Food-Drug Synergy and Safety

by Thompson; Lilian U.

• ISBN13: 9780849327759
• ISBN10: 084932775X
• Format: Hardcover
• Copyright: 2005-08-23
• Publisher: CRC Press

Summary

Scientists, health professionals, and consumers are increasingly interested in the relationships between food components and food-drug combinations as they strive to find more effective ways to prevent or treat chronic disease. As one of the first unified and in-depth sources in this emerging topic, Food-Drug Synergy and Safety explores the vast potential benefits of food and food-drug synergy.The book addresses the interaction of two or more components within a single food, between several foods, or between foods and drugs consumed together, in which the potential health benefit is greater than the effect of the single component, food, or drug. Each chapter follows a consistent framework and addresses the health benefits, mechanisms of action, and safety aspects pertaining to the food and food-drug synergies. Sections discuss food and food-drug synergies in the context of specific disease groups, such as cardiovascular disease, cancer, osteoporosis, inflammatory diseases, hypertension, and obesity, for easy reference in a clinical setting. A separate section focuses entirely on performance enhancers, including caffeine, creatine, and ephedrine/ephedra, and their potential to influence human health in addition to ergogenic applications.The final section provides scientists with a framework for designing experiments that elucidate the heath benefits and safety aspects of food and food-drug synergies. Food-Drug Synergy and Safety lays the essential foundation in this new direction of research as it gains momentum in the fields of food, nutrition, medicine, and pharmaceutical sciences.

Table of Contents

Section I Introduction
1 Understanding Food and Food-Drug Synergy	3	(8)
Wendy E. Ward and Lilian U. Thompson
1.1 Introduction	3	(1)
1.2 Definitions	4	(1)
1.3 Significance	5	(1)
1.4 Examples of Food Synergy	5	(2)
1.5 Examples of Food-Drug Synergy	7	(1)
1.6 Conclusions	7	(4)
Section II Cardiovascular Disease
2 Lipid Sources and Plant Sterols: Effect of Food and Food-Drug Synergy on Cardiovascular Disease Risk	11	(16)
Krista A. Varady and Peter J.H. Jones
2.1 Introduction	12	(1)
2.2 Food Synergy and Cardiovascular Disease	12	(5)
2.2.1 Fish Oil	12	(1)
2.2.1.1 Fish Oil Combined with Olive Oil	13	(1)
2.2.1.2 Fish Oil Combined with γ-Linolenic Acid	14	(1)
2.2.1.3 Fish Oil Combined with Garlic	14	(1)
2.2.2 Oil Containing Medium Chain Triglycerides (MCT Oil)	15	(1)
2.2.2.1 MCT Oil Alone	15	(1)
2.2.2.2 MCT Oil Combined with η-3 Fatty Acids and Plant Sterols	15	(1)
2.2.3 Plant Sterols	16	(1)
2.2.3.1 Plant Sterols Alone	16	(1)
2.2.3.2 Plant Sterols Combined with Various Food Constituents	16	(1)
2.3 Food–Drug Synergy and Cardiovascular Disease	17	(2)
2.3.1 Fish Oil Combined with Pharmacological Therapy	17	(1)
2.3.1.1 Fish Oil Combined with Statin Therapy	17	(1)
2.3.1.2 Fish Oil Combined with Other Forms of Pharmacological Therapy	18	(1)
2.3.2 Plant Sterols Combined with Pharmacological Therapy	18	(1)
2.3.2.1 Plant Sterols Combined with Statin Therapy	18	(1)
2.3.2.2 Plant Sterols Combined with Other Forms of Pharmacological Therapy	19	(1)
2.4 Safety Aspects	19	(2)
2.4.1 Interactions of Fish Oil When Combined with Diet or Drug Therapy	19	(1)
2.4.2 Interactions of MCT Oil When Combined with Diet or Drug Therapy	20	(1)
2.4.3 Interactions of Plant Sterols When Combined with Diet or Drug Therapy	21	(1)
2.5 Conclusions	21	(1)
References	22	(5)
3 Antioxidant Phytochemicals and Potential Synergistic Activities at Reducing Risk of Cardiovascular Disease	27	(36)
David D. Kitts
3.1 Introduction	28	(3)
3.2 Antioxidant Phytochemicals in Food Sources	31	(16)
3.2.1 Tea Polyphenols	31	(1)
3.2.1.1 Phenolic Acids	31	(1)
3.2.1.2 Flavonoids	32	(1)
3.2.1.3 Catechins	33	(1)
3.2.1.4 Tannins	35	(1)
3.2.2 Fruits and Vegetables	35	(1)
3.2.2.1 Flavonols	35	(1)
3.2.2.2 Flavones	36	(1)
3.2.2.3 Flavonones	37	(1)
3.2.2.4 Anthocyanidins	37	(1)
3.2.2.5 Carotenoids	38	(2)
3.2.3 Grapes and Wine	40	(1)
3.2.3.1 Resveratrol	40	(1)
3.2.4 Soybeans	41	(1)
3.2.4.1 Isoflavones	41	(2)
3.2.5 Garlic and Onion	43	(1)
3.2.5.1 Organosulfur Compounds	44	(1)
3.2.6 Ginseng	45	(1)
3.2.6.1 Ginsenosides	46	(1)
3.3 Positive Interactions and Synergies	47	(2)
3.3.1 Nutrient-Nutrient Antioxidant Interactions	47	(1)
3.3.2 Polyphenol-Nutrient Antioxidant Interactions	47	(2)
3.4 Adverse Reactions	49	(1)
3.4.1 Redox-Active Metals and Reducing Agents	49	(1)
3.5 Conclusions	50	(1)
References	51	(12)
4 Synergy of Portfolio Diet Components and Drugs in Coronary Heart Disease	63	(14)
David J.A. Jenkins, Augustine Marchie, Julia M.W. Wong, Russell de Souza, Azadeh Emam, and Cyril W.C. Kendall
4.1. Introduction	63	(1)
4.2 CHD Risk Reduction	64	(6)
4.2.1 Blood Lipids	64	(1)
4.2.2 Food Components and Drugs with Similar Mechanisms of Action	64	(1)
4.2.2.1 Viscous Fibers and Anion Exchange Resins	64	(1)
4.2.2.2 Soy, Vegetable Proteins, and Statins	65	(1)
4.2.2.3 Plant Sterols and Ezetimibe	66	(1)
4.2.2.4 Nuts	67	(1)
4.2.2.5 Food Combination or Portfolio Effects with Drugs	67	(2)
4.2.3 Blood Pressure	69	(1)
4.3 Type 2 Diabetes	70	(1)
4.4 Conclusions	70	(1)
References	71	(6)
5 The Role of Complementary Vitamins, Folate, Vitamin B6, and Vitamin B12, in Cardiovascular Disease	77	(34)
Louise Mennen, Pilar Galan, and Angelika de Bree
5.1 Introduction	78	(2)
5.1.1 Folate	78	(1)
5.1.2 Vitamin B6	79	(1)
5.1.3 Vitamin B12	79	(1)
5.2 Homocysteine Metabolism	80	(3)
5.2.1 Homocysteine Metabolizing Pathways	80	(1)
5.2.2 Genetic Determinants of Homocysteine	81	(1)
5.2.3 Environmental Determinants of Homocysteine	82	(1)
5.3 Homocysteine and Cardiovascular Diseases	83	(2)
5.3.1 History	83	(1)
5.3.2 Meta-Analyses of Observational Studies	84	(1)
5.4 Folate, Vitamin B6, and B12 Synergy in Lowering Homocysteine	85	(4)
5.4.1 Effect of Folate, Vitamin B6, and B12 on Homocysteine Concentration	85	(2)
5.4.2 The Effect of [6S]-5-Methyltetrahydrofolate	87	(1)
5.4.3 Folate Fortification	88	(1)
5.5 Folate, Vitamin B6, and Vitamin B12 Synergy and Cardiovascular Disease	89	(4)
5.5.1 Prospective Cohort Studies	89	(1)
5.5.2 Intervention Trials	90	(3)
5.6 B Vitamins and Other Food Components Synergy and Cardiovascular Disease	93	(2)
5.6.1 B Vitamins and n-3 Fatty Acids	93	(1)
5.6.2 B Vitamins and Antioxidant Vitamins	93	(1)
5.6.3 B Vitamins and Iron	94	(1)
5.6.4 B Vitamins and Alcohol	94	(1)
5.7 Food—Drug Synergy and Cardiovascular Disease	95	(1)
5.7.1 Lipid-Lowering Drugs and B Vitamins	95	(1)
5.7.2 Other Drugs and B Vitamins	95	(1)
5.8 Safety Aspects of Folate, Vitamin B6, and Vitamin B12	96	(1)
5.8.1 B Vitamins	96	(1)
5.8.2 Interactions of B Vitamins with Other Drugs	97	(1)
5.9 Conclusions	97	(1)
References	97	(14)
6 Food Synergy in Dietary Patterns and Risk for Chronic Diseases	111	(14)
Rob M. van Dam
6.1 Introduction	111	(2)
6.1.1 Why Are Dietary Patterns of Interest?	111	(1)
6.1.2 How Can Dietary Patterns Be Studied?	112	(1)
6.1.2.1 Exploratory Approach	112	(1)
6.1.2.2 Hypothesis-Oriented Approach	113	(1)
6.2 Evidence for Health Benefits of Various Dietary Patterns	113	(6)
6.2.1 Mediterranean Dietary Pattern	113	(3)
6.2.2 Major Dietary Patterns in Western Countries	116	(1)
6.2.3 Dietary Approaches to Stop Hypertension	117	(1)
6.2.4 Dietary Recommendations	118	(1)
6.2.5 Other Approaches to Study Dietary Patterns	119	(1)
6.3 Conclusions	119	(2)
References	121	(4)
Section III Cancer
7 Soy-Food and Soy-Drug Interactions in Prevention and Treatment of Cancer	125	(22)
Jin-Rong Zhou
7.1 Introduction	126	(1)
7.2 Interactive Effects between Soy and Food or Drug	126	(10)
7.2.1 Soy and Food Components	127	(1)
7.2.1.1 Soy and Tea	127	(1)
7.2.1.2 Soy and Vitamin D	131	(1)
7.2.1.3 Soy and Other Food Components	132	(1)
7.2.2 Soy and Drugs	133	(1)
7.2.2.1 Soy and TAM Interactions in Breast Cancer Prevention and Treatment	133	(1)
7.2.2.2 Genistein and Other Chemotherapeutic Drugs	135	(1)
7.3 Critical Issues and Future Directions in Research on Soy—Food or Soy—Drug Interactions	136	(4)
7.3.1 Identification of Other Soy Components That May Have Synergistic Effect with Other Foods/Drugs: Effects of Whole Soy Food vs. Supplements	136	(1)
7.3.2 Mechanism Elucidation and Mechanism-Based Design of Synergy Strategies for Cancer Prevention and Treatment	137	(1)
7.3.3 Systematic Evaluation of Synergistic Combinations and Identification of Biomarkers	138	(1)
7.3.4 Individual Responses to Chemopreventive and Treatment Combinations	139	(1)
7.3.5 Safety Issues Related to Synergistic Combination Strategies	140	(1)
7.4 Conclusions	140	(1)
References	141	(6)
8 Flaxseed, Lignans, n-3 Fatty Acids, and Drug Synergy in the Prevention and Treatment of Cancer	147	(28)
Lilian U. Thompson
8.1 Introduction	148	(1)
8.2 Food Synergy	148	(7)
8.2.1 Flaxseed	148	(3)
8.2.2 α–Linolenic Acid Combined with Flaxseed Lignans	151	(1)
8.2.3 Flaxseed Combined with Soy	152	(1)
8.2.4 Lignans Combined with Genistein	152	(1)
8.2.5 α-Linolenic Acid Combined with γ-Linolenic Acid	153	(1)
8.2.6 α-Linolenic Acid Combined with Phytosterols	153	(1)
8.2.7 Sesame Seed Lignans, n-3 Fatty Acids, and Tocopherols	154	(1)
8.3 Food–Drug Synergy	155	(6)
8.3.1 Flaxseed and Its Lignans Combined with Tamoxifen	155	(1)
8.3.1.1 Athymic Mice Study with ER+ MCF-7 Breast Tumors	158	(1)
8.3.1.2 In Vitro Study with ER-MDA MB 435 Breast Cancer Cells	158	(1)
8.3.2 n-3 Fatty Acids Combined with Cancer Drugs	159	(2)
8.4 Safety Aspects	161	(3)
8.5 Conclusions	164	(1)
Acknowledgments	165	(1)
References	165	(10)
9 Whole-Grain Component Synergy and Cancer	175	(18)
Joanne Slavin
9.1 Introduction	175	(1)
9.2 Diet and Cancer	176	(1)
9.3 Whole Grains	176	(1)
9.4 Whole-Grain Recommendations	177	(1)
9.5 Whole-Grain Components	178	(1)
9.6 Epidemiological Studies of Whole Grains and Cancer	178	(2)
9.7 Mechanistic Studies of Whole Grains	180	(5)
9.7.1 Large Bowel Effects of Whole Grains	181	(1)
9.7.2 Antioxidants in Whole Grains	182	(1)
9.7.3 Lignans	183	(1)
9.7.4 Antinutrients	184	(1)
9 .8 Feeding Studies with Whole Grains with Cancer Biomarkers	185	(2)
9.8.1 Dietary Fiber Interventions	185	(1)
9.8.2 Whole-Grains Interventions	186	(1)
9.9 Conclusions	187	(1)
References	187	(6)
10 Synergy and Safety of Antioxidants with Cancer Drugs	193	(1)
Kedar N. Prasad
10.1 Introduction	194	(1)
10.2 Types of Antioxidants and Their Derivatives, Doses, and Treatment Schedule	195	(1)
10.3 Use of Antioxidants by Cancer Patients and Oncologist's Recommendation to Cancer Patients	196	(1)
10.4 Selective Growth-Inhibitory Effect of Individual Dietary Antioxidant and Their Derivatives on Cancer Cells	197	(1)
10.5 Mechanisms of Action of High-Dose Individual Dietary Antioxidants and Their Derivatives on Cancer Cells	197	(3)
10.5.1 Differential Accumulation of Dietary Antioxidants and Their Derivatives?	197	(2)
10.5.2 Imbalance of Redox Status in Cancer Cells	199	(1)
10.5.3 Alteration in Gene Expression, Protein Level, and Protein Translocation in Cancer Cells	199	(1)
10.6 Effect of Multiple Dietary Antioxidants and Their Derivatives on Cancer Cells	200	(1)
10.7 Effect of Individual Endogenously Made Antioxidants on Cancer Cells	200	(1)
10.8 Effect of Antioxidant Deficiency on Cancer Cells	201	(1)
10.9 Interaction of Antioxidants and Their Derivatives with Therapeutic Agents	202	(5)
10.9.1 Protective Effect of Individual Antioxidants and Their Derivatives on Cancer Cells during Radiation Therapy	202	(1)
10.9.2 Enhancing Effect of Individual Antioxidants and Their Derivatives on Cancer Cells During Chemotherapy: In Vitro Studies	203	(1)
10.9.3 Enhancing Effect of Individual Antioxidants and Their Derivatives on Cancer Cells during Chemotherapy: In Vivo Studies	203	(3)
10.9.4 Enhancing Effect of Multiple Antioxidants and Their Derivatives on Cancer Cells during Chemotherapy: In Vitro Studies	206	(1)
10.10 Protection of Normal Cells against Damage Produced by x-Irradiation and Chemotherapeutic Agents by High-Dose Individual Dietary Antioxidants and Their Derivatives	207	(1)
10.11 Clinical Studies with Multiple Dietary Antioxidants in Combination with Standard Therapy	207	(2)
10.12 Mechanisms of Enhancement of the Effect of Standard Therapeutic Agents on Cancer Cells by High-Dose Dietary Individual Antioxidants and Their Derivatives	209	(1)
10.13 Enhancement of the Effect of Certain Biological Response Modifiers on Cancer Cells by High-Dose Individual Dietary Antioxidants and Their Derivatives	209	(2)
10.14 Proposed Micronutrient Protocols as an Adjunct to Standard Cancer Therapy	211	(1)
10.14.1 Active Treatment Protocol	211	(1)
10.14.2 Maintenance Protocol	212	(1)
10.15 Conclusions	212	(1)
Acknowledgment	213	(1)
References	213	(6)
11 Probiotics: Synergy with Drugs and Carcinogens in Diet	219	(1)
Seppo Salminen, Hani El-Nezami, Eeva Salminen, and Hannu Mykkänen
11.1 Introduction	219	(1)
11.2 Probiotics and Prebiotics	220	(5)
11.2.1 Role of Intestinal Microbiota in Well-Being	221	(1)
11.2.2 Probiotic Bacteria and Interaction with Antibiotics	222	(1)
11.2.3 Probiotics and Alcohol	223	(1)
11.2.4 Probiotics and Carcinogens	224	(1)
11.3 Probiotics and Carcinogen Binding	225	(1)
11.4 Probiotics and Cancer	226	(2)
11.5 Probiotics and Toxins	228	(1)
11.6 Prebiotics and Other Toxins	228	(1)
11.7 Conclusions	229	(1)
References	229	(6)
Section IV Osteoporosis
12 Synergy of Soy, Flaxseed, Calcium, and Hormone Replacement Therapy in Osteoporosis	235	(52)
Wendy E. Ward
12.1 Introduction	236	(1)
12.2 Evaluation of Bone Metabolism	237	(2)
12.2.1 Evaluation of Bone Metabolism in Human Studies	237	(1)
12.2.2 Evaluation of Bone Metabolism in Animal Studies	238	(1)
12.3 Food Synergy and Osteoporosis	239	(6)
12.3.1 Soy	239	(1)
12.3.2 Soy Combined with Calcium	240	(4)
12.3.3 Flaxseed	244	(1)
12.3.4 Soy Combined with Flaxseed	244	(1)
12.3.5 Combination of Soy, Flaxseed, and Calcium	245	(1)
12.4 Food-Drug Synergy and Osteoporosis	245	(2)
12.4.1 Calcium and Hormone Replacement Therapy (HRT)	245	(1)
12.4.2 Soy Combined with HRT	246	(1)
12.5 Safety Aspects	247	(1)
12.6 Conclusions	248	(1)
Acknowledgments	249	(1)
References	249	(6)
13 Synergy of Protein, Fats, and Calcium; Potential Synergies with Drugs for Osteoporosis	255	(1)
Marlena C. Kruger and Raewyn C. Poulsen
13.1 Introduction	256	(2)
13.2 Calcium and Bone Health	258	(2)
13.2.1 Dairy Products as a Source of Calcium	259	(1)
13.2.2 Calcium Bioavailability: Effects of Other Nutrients	259	(1)
13.3 Protein and Bone Health	260	(2)
13.4 Protein and Calcium Interactions	262	(2)
13.5 Lipids and Bone Health	264	(1)
13.6 Lipids and Calcium Interaction	264	(5)
13.6.1 Lipids and Intestinal Structure and Function	264	(1)
13.6.2 Lipids and Calcium Absorption	265	(1)
13.6.2.1 Transcellular Calcium Transport	265	(1)
13.6.2.2 Paracellular Calcium Transport	266	(1)
13.6.3 EFAs, Calcium, and Bone Metabolism	266	(1)
13.6.3.1 EFAs and Calcium Absorption	266	(1)
13.6.3.2 EFAs and Calcium Excretion	267	(1)
13.6.3.3 EFAs and Bone Density	267	(2)
13.7 Lipids and Other Nutrients	269	(1)
13.8 Synergy between Drug and Nutrient Therapies for Osteoporosis	270	(4)
13.8.1 Use of Calcium in Combination with Various Drugs	271	(2)
13.8.2 Protein and Phosphorous Required for Bone Maintenance in Combination with Drugs	273	(1)
13.8.3 Lipids and Drugs	273	(1)
13.8.3.1 Essential Fatty Acids and Estrogen	273	(1)
13.8.3.2 Essential Fatty Acids and Statins	274	(1)
13.9 Safety Issues around a High Intake of Calcium, Protein, and Lipids	274	(3)
13.9.1 Safety and Recommended Intake of Lipids	275	(1)
13.9.2 Recommended Intakes of Specific Fatty Acids	275	(1)
13.9.3 Safety of n-3 EFAs	276	(1)
13.9.4 Ratio of n-6:n-3 EFAs	276	(1)
13.10 Sources of Food to Supply Nutrients Required for Maintenance of Bone Health	277	(1)
13.11 Conclusions	278	(1)
References	278	(9)
Section V Inflammatory Disease, Hypertension, and Obesity
14 Molecular Targets for Antiinflammation and Dietary Component—Drug Synergy	287	(88)
Akira Murakami and Hajime Ohigashi
14.1 Introduction	287	(2)
14.2 Proinflammatory Enzymes	289	(5)
14.2.1 Cyclooxygenase	289	(3)
14.2.2 Nitric Oxide Synthase	292	(1)
14.2.3 NADPH Oxidase	293	(1)
14.3 Antiinflammatory Drugs and Dietary Factors	294	(7)
14.3.1 Synthetic COX Inhibitors	294	(2)
14.3.2 Natural COX Suppressants	296	(2)
14.3.3 Synthetic NOS Inhibitors	298	(1)
14.3.4 Natural NOS Suppressants	299	(1)
14.3.5 Synthetic NOX Inhibitors	300	(1)
14.3.6 Natural NOX Suppressants	300	(1)
14.4 Combination Effects	301	(4)
14.4.1 n-3 Fatty Acids	301	(1)
14.4.2 Antioxidants	302	(2)
14.4.3 Antiinflammatory Agents	304	(1)
14.5 Conclusions	305	(1)
Acknowledgments	305	(1)
References	306	(13)
15 Food and Food—Drug Synergies: Role in Hypertension and Renal Disease Protection	319	(1)
Manuel T. Velasquez
15.1 Introduction	320	(1)
15.2 Hypertension	320	(9)
15.2.1 General Considerations	320	(1)
15.2.2 Dietary or Food Factors in Hypertension	320	(2)
15.2.3 Dietary Interventions in the Treatment of Hypertension	322	(2)
15.2.4 Diet Combinations and Food Synergy in the Treatment of Hypertension	324	(2)
15.2.5 Food-Drug Synergy in the Treatment of Hypertension	326	(1)
15.2.6 Biological Activities of Foods or Food Constituents Related to Protection against Hypertension	327	(2)
15.3 Chronic Kidney Disease (CKD)	329	(8)
15.3.1 General Considerations and Overview of Pathophysiology	329	(1)
15.3.2 Dietary Factors in CKD	330	(1)
15.3.3 Dietary Modifications in the Treatment of CKD	331	(2)
13.3.4 Food Synergy in the Treatment of CKD	333	(1)
15.3.5 Food-Drug Synergy in the Treatment of CKD	334	(1)
15.3.6 Biological Actions of Foods or Food Constituents Related to Renal Disease Protection	335	(2)
15.4 Diet and Food Safety Issues	337	(1)
15.5 Conclusions	338	(1)
References	339	(8)
16 Milk Proteins in Food—Food and Food—Drug Synergy on Feeding Behavior, Energy Balance, and Body Weight Regulation	347	(1)
Alfred Aziz and G. Harvey Anderson
16.1 Introduction	348	(1)
16.2 The Regulation of Food Intake and Energy Balance	349	(3)
16.2.1 The Role of Gut Hormones in Regulating Short-Term Food Intake	350	(1)
16.2.2 Macronutrients and Gut Hormones	351	(1)
16.2.2.1 CCK	351	(1)
16.2.2.2 GLP-1	351	(1)
16.2.2.3 Opioids	352	(1)
16.3 Food—Food Synergy on Energy Intake, Subjective Appetite, and Body Weight Regulation: The Role of Dairy Components	352	(7)
16.3.1 Milk Proteins and Their Components	353	(1)
16.3.1.1 Milk Proteins and Food Intake	353	(1)
16.3.1.2 Antiobesity Effect of ACE Inhibitory Peptides	354	(1)
16.3.1.3 The Role of BCAA in Energy Partitioning	355	(1)
16.3.2 Adiposity Regulation by Dietary Calcium	355	(1)
16.3.2.1 Observational Studies	355	(1)
16.3.2.2 Animal Studies	356	(1)
16.3.2.3 Human Studies	356	(1)
16.3.2.4 Mechanisms of Adiposity Regulation by Calcium	357	(1)
16.3.3 Milk Fat and the Regulation of Food Intake, Body Weight, and Adiposity	357	(1)
16.3.3.1 The Role of MCT	357	(1)
16.3.3.2 The Role of CLA	358	(1)
16.4 Food—Drug Synergy, Food Intake, and Body Weight	359	(5)
16.4.1 Pharmacological Treatment of Obesity	359	(1)
16.4.2 Food—Drug Synergies: Examples	360	(1)
16.4.2.1 Dairy Protein, Exendin-4, and Food Intake	360	(1)
16.4.2.2 High-Protein or High-Carbohydrate Diets and Sibutramine or Phentermine	361	(1)
16.4.2.3 High-Protein Diets and Leptin	363	(1)
16.4.2.4 Fermentable Fiber and Orlistat	363	(1)
16.5 Safety Issues	364	(1)
16.6 Conclusions	364	(1)
References	365	(10)
Section VI Ergogenics
17 Caffeine, Creatine, and Food—Drug Synergy: Ergogenics and Applications to Human Health	375	(38)
Terry E. Graham and Lesley L. Moisey
17.1 Introduction	376	(1)
17.2 Caffeine	376	(18)
17.2.1 The Compound and Its Mode of Action	376	(3)
17.2.2 Sources of Caffeine	379	(3)
17.2.3 Caffeine as an Ergogenic Aid	382	(1)
17.2.4 Caffeine—Food Interactions and Ergogenics	383	(2)
17.2.5 Caffeine—Drug Interactions and Ergogenics	385	(1)
17.2.6 Caffeine, Foods, and Health and Safety Issues: Insulin Resistance	386	(6)
17.2.7 Caffeine and Health and Safety Issues: Weight Loss Supplements	392	(2)
17.3 Creatine	394	(7)
17.3.1 The Mode of Action	394	(1)
17.3.2 Creatine Production and Metabolism	395	(1)
17.3.3 Creatine as an Ergogenic Aid	395	(2)
17.3.4 Mechanism of Action	397	(1)
17.3.5 Creatine—Food Interactions and Ergogenics	398	(1)
17.3.6 Creatine—Drug Interactions and Ergogenics	399	(1)
17.3.7 Creatine and Health	400	(1)
17.4 Conclusions	401	(1)
Acknowledgment	402	(1)
References	402	(11)
Section VII Experimental Designs
18 Designing Experiments for Food—Drug Synergy: Health Aspects	413	(48)
Lyn M. Steffen
18.1 Introduction	414	(1)
18.1.1 An Emerging Problem of Adverse Effects of Food Intake on Drug Action	414	(1)
18.2 Diet and Food Factors	415	(7)
18.2.1 Food and Drug Administration (FDA) Requirements	415	(1)
18.2.2 Composition of Foods and Meals	415	(4)
18.2.3 Macronutrients	419	(1)
18.2.4 Fiber	419	(1)
18.2.5 Fat Substitutes	419	(1)
18.2.6 Fortified Foods	419	(1)
18.2.7 Fruit Juice and Flavonoids	420	(1)
18.2.8 Caffeine	421	(1)
18.2.9 Alcohol	421	(1)
18.2.10 Probiotics	421	(1)
18.2.11 Other Dietary Factors	421	(1)
18.3 Experimental Design	422	(4)
18.3.1 Study Hypothesis	423	(1)
18.3.2 Study Design	423	(1)
18.3.3 Study Population	423	(1)
18.3.3.1 Age	424	(1)
18.3.3.2 Gender	425	(1)
18.3.3.3 Physiological Status	425	(1)
18.3.4 Drug Considerations	426	(1)
18.3.4.1 Drug Formulation	426	(1)
18.3.4.2 Drug Dose	426	(1)
18.3.4.3 Timing and Duration of Coadministration	426	(1)
18.4 Conclusions	426	(1)
References	427	(4)
19 Designing Experiments for Food—Drug Synergy: Safety Aspects	431	(1)
V.J. Feron, J.P. Groten, R.J.J. Hermus, D. Jonker, I. Meijerman, G.J. Mulder, F. Salmon, and E.D. Schoen
19.1 Introduction	432	(1)
19.2 What Foods and Drugs Have in Common	433	(1)
19.3 Terminology and Basic Concepts in Mixture Toxicology	434	(3)
19.3.1 Terminology	434	(1)
19.3.2 Basic Concepts	435	(1)
19.3.2.1 Independent (Dissimilar) Joint Action	435	(1)
19.3.2.2 Similar Joint Action	436	(1)
19.3.2.3 Interaction	436	(1)
19.4 Test Systems and Study Designs	437	(12)
19.4.1 Test Systems	439	(1)
19.4.1.1 In Vivo Systems	439	(1)
19.4.1.2 In Vitro Systems	439	(1)
19.4.1.3 Physiologically Based Pharmacokinetic Modeling and in Silico Systems	441	(1)
19.4.2 Study Designs	442	(1)
19.4.2.1 Whole-Mixture/Combination Studies	443	(1)
19.4.2.2 Component-Based Studies	444	(5)
19.5 Examples	449	(4)
19.5.1 Example 1: Four-Week Rat Toxicity Study of Soy and Tamoxifen	450	(1)
19.5.2 Example 2: In Vitro Studies with Doxorubicin and Grape Seed Extract	450	(1)
19.5.2.1 Introduction	450	(1)
19.5.2.2 Biotransformation	451	(1)
19.5.2.3 Drug Transport	452	(1)
19.5.2.4 Pharmacodynamics	452	(1)
19.5.2.5 Clinical Toxicology	452	(1)
19.6 Conclusions	453	(1)
References	454	(7)
Index	461