.0
`Liver, lamb
`Haddock, flesh
`3.0
`Tuna, flesh
`98.0
`Clams
`Flounder, flesh
`2.1
`Lamb
`80.0
`Liver, beef
`Scallops
`2.0
`Eggs
`63.0
`Kidneys, lamb
`Cheddar cheese
`2.0
`Whey, dried
`60.0
`Liver, calf
`Cottage cheese
`1.8
`Beef, lean
`31.0
`Kidneys, beef
`Mozzarella cheese
`1.8
`Edam cheese
`25.0
`Liver, chicken
`Halibut
`1.8
`Swiss cheese
`18.0.
`Oysters
`Perch, filets
`1.6
`Brie cheese
`17.0
`Sardines
`Swordfish, flesh
`Gruyére cheese 1.6
`5.0
`Trout
`......._,....,.._......_........,.....m_._..1_.....-.,.........
`
`
`1.4
`1.3
`1.2
`1.2
`1.0
`1.0
`1.0
`1.0
`1.0
`1.0
`
`127
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`Sandoz V. Eli Lilly, Exhibit 1087-0013
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1087-0013
`
`

`
`VITAMINS
`
`
`content in fermented foods, some evidence indicates that the form of B12 in these
`foods is not exactly the form that meets our body requirements and is therefore use-
`less. The same holds true of certain cooked sea vegetables. Although the vitamin B12
`content of these foods is in the same range as beef, scientists do not know how well
`our bodies utilize this form. Therefore, at this time I would recommend that vegetar-
`ians supplement their diets with vitamin B12.
`
`Deficiency Signs and Symptoms
`
`Unlike other water~soluble nutrients, vitamin B12 is stored in the liver, kidney, and
`other body tissues. As a result, signs and symptoms of vitamin B12 deficiency may
`not show themselves until 5 to 6 years of poor dietary intake or inadequate secretion
`of intrinsic factor. The classic deficiency symptom of vitamin B12 deficiency is perni-
`cious anemia. However, a deficiency of vitamin B12 actually affects the brain and ner-
`vous system first.
`A vitamin B12 deficiency results in impaired nerve function, which can cause
`numbness, pins~and-needles sensations, or a burning feeling. It can also cause im-
`paired mental function that in the elderly mimics Alzheimer's disease. Vitamin B12
`deficiency is thought to be quite common in the elderly and is a major cause of de-
`pression in this age group.
`In addition to anemia and nervous system symptoms, a vitamin B12 deficiency can
`also result in a smooth, beefy red tongue and diarrhea. This occurs because rapidly
`reproducing cells such as those that line the mouth and entire gastrointestinal tract
`cannot replicate without vitamin B12. Folic acid supplementation masks this defi-
`ciency symptom.
`Measuring the level in the blood (serum cobalamin) or the level of methylmalonic
`acid in the urine is the best method to determine vitamin B12 deficiency. In addition,
`measuring the level of plasma homocysteine is emerging as a method to determine
`the status of both vitamin B12 and folate. Another test, the Schilling test, is used to de-
`termine whether there is sufficient output of intrinsic factor. The test involves oral
`administration of radioactive vitamin B12 and then measuring the level excreted in
`the urine. Below-normal urinary excretion of the vitamin suggests impaired absorp-
`tion because of lack of intrinsic factor.
`Several investigators have found the level of vitamin B12 declines with age and
`that vitamin. B12 deficiency is found in 3 to 42 percent of persons aged 65 and over.
`Physicians should attempt to diagnose cobalamin deficiency early in the elderly be-
`cause it is easily treatable and, if left untreated, can lead to impaired neurological and
`cognitive function.”
`Researchers recently studied 100 consecutive geriatric outpatients who were seen
`in office~based settings for various acute and chronic medical illnesses; none of these
`outpatients presented symptoms of vitamin B12 deficiency-related diseases like per-
`nicious anemia. In this group, 11 patients had serum cobalamin levels at 148 pmol/ L
`(picomole per liter) or below, 30 patients had levels between 148 and 295 pmol/L,
`and 59 patients had levels above 296 pmol/L. After the initial cobalamin determina-
`tion, the subjects were followed for up to 3 years. The patients with cobalamin levels
`128
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`Sandoz V. Eli Lilly, Exhibit 1087-0014
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`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1087-0014
`
`

`
`COBALAMIN (VITAMIN B12)
`
`below 148 pmol/ L were treated and were not included in the analysis of declining
`cobalamin levels. The average annual serum cobalamin level decline was 18 pmol/ L
`for patients who had higher initial serum cobalamin levels (actual range, from 224 to
`292 pmol/L). For patients with lower initial cobalamin levels, the average annual
`serum cobalamin decline was much higher at 28 pmol/ L.3
`These results indicate that in the elderly the following screen tests for vitamin B12
`have a high cost—to-benefit ratio:45
`
`0 Level of vitamin B12 in the blood (serum cobalamin)
`
`- Urinary excretion of methylmalonic acid
`
`0 Level of homocysteine
`Of these three tests, the urinary methylmalonic acid assay is perhaps the best test
`because it is sensitive, noninvasive, and relativel convenient for the atient. Correc~
`Y
`P
`tion of an underlying vitamin B12 deficiency improves mental function and quality of
`life in these patients quite significantly.
`
`0
`Recommended Dietary Allowance
`Recommended Dietary Allowance of Cobalamin (Vitamin B1,)
`
`
`
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`INFANTS
`Under 6 months
`6~12 months
`
`CHILDREN
`1-3 years
`figears
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`YOUNG ADULTS AND Aoums
`
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`11+ years
`2.2
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`2.1
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`“”“‘“““"“‘“”“'”‘”“‘""”””‘“”"'"’“”““”“’““‘“‘““““““‘“"”‘””“‘““”"‘
`
`Beneficial Effects
`
`Vitamin B12, like folic acid, function as a ”methyl donor.” A methyl donor is a com-
`pound that carries and donates methyl‘ groups (a molecule of one carbon and three
`hydrogen molecules) to other molecules, including cell membrane components and
`neurotransmitters. As a methyl donor, vitamin B12 is involved in homocysteine me~
`tabolism and plays a critical role in proper energy metabolism, immune function,
`and nerve function.
`
`129
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`
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`Sandoz Inc. IPR2016-00318
`
`Sandoz V. Eli Lilly, Exhibit 1087-0015
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1087-0015
`
`

`
`
` VITAMINS
`
`
`
`
` Homocysteine is a factor in the progression of both atherosclerosis and osteoporo-
`sis. In fact, elevations in homocysteine are an independent risk factor for having a
`
`
`
`heart attack Approximately 20 to 40 percent of patients with heart disease exhibit el~
`
`not lower homocysteine levels i
`.
`.
`supple~
`
`
`
`mentation lowers homocysteine levels only if there are adequate levels of vitamin B12
`and B6. Because of the interconnectedness of these three B vitamins, it is best to
`
`
`supplement with all three.“ Folic acid and vitamin B12 supplementation lowers
`homocysteine levels even in individuals with normal vitamin B12, folic acid, and
`
`
`homocysteine Ievels.9
`
`
`
`
`Available Forms
` Vitamin B12 is available in several forms. The most common form is cyanocobalamin;
`however, vitamin B12 is active in only two forms, methylcobalamin and adenosyl—
`cobalamin. Methylcobalamin is the only active form of vitamin B12 available com-
`
`
`
`mercially in tablet form in the United States. While methylcobalamin is active
`
`
`
`
`
`available form.
`
`
`
`Oral versus Injectable
`Although it is popular to inject vitamin B12, injection is not necessary. The oral ad-
`ministration of an appropriate dosage, even in the absence of intrinsic factor, results
`in effective elevations of vitamin B12 in the blood. Most physicians have ignored this
`fact. An editorial entitled ”Oral Cobalamin for Pernicious Anemia, Medicine's Best
`Kept Secret,” which appeared in the January 2, 1991, edition of [AMA (]ourrzal of the
`American Medical Association) states that oral therapy produces reliable and effective
`treatment, even in severe cases of pernicious anemia.“
`In the United States, physicians rarely use oral vitamin B12 therapy despite the fact
`that it is fully (100 percent) effective in the long-term treatment of pernicious anemia.
`
` 130
`
`
`
`
`
`
`
`
`
`
`,.
`i
`
`;.
`"
`
`
`
`
`
`
`
`
`
`
`
`Sandoz Inc. IPR2016-00318
`
`Sandoz v. Eli Lilly, Exhlblt 1087-0016
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1087-0016
`
`

`
`
`
`COBALAMIN (VITAMIN B12)
`
`Let's first discuss the data showing effectiveness with oral administration before dis~
`cussing the dogma cited for injectable administration.
`Almost as soon as scientists isolated vitamin B12 in 1948, companies introduced an
`injectable form. Researchers busily sought an oral alternative. They tried oral prepa-
`rations containing intrinsic factor, but some patients developed antibodies against
`intrinsic factor and, therefore, would not respond.” Other studies soon documented
`that a small but constant proportion of an oral dose of cyanocobalamin was absorbed
`without intrinsic factor through the process of diffusion; therefore, by sufficiently in~
`creasing the dose, they could obtain adequate absorption.13«"‘
`Early studies show that pernicious anemia could be completely controlled with
`doses of cyanocobalamin in the range of 300 to 1,000 micrograms daily.15"“’ The
`largest of these studies described 64 Swedish patients with pernicious anemia (and
`other vitamin B12-deficiency states) who were treated with 1,000 micrograms oral
`cyanocobalamin daily.‘7'“’ In all patients studied over a 3 year period, the researchers
`observed complete normalization of serum levels and liver stores for vitamin B12 as
`well as full clinical remission.
`Despite this research, physicians in the United States do not use oral vitamin B12
`therapy. Why? Education and bias. Medical texts first state that oral vitamin B12 ther-
`apy of pernicious anemia is ”unpredictable,” has poor patient compliance, and is
`more costly. Then after establishing this bias against oral therapy, they state that oral
`cobalamin is effective and can be used when injection therapy is problematic. In a
`survey of internists, 91 percent erroneously believed that vitamin B12 could not be ab-
`sorbed in sufficient quantities without intrinsic factor. Interestingly, 88 percent of
`these doctors also stated that an effective oral vitamin B12 therapy would be useful in
`their practice and further st