01.Carnitine Deficiency and Insufficiency in Medicine
03.Words of Recommendation
06.1. Discovery of Carnitine
07.1.1 Discovery of Carnitine from Muscle Extract
08.1.2 Determination of the Chemical Structure of Carnitine
09.1.3 Subsequent Studies of the Physiological Actions of Carnitine
10.1.4 Discovery of the Physiological Actions of Carnitine in Insect Nutrition
11.1.4.1 What Is Insect Nutrition?
12.1.4.2 Research on Vitamin BT by Dr. Fraenkel et al.
13.2. Establishing the Carnitine Cycle
14.2.1 What Is the Carnitine Cycle?
15.2.2 The Discovery of Carnitine Palmitoyltransferase (CPT)
16.2.2.1 Research by Fraenkel
17.2.2.2 Studies by Fritz et al.
18.2.2.3 Studies by Bremer
19.2.2.4 Presence of Two Types of CPTs
20.2.3 Discovery of Carnitine-Acylcarnitine Translocase (CACT)
21.2.3.1 Studies by Pande et al.
22.2.3.2 Studies by Ramsay et al.
23.2.4 Discovery of Carnitine Transporter
24.2.4.1 Assumption of Carnitine Transporter
25.2.4.2 Muscle Carnitine Deficiency (MCD)
26.2.4.3 Systemic Carnitine Deficiency (SCD)
27.2.4.4 Discovery of Juvenile Visceral Steatosis (JVS) Mice and Subsequent Research
28.2.4.5 Discovery of Carnitine Transporter (OCTN2)
29.2.4.6 Mutation in Human and Mice OCTN2
32.3.2 Chemical Structure of Carnitine
33.3.3 Salts of Carnitine Preparations
34.3.4 Physical Properties of Carnitine
35.3.5 Misconceptions About Carnitine: An Amino Acid? B Vitamin?
36.3.6 What Is the Acyl Group Carried by Carnitine?
37.3.7 What Is Coenzyme A (CoA)?
38.3.8 Biochemical and Physiological Actions of Carnitine
39.3.9 Free Carnitine and Acylcarnitine
40.3.10 Transport of Long-Chain Fatty Acids into Mitochondria
41.3.10.1 Carnitine Cycle and Energy Metabolism
42.3.10.2 How Much ATP Do Humans Consume?
43.3.10.3 Numbers of ATP Produced from Glucose and Long-Chain Fatty Acids
44.3.11 Excretion of Harmful Acyl Compound and Modulation of Acyl-CoA/Free CoA Ratio
45.3.11.1 The Concept of Carnitine Insufficiency
46.3.11.2 Enzymes Inhibited by Acyl-CoA
47.3.11.3 Types and Roles of Carnitine Acyltransferase
48.3.12 L-Carnitine in Pharmaceuticals and Supplements
49.3.13 Acetyl-L-Carnitine and Propionyl-L-Carnitine
50.3.13.1 Acetyl-L-Carnitine (ALC)
51.3.13.2 Propionyl-L-Carnitine (PLC)
52.4. Homeostasis of Carnitine
54.4.2 Overview of Carnitine Distribution and Homeostasis
55.4.3 Tissue Content of Carnitine
56.4.4 Dietary Intake of Carnitine
57.4.4.1 Absorption of Carnitine from the Gastrointestinal Tract
58.4.4.2 Content of Carnitine in Foods
59.4.4.2.1 Content of Carnitine in Foods Ingested on a Daily Basis
60.4.4.2.2 Carnitine Intake in Vegetarians
61.4.5 Biosynthesis of Carnitine
62.4.5.1 Characteristics of Carnitine Biosynthesis
63.4.5.2 Biosynthetic Pathway of Carnitine
64.4.5.3 Organ Distribution of Carnitine Biosynthetic Enzymes and Organ–Organ Interactions
65.4.6 Excretion and Reabsorption of Carnitine from the Kidney
66.4.6.1 Handling of Free Carnitine and Acylcarnitine in the Kidney
67.4.7 Disruption of Carnitine Homeostasis in Various Diseases
68.4.7.1 Inherited Metabolic Disorders
71.4.7.4 Dialysis Patients
72.4.7.5 Fanconi Syndrome
73.4.7.6 Patients Receiving Valproate
74.5. What Are Carnitine Deficiency and Carnitine Insufficiency?
75.5.1 Definition of Carnitine Deficiency and Carnitine Insufficiency
76.5.2 Two Types of Carnitine Deficiency: Carnitine Deficiency and Carnitine Insufficiency
77.5.3 Significance of Carnitine Supplementation Therapy
78.5.4 Classification of Carnitine Deficiency by Etiology
79.5.4.1 Primary Carnitine Deficiency
80.5.4.2 Secondary Carnitine Deficiency
81.5.4.2.1 Due to Inherited Metabolic Diseases (Excluding Primary Carnitine Deficiency)
82.5.4.2.2 Due to Acquired Medical Conditions
83.Reduction of Biosynthesis
86.Decrease in Body Storage/Increase in Requirement
88.5.4.2.3 Carnitine Deficiency Caused by Iatrogenic Treatment
90.Drug-Induced Carnitine Deficiency
91.5.5 Clinical Symptoms of Carnitine Deficiency
92.5.5.1 Acute Metabolic Compensatory Failure Associated with Fasting
93.5.5.2 Recurrent Hypoketotic Hypoglycemic Attacks
94.5.5.3 Tissues That Are Highly Dependent on Efficient Fatty Acid Oxidation at All Times
95.5.5.4 Changes in Serum and Tissue Carnitine Concentrations
96.5.5.5 Laboratory Abnormalities Commonly Seen in Carnitine Deficiency
97.5.6 Animal Models of Carnitine Deficiency
98.6. Appetite Enhancement and Digestive Enzyme Secretion Promoting Effects of Carnitine
100.6.2 Digestive Enzyme Secretion Stimulating Effects of DL-Carnitine Preparation (Bicarnesine)
101.6.3 Appetite Enhancement and Weight Gain Effects of Bicarnesine
102.6.3.1 Group I: Infants
103.6.3.2 Group II: Children 2 Years and Older
104.6.3.3 Group III: Preterm Infants
105.6.4 Digestive Secretion Promotion Effect of Bicarnesine, D-Carnitine and L-Carnitine
106.6.5 DL-Carnitine Chloride Preparation in Japan
107.6.6 Gastrointestinal Motility Disorders, Constipation and Carnitine Deficiency
108.6.7 Orexin and Carnitine
109.6.8 Remaining Issues in Appetite Enhancement and Digestive Enzyme Secretion Promoting Effects of Carnitine
110.7. Anti-inflammatory, Antioxidant, and Anti-apoptotic Effects of Carnitine
112.7.2 Role of the Transcription Factor NF-κB in the Inflammatory Response
113.7.3 Stress Response and Nrf2-Keap1 System
114.7.4 Anti-inflammatory, Antioxidant, and Anti-apoptotic Effects of Carnitine
115.7.4.1 Interaction Between the Nrf2-Keap1 and NF-κB System
116.7.4.2 Anti-inflammatory, Antioxidant and Anti-apoptotic Effects of Carnitine (Cellular-Level Studies)
117.7.4.3 Anti-inflammatory, Antioxidant, and Anti-apoptotic Effects of Carnitine (Animal-Level Studies)
118.7.4.4 Anti-inflammatory, Antioxidant, and Anti-apoptotic Effects of Carnitine (Clinical Studies)
119.7.4.5 Sarcopenia-MIA Syndrome and Carnitine
120.7.4.6 Potential of Carnitine in Hereditary Neurometabolic Diseases and Neurodegenerative Diseases
122.8. Quantification and Pharmacokinetics of Carnitine
124.8.2 Overview of Old Analytical Measurement Methods for Carnitine
125.8.2.1 Principle of Enzyme Method and Radioenzyme Method
126.8.2.2 Short-Chain Acylcarnitine and Long-Chain Acylcarnitine
127.8.3 Current Carnitine Measurement Methods
128.8.3.1 Determination of Acylcarnitine by Tandem Mass Spectrometer
129.8.3.2 Principle of Determination of Free and Acylcarnitine by Enzyme Cycling Method
130.8.3.3 Determination of Carnitine by HPLC Method
131.8.3.4 Selecting the Right Measurement Method for the Purpose of the Research
132.8.4 Absorption and Bioavailability of Orally Administered Carnitine
133.8.5 Distribution of Carnitine in the Body
134.8.6 Metabolism of Carnitine
135.8.7 Excretion of Carnitine
136.9. Safety of Carnitine
138.9.2 Daily Intake of Carnitine as a Food
139.9.3 Risk Assessment of Carnitine
140.9.4 Carnitine and Fish Odor Syndrome
141.9.5 Carnitine and Atherosclerosis
142.9.5.1 Overview of the Study by Koeth et al.
143.9.5.2 Rebuttal to the Research of the Hazen‘S Group
144.9.6 Other Safety Considerations Carnitine
145.9.6.1 Aggravation of Symptoms Due to Carnitine’s Stimulatory Effect on Digestive Enzyme Secretion
146.9.6.2 Side Effects of D-Carnitine
147.10. Carnitine Deficiency in Inherited Metabolic Diseases
149.10.2 Etiology and Pathophysiology of Carnitine Deficiency in Organic Acidemia
150.10.3 Overview of Fatty Acid β Oxidation and Its Abnormalities
151.10.4 Urea Cycle Disorders and Carnitine Deficiency
152.10.5 Dosage of Carnitine for Inherited Metabolic Diseases
153.10.6 Mitochondrial Diseases
154.10.7 Other Inherited Metabolic Diseases and Carnitine
155.11. Tube Feeding, Total Parenteral Nutrition (TPN), Specific Milk Formula, and Carnitine Deficiency
156.11.1 Tube Feeding, TPN, Specific Milk, and Carnitine Deficiency
157.11.2 Species of Tube Feeding Products and Carnitine Contents
158.11.3 Case Reports of Carnitine Deficiency in Severely Handicapped Children (Patients) Undergoing Tube Feeding
159.11.4 Carnitine Deficiency in Intravenous Nutrition
160.11.5 Hepatobiliary Dysfunction Due to TPN
161.11.6 Celiac Disease and Cardiomyopathy
162.11.7 Carnitine Deficiency Caused by Specific Milk
163.11.8 Monitoring of Carnitine Deficiency in Patients Nutritionally Managed by Tube Feeding
164.12. Carnitine Deficiency Due to Sodium Valproate
165.12.1 Outline of Sodium Valproate
166.12.1.1 Chemical Structure of Sodium Valproate
167.12.1.2 Discovery of the Antiepileptic Effect of Valproic Acid
168.12.1.3 Current Indications for Valproic Acid
169.12.1.4 History of Clinical Application of Valproic Acid
170.12.1.5 Side Effects of Valproic Acid
171.12.2 Valproate-Induced Hepatotoxicity (VHT)
172.12.2.1 Early VHT Case Reports
173.12.2.2 Clinical Characteristics of VHT Cases
174.12.2.2.1 Age of Onset and Clinical Signs
175.12.2.2.2 Estimation of the Pathogenic Mechanism
177.Pathological and Histological Characteristics
178.Dosage of Valproic Acid and Other Concomitant Medications
179.Necessity of Liver Function Monitoring
180.12.3 Valproate-Induced Hyperammonemic Encephalopathy (VHE)
181.12.4 Epidemiological Studies of VHT and VHE
182.12.5 Overview of Studies on the Causes of VHT and VHE
183.12.5.1 Carnitine Deficiency Due to Valproic Acid
184.12.5.1.1 Early Clinical Studies Such as Blood Carnitine Concentrations in Patients Receiving Valproate
185.12.5.1.2 Basic and Clinical Research on Carnitine Deficiency Caused by Valproic Acid
186.Suppression of Mitochondrial Function by Valproic Acid
187.Blood Carnitine Concentration in Epilepsy Patients Treated with Valproate
188.Rationality for the Diagnosis of Carnitine Deficiency
189.Association Between VHT and Carnitine Deficiency
190.VHE and Carnitine Deficiency
191.Risk Factors for Carnitine Deficiency
192.12.6 Carnitine Supplementation Therapy
193.12.6.1 The Ideas of Initial Carnitine Supplementation Therapy
194.12.6.2 Effect of Carnitine Supplementation Therapy for VHT on Liver Survival Rate
195.12.7 Recommendation of Carnitine Supplementation Therapy for Children with Epilepsy
197.12.7.2 Recommendations for Carnitine Supplementation Therapy by the Expert Committee
198.12.7.2.1 Functions of Carnitine in the Metabolism
199.12.7.2.2 Carnitine Deficiency in Patients with Epilepsy
200.12.7.2.3 Carnitine Deficiency with Valproic Acid and Other Antiepileptic Drugs
201.12.7.2.4 Ketogenic Diet and Carnitine Deficiency
202.12.7.2.5 Risk Factors for Carnitine Deficiency in Patients with Epilepsy
203.12.7.2.6 Clinical Perspectives of Carnitine Supplementation Therapy
204.12.7.2.7 Summary: Carnitine Supplementation Therapy for Pediatric Epilepsy Patients
206.Rational Use of Carnitine Supplementation Therapy
207.12.7.2.8 Recommendation of Carnitine Treatment
208.12.7.2.9 Carnitine Dosage Recommendation
209.12.8 Asymptomatic Hyperammonemia Caused by Valproic Acid
210.12.8.1 Systematic Review of Studies on Valproic Acid-Induced Hyperammonemia
211.12.8.2 Studies on the Incidence of Hyperammonemia in Epilepsy Patients in Japan
212.12.9 Hyperammonemic Encephalopathy Caused by Valproic Acid in Psychiatry
213.12.9.1 Case Reports of VHE in Psychiatry
214.12.9.1.1 Overseas Case Reports
215.12.9.1.2 Case Reports in Japan
216.12.9.2 Prevalence of Valproic Acid-Induced Hyperammonemia in Psychiatry
217.12.10 Central Toxicity of Ammonia
218.12.11 Carnitine Supplementation Therapy for Valproate Poisoning
219.12.11.1 Valproic Acid Poisoning
220.12.11.2 Hemodialysis/Direct Hemoperfusion Therapy for Valproic Acid Poisoning
221.12.11.3 Carnitine Supplementation Therapy for Patients with Valproic Acid Poisoning
222.12.12 Pathogenic Mechanism of VHT and VHE
223.12.12.1 Carnitine Deficiency Due to Valproic Acid
224.12.12.2 Mechanism of Hyperammonemia Induced by Valproic Acid
226.13. Carnitine Deficiency Caused by Antibiotics Containing Pivoxil Group
227.13.1 What Are Antibiotics Containing Pivoxil Group?
228.13.2 Metabolism of Pivalic Acid
229.13.3 Clinical Pharmacological Study of Carnitine Deficiency with Pivoxil-Containing Antibiotics
230.13.4 Case Report of Carnitine Deficiency Caused by Pivoxil-Containing Antibiotics in Japan
231.13.5 Examination of Carnitine Deficiency Caused by a Pivoxil-Containing Antibiotics with a Tandem Mass Analysis
232.13.6 Issues from a Regulatory Science Perspective
233.13.6.1 Approval Status of Pivoxil-Containing Antibiotics in Japan and Overseas
234.13.6.2 Examination of Carnitine Deficiency in Clinical Trials at the Time of Application for Approval of Pivoxil-Containing Antibiotics
235.13.6.3 Responses of Related Academic Societies
237.14. Carnitine Deficiency in Patients with Renal Failure
239.14.2 Carnitine Kinetics in Patients with Conservative Kidney Management
240.14.3 Carnitine Kinetics in Dialysis Patients
241.14.3.1 Early Study on Carnitine Kinetics in Dialysis Patients
242.14.3.2 Carnitine Kinetics and Carnitine in Muscles in Dialysis Patients
243.14.3.3 Kinetics of Acylcarnitine in Dialysis Patients
244.14.3.4 Acylcarnitine Accumulation in Dialysis Patients and Pathophysiology
245.14.3.5 Dialysis Properties of Long-Chain Acylcarnitines
246.14.3.6 Carnitine Kinetics in Peritoneal Dialysis Patients
247.14.4 Clinical Manifestations of Carnitine Deficiency in Dialysis Patients and Carnitine Supplementation Therapy
248.14.4.1 Lipid Metabolism Disorders
249.14.4.2 Muscular Symptoms and Decreased Physical Function in Dialysis Patients
250.14.4.3 Cardiac Symptoms
251.14.4.4 Inflammation, Atherosclerosis and Carnitine in Dialysis Patients
252.14.4.5 EPO-Resistant Anemia and Carnitine Supplementation Therapy
253.14.4.6 Metabolic Actions of Carnitine
254.14.4.7 Biophysical Action
255.14.4.7.1 Rheology of Red Blood Cells
256.14.4.7.2 Effects of Carnitine on the Deformability of Red Blood Cells
257.14.4.8 Anti-apoptotic Action of Carnitine
258.14.4.8.1 Apoptosis in the Production Process Inside the Red Blood Cells and Action of Carnitine
259.14.4.8.2 The Eryptosis and the Action of Carnitine in the Process of Decay of Erythrocytes in the Circulation
260.14.4.9 Detail of the Studies on PS Exposure in Erythrocyte
261.14.5 Hospitalization of Dialysis Patients and Carnitine
262.14.6 Status of Carnitine Supplementation Therapy for Dialysis Patients in the Worldwide
263.14.6.1 Approval Status in Each Country
264.14.6.2 Status of Carnitine Supplementation in Hemodialysis Patients
265.14.6.3 Controversy Over the Pros and Cons of Carnitine Supplementation Therapy for Dialysis Patients in the United States
266.14.7 Role of Carnitine Supplementation in Dialysis Treatment in Japan
268.15. Carnitine Deficiency in Patients with Liver Diseases
270.15.2 Carnitine Kinetics in Liver Diseases
271.15.3 Hepatic Encephalopathy and Hyperammonemia in Patients with Cirrhosis
272.15.3.1 Causes of Hepatic Encephalopathy and Hyperammonemia in Patients with Cirrhosis
273.15.3.2 Protective Effect of Carnitine in Animal Models of Hepatic Encephalopathy
274.15.3.3 Ammonia Toxicity at the Cellular Level and Effects of Carnitine
275.15.3.4 Effect of Carnitine on Hepatic Encephalopathy in Patients with Cirrhosis
276.15.3.4.1 Overseas Clinical Research
277.15.3.4.2 Clinical Studies of Carnitine in Patients with Liver Cirrhosis in Japan
278.15.3.4.3 Effect of Carnitine on Patients with Minimal Hepatic Encephalopathy
279.15.4 Effect of Carnitine on Severe Muscle Cramps in Patients with Cirrhosis
280.15.4.1 Case Reports of Carnitine Administration
281.15.4.2 Multicenter Survey Study
282.15.5 Abnormal Energy Metabolism in Patients with Cirrhosis and Effects of Carnitine
283.15.5.1 Abnormal Energy Metabolism in Cirrhosis Patients
284.15.5.2 Effect of Carnitine on Abnormal Energy Metabolism in Cirrhosis Patients
285.15.6 Nutritional Status, QOL, and Effects of Carnitine on Sarcopenia in Patients with Cirrhosis
286.15.6.1 Nutritional Status, QOL Sarcopenia, and Life Prognosis of Patients with Cirrhosis
287.15.6.2 Clinical Studies of Carnitine Administration for Sarcopenia in Patients with Cirrhosis
288.15.7 Positioning of Carnitine Supplementation Therapy in the Treatment of Patients with Cirrhosis
289.15.8 NASH, NAFLD, and Carnitine
290.15.8.1 Effect of Carnitine in Animal Models of NASH/NAFLD
291.15.8.1.1 Choline-Deficient Diet and Carnitine
292.15.8.1.2 Effects of Carnitine in Other NASH Model Animals
293.15.8.1.3 Mechanism of Action of Carnitine in NASH/NAFLD Model
294.15.8.2 Carnitine Kinetics and Effects of Carnitine Administration in NASH Patients
295.15.9 Pancreatic Cancer, NASH/NAFLD-Related Hepatocellular Carcinoma, and Carnitine Kinetics
297.16. Cardiovascular Diseases and Carnitine Deficiency
299.16.2 Ischemic Heart Disease and Carnitine
300.16.2.1 Exertional Angina Pectoris and Carnitine
301.16.2.2 Myocardial Infarction and Carnitine
302.16.2.2.1 Basic Research on Ischemic Myocardial Animal Models
303.16.2.2.2 Effect of Carnitine Administration in Patients with Acute Myocardial Infarction
304.16.3 Arrhythmias and Carnitine
305.16.3.1 Basic Research
306.16.3.2 Clinical Research
307.16.4 Meta-Analysis of Carnitine Administration Trials in Ischemic Heart Disease
308.16.5 Heart Failure and Carnitine
309.16.5.1 Carnitine Kinetics in Myocardial Tissue in Patients with Heart Failure
310.16.5.2 Long-Chain Acylcarnitine in Blood and Prognosis in Patients with Heart Failure
311.16.5.3 Carnitine Insufficiency and Metabolic Inflexibility in Heart Failure
312.16.5.4 Effects of Carnitine Administration in Patients with Heart Failure
313.16.5.5 Diastolic Heart Failure (HFpEF) and Carnitine
314.16.5.6 Micronutrient Deficiency in Patients with Heart Failure
315.16.6 Peripheral Arterial Disease and Carnitine
316.16.6.1 Effect of Carnitine Administration in Patients with Intermittent Claudication (IC)
317.16.6.2 Position of Carnitine Administration in the Peripheral Arterial Disease Guidelines
318.16.6.3 Research and Future Prospects of Carnitine in PAD Patients in Japan
319.17. Other Diseases and Carnitine
321.17.2 Influenza-Associated Encephalopathy and Carnitine
322.17.3 Amyotrophic Lateral Sclerosis (ALS) and Carnitine
323.17.4 Chronic Fatigue Syndrome and Carnitine
324.17.5 Inflammatory Bowel Disease and Carnitine
325.17.6 Alcoholism and Carnitine
326.17.7 Attention-Deficit/Hyperactivity Disorder (ADHD)/Autism and Carnitine
327.17.7.1 ADHD and Carnitine
328.17.7.2 Autism/Autism Spectrum Disorder and Carnitine
329.17.8 Infertility and Carnitine
330.17.8.1 Male Infertility
331.17.8.2 Female Infertility
333.18. Guidelines for the Diagnosis and Treatment of Carnitine Deficiency
335.18.2 Necessity of Diagnostic Reagents for Carnitine Deficiency and History of Diagnostic Reagent Insurance Coverage in Japan
336.18.3 Measurement of Blood Carnitine Two Fractions Suitable for the Diagnosis of Carnitine Deficiency and Insufficiency
337.18.3.1 Enzyme Cycling Method (Blood Carnitine 2 Fractions Test)
338.18.3.2 Tandem Mass Method
339.18.3.3 Comparison of Both Measurement Methods
340.18.4 Actual Measurement of Blood Carnitine with 2 Fractions Tests
341.18.5 Insurance Coverage of Carnitine 2 Fractions Test Using Enzyme Cycling Method in Japan
342.18.6 Overview of Diagnosis and Treatment of Carnitine Deficiency and Insufficiency
343.18.6.1 Target Patients
344.18.6.2 Clinical Symptoms and Signs of Suspected Carnitine Deficiency
345.18.6.3 General Clinical Laboratory Findings Suggesting Carnitine Deficiency
346.18.6.4 Flow of Diagnosis of Carnitine Deficiency
347.18.6.5 Reference Standard Value (Normal Value)
348.18.6.6 The Process from Diagnosis to Treatment of Carnitine Deficiency
349.18.6.7 Monitoring After Carnitine Supplementation
350.18.6.7.1 Useful for Monitoring the Chronic Phase of Inherited Metabolic Diseases
351.18.6.7.2 In the Case of Monitoring of General Carnitine Deficiency
352.18.6.7.3 Proposal for a New Monitoring Method
353.18.6.8 Standard Usage and Dosage in Carnitine Supplementation Therapy
354.18.6.9 Considerations for Carnitine Supplementation Therapy
355.19. Clinical Pharmacological Issues Related to Carnitine
357.19.2 History of the Development of Carnitine as a Pharmaceutical Product
358.19.3 Trends of Resolution of Drug-Lag and Expansion of the Indication for L-Carnitine in Japan
359.19.3.1 “2 Section Chief’s Notification” and “Public Knowledge Application”
360.19.3.2 Development of the “Priority List”
361.19.3.3 Study Council on the Use of Unapproved Drugs
362.19.3.4 New Framework for Eliminating Drug-Lag and Price Maintenance Premium
363.19.3.5 Background of the Expansion of Indications for L-Cartin® Tablets Through “Public Knowledge Application”
364.19.3.6 Development of Internal Liquid and Intravenous Injection of L-Cartin®
365.19.4 Development of Medicines for Pediatric Use
366.19.5 Insurance Coverage for Diagnostic Reagents for Carnitine Deficiency
880.Basillica di Santa Maria degli Angeli, Rome, July 2010, after licensing meeting with Sigma-tau
881.Fig. 1.1: Chemical structure of L-carnitine
882.Fig. 1.2: Gottfried S. Fraenkel (1901–1984), who discovered the role of carnitine in insect nutrition (left), and their bioassay system of vitamin BT. Growth of Tribolium confusum on a diet consisting of casein, glucose, cholesterol, salts, and water, with the addition of graded quantities of dried brewers’ yeast. (From Ref. [24])
883.Fig. 1.3: The process of transformation of meal worm (Tenebrio molitor) from larva → pupa → adult. Vitamin BT (L-carnitine) was found to be an essential nutrient for transformation from larva to pupa. (From Sankyo Remake Co., Ltd. Home page, with permission, http://www.sankyoremake.com/syokug_control_s.html)
884.Fig. 2.1: Carnitine cycle. Carnitine cycle is also called carnitine shuttle. Above the dotted line: Uptake of long-chain fatty acid into mitochondria. The acyl-group of long-chain fatty acid is converted to acyl-CoA by ACS, and acyl group is transferred to carnitine to form acylcarnitine by CPT1 located in mitochondrial outer membrane, then transferred into mitochondria by CACT located in mitochondrial inner membrane. Acylcarnitine is again backed to acyl-CoA and free carnitine by CPT2 located at inner side of mitochondrial inner membrane, and this acyl-CoA is transferred to β-oxidation and produces energy, and free carnitine back to outside of inner membrane through exchange reaction of CACT with acylcarnitine. Under the dotted line: Accumulated harmful acyl-CoA by metabolic abnormality or various pathological conditions is converted to acyl-CoA by CPT2 and transferred to outside of mitochondrial inner membrane by CACT, and finally excreted outside of cells, and the toxicity of acyl-CoA is removed, and released free CoA can be used for various mitochondrial metabolism such as energy metabolism. In this situation, free carnitine and acylcarnitine are exchanged through CACT reaction. AC acylcarnitine, ACS acyl-CoA synthetase, CACT carnitine acylcarnitine translocase, CoA coenzyme A, CPT1 carnitine palmitoyltransferase 1, CPT2 carnitine palmitoyltransferase 2, FC free carnitine, OCTN2 carnitine transporter
885.Fig. 2.2: Role of carnitine in long-chain fatty acid oxidation proposed by Fritz. Hypothetical site of action of carnitine on fatty acid metabolism. This scheme shows functional compartment of acyl-CoA pools postulated to account for carnitine stimulation of fatty acid oxidation. (From Ref. [10])
886.Fig. 2.3: Role of carnitine and transport of acyl-group through CACT proposed by Pande. A scheme for the L-carnitine-dependent transport of fatty acyl groups across mitochondrial inner membrane. Although only the inward transport is depicted above, the reactions involved, being readily reversible, would facilitate outward transport as well. CACT carnitine acylcarnitine translocase. (From Ref. [26])
887.Fig. 2.4: Postulated acylcarnitine-carnitine exchange carrier in the mitochondrial inner membrane proposed by Ramsay. (From Ref. [27])
888.Fig. 2.5: Carnitine transport by Chinese hamster ovary (CHO) cells expressing normal and mutant carnitine transporters identified from symptomatic patients and asymptomatic mothers. Panel a: Data for individual missense mutations of symptomatic patients and asymptomatic mothers. Points are averages ± SE of six samples. Panel b: The average for mutations identified in symptomatic patients and asymptomatic mothers. Note the logarithmic scale in panel b. In both groups, carnitine transport was significantly (P < 0.01 using ANOVA) reduced as compared to wild-type OCTN2, but there was no significant difference between the groups of missense mutations identified in symptomatic patients versus asymptomatic mothers using ANOVA. ANOVA analysis of variance, SE standard error. (From Ref. [84])
889.Fig. 3.1: Chemical structure of L-carnitine
890.Fig. 3.2: Role of coenzymes and cofactors. Most vitamins or trace metals, whose deficiencies are important in nutrition, act as a prosthetic factor of various metabolic enzymes. These coenzymes or cofactors bind near the active center of enzyme and transform from the inactive form to the active form and progress the enzyme reactions. Carnitine does not have these roles as coenzymes or cofactors
892.Fig. 3.4: Chemical structure of coenzyme A. Coenzyme A is biosynthesized from cysteine, pantothenic acid (vitamin B5), and ATP. Coenzyme A is usually called as CoA, and the left-side SH- group is highly reactive and bound with acyl group forming acyl-CoA that acts as an acyl group carrier. So it is described as CoASH in the chemical reaction formula
893.Fig. 3.5: Biosynthesis pathway of coenzyme A (CoA) in humans. Coenzyme A is biosynthesized from pantothenic acid with five steps of reactions that require four molecules of ATP and cysteine. The first pantothenic acid kinase (PanK) reaction is the rate-limiting step. The last two steps are processed multifunctionally by one CoA synthase, addition of nucleotide part, and phosphorylation reaction. (From Ref. [3])
894.Fig. 3.6: Cellular functions of CoA and its derivatives. CoA thioester derivatives are Implicated in diverse cellular functions, including Krebs cycle, ketogenesis, biosynthesis of cholesterol or acetylcholine, degradation of amino acids, the synthesis and oxidation of fatty acid, biosynthesis of neurotransmitters, and the regulation of gene expression. Protein CoAlation is a novel, unconventional function of CoA in redox regulation and antioxidant defense. These metabolic functions of CoA are described in textbooks of biochemistry. However, it is discovered recently that CoAs not only have these functions but also act as gene expression modulator by acetylation of nuclear protein such as histone and act as metabolic modulator by acetylation of various metabolic enzymes. Furthermore, CoA acts as a defense function from oxidative stress by protein CoAlation. (From Ref. [13])
895.Fig. 3.7: An easy-to-understand schematic diagram showing the role of carnitine compared to a cargo truck. This figure explains the three functions of carnitine listed within Table 3.3: first, transport long-chain fatty acid into mitochondria; second, excrete harmful acyl compounds that accumulate in mitochondria; this excretion function results in the third function, maintenance of acyl-CoA/CoA ratio constant. (With permission from: Dr. Akiko Wakisaka, Pediatrics, NHO Iou National Hospital, Kanazawa, Japan)
896.Fig. 3.8: Relationship of carnitine cycle and energy metabolism. The blue area surrounded with dashed-dotted line is called carnitine cycle (or carnitine shuttle), which is closely linked to mitochondrial energy metabolism such as fatty acid β-oxidation and TCA cycle. ACS acyl-CoA synthetase, CACT carnitine acylcarnitine translocase, CPT1 carnitine palmitoyltransferase 1, CPT2 carnitine palmitoyltransferase 2, FADH2 reduced flavin adenine dinucleotide, Mt mitochondria, NADH reduced nicotinamide adenine dinucleotide, OCTN2 carnitine transporter, TCA tricarboxylic acid
897.Fig. 3.9: Number of ATP generated by β-oxidation of one molecule of palmitate is shown when P/O ratio is assumed for NADH 2.5, and for FADH2 1.5. (In the case of P/O ratio is assumed for NADH 3.0 and FADH2 2.0, total 129 ATP is generated by β-oxidation of 1 molecule of palmitate)
898.Fig. 3.10: Proposed model of mitochondrial fatty acid uptake with the malonyl-CoA binding site (r) of CPT-I exposed to the cytosol and catalytic site (c) exposed to the intermembrane face of the outer membrane. BP postulated matrix binding protein for palmitoylcarnitine, CACT carnitine acylcarnitine translocase, CPT-I malonyl-CoA sensitive carnitine palmitoyltransferase, CPT-II malonyl-CoA insensitive carnitine palmitoyltransferase, LCAS long-chain acyl-CoA synthase. (From Ref. [40])
899.Fig. 3.11: Proteins of the carnitine system connect pools of acetyl-CoA. Malonyl-CoA sensitive enzymes such as CPT 1, shown as black squares, act on cytosolic long-chain substrate. CrAT is found only inside the organelles using matrix acetyl-CoA and acetyl-carnitine. The mitochondrial exchange carrier (CACT, striped squares) transfers carnitine and its esters across the membranes and similar transport proteins are suggested of other organelles. The sodium-dependent organic cation transporter (OCTN2) is the high-affinity carnitine transporter for uptake of carnitine into the cell but the mechanism for export from the cell is not well characterized. CACT () carnitine acylcarnitine translocase, COT carnitine octanoyltransferase, CPT 1 (■) carnitine palmitoyltransferase 1, CPT 2 () carnitine palmitoyltransferase 2, CrAT carnitine acetyltransferase, OCTN2 carnitine transporter. (From Ref. [41])
900.Fig. 3.12: Chemical structures of hydrochloride of L-carnitine, acetyl-L-carnitine, and propionyl-L-carnitine
901.Fig. 4.1: Distribution of carnitine in the body and factors that influence carnitine homeostasis. OCTN2 carnitine transporter. (Modified from Ref. [1])
902.Fig. 4.2: Expression of OCTN2 mRNA along the human intestinal tract. The columns represent relative mRNA expression levels (OCTN2 cDNA copy numbers normalized to villin cDNA copy numbers). Data points (○) indicate the mRNA expression levels in individual patients. Individuals with OCTN2 mRNA expression level greater than mean + 1 SD (standard deviation) are identified by their identification numbers. ca colon ascendens, cd colon descendens, ct colon transversum, duo duodenum, ile ileum. (Modified from Ref. [12])
903.Fig. 4.3: Biosynthesis pathway of L-carnitine. (Created with reference to Refs. [4, 6, 9])
904.Fig. 4.4: Schematic representation of carnitine homeostasis and Inter-organ interaction in carnitine biosynthesis. About 75% of body carnitine comes from dietary carnitine absorbed through intestinal OCTN2 (carnitine transporter). About 25% of body carnitine comes from biosynthesis mainly in liver and kidney. These tissues have all four biosynthesis enzymes of carnitine (TML ⇒ HTML ⇒TMABA ⇒BB ⇒ carnitine). Muscles are important tissues for carnitine homeostasis because it contains more than 97% of body carnitine. However, muscle does not have a final biosynthesis enzyme which convert BB into carnitine. Muscle is considered as a major supply site of TML and BB to liver and kidney through blood circulation. TML is also derived from endogenous degradation of proteins such as actin, myosin, and histones. Kidney is an important tissue to maintain carnitine homeostasis because it reabsorbs most free carnitine and BB through OCTN2. BB trimethylaminobutyrate (butyrobetaine), HTML 3-OH-trimethyllysine, OCTN2 carnitine transporter, TMABA 4-trimethylaminobutyraldehyde, TML 6-N-trimethyllysine. (Created using Refs. [2–11])
905.Fig. 5.1: An easy-to-understand illustration explaining the role of carnitine compared to cargo trucks in two types of carnitine deficiency. (a) (upper part of dotted line): Absolute deficiency of free carnitine (cargo trucks) causes trouble for energy production because fuel (long-chain fatty acid) cannot be transported into the powerplant (mitochondrial β-oxidation). (b) (lower part of dotted line): Relative deficiency of free carnitine (cargo trucks) in mitochondria causes trouble to excrete and remove the toxicity of accumulated harmful acyl-compound in mitochondria. The amount of free carnitine needed to remove acyl-compound is dependent on the amount of acyl-compound (relative). In other words, a is inward-transport of acyl group in long-chain fatty acid for energy production (classical role of carnitine). The deficiency of carnitine causes disturbance for energy production. b is a kind of new role of carnitine. The accumulated harmful acyl-compound(s) in various pathophysiology disturbs mitochondrial metabolism such as energy production, etc., so relative deficiency of carnitine causes trouble in outward transportation of acyl-group to excrete and detoxify them. AC acylcarnitine, FC free carnitine, TC total carnitine (=free carnitine + acylcarnitine). (With permission from Dr. Akiko Wakisaka, Pediatrics, NHO Iou National Hospital, Kanazawa, Japan)
906.Fig. 5.2: Schematic diagram of the mechanisms to maintain blood glucose level. Disruption of these mechanisms due to unavailability of fatty acids in fasting situation in fatty acid oxidation disorders and carnitine deficiency due to the disruption of this system results in acute metabolic dysfunctions such as hypoketotic hypoglycemia. In healthy subjects, blood glucose level is maintained utilizing carbohydrates (glucose) from meal and then switched to glycolysis utilizing glycogen stored in the liver or muscle along with time course after meal. During fasting condition after glycogen is depleted, β-oxidation of fatty acids can be utilized to provide energy (the bold black arrow). Acetyl-CoA produced by β-oxidation of fatty acids flows into TCA cycle and electron transfer chain in mitochondria and ATP is produced. Using this ATP, glucose or ketone bodies are synthesized by gluconeogenesis and ketogenesis, and the blood glucose levels are maintained, and brain can utilize ketone bodies. In the case of patients with fatty acid oxidation disorders or carnitine deficiency (X), this ATP production by fatty acid oxidation cannot be utilized in fasting state, so they are prone to hypoketotic hypoglycemia. Especially these acute metabolic dysfunctions occur in increased energy-demand situations such as starvation, fever, infection, vigorous exercise, and vomiting. (Modified from Ref. [211])
907.Fig. 5.3: Inhibitory activity of various acylcarnitines on carnitine uptake in the HEK293 cell expressed human OCTN2. The uptake of L-[3H]-carnitine (10 nM) is studied in the presence of 5 or 50 μM of various acylcarnitines (37 °C, 3 min). Data shows Mean ± SE of three experiments. *Significant differences between control. SE standard error. (Modified from Ref. [210])
908.Fig. 5.4: The “low cost” of the urea production by urea cycle and the related amino acid metabolic systems. AST aspartate aminotransferase, GDH glutamate dehydrogenase, MDH malate dehydrogenase. (Modified from Ref. [220])
909.Fig. 5.5: Coupling of urea cycle, ornithine metabolism, and energy production systems. The urea cycle is not working alone but coupled and associated with ornithine metabolism and energy production systems such as TCA cycle and oxidative phosphorylation in mitochondria. ARG arginase, ASL arginosuccinate lyase, ASS arginosuccinate synthetase, CPS1 carbamyl phosphate synthetase, GDH glutamate dehydrogenase, GSDH glutamate-5-semialdehyde dehydrogenase, OKT ornithine α-ketoglutarate transaminase, OTC ornithine transcarbamylase. (From Ref. [220])
910.Fig. 5.6: Relationship between carnitine cycle and urea cycle. Long-chain fatty acids are transported into mitochondria by carnitine cycle and acetyl-CoA is produced by β-oxidation. N-acetylglutamate (NAG), a positive cofactor for the first enzyme of urea cycle, is produced from acetyl-CoA and glutamate by NAG synthase (NAGS). CPS1 converts ammonia to carbamyl phosphate with the aid of NAG. This CPS1 reaction needs two ATPs and also ASS reaction needs one ATP, so total three ATPs are required to convert one NH3 into urea by urea cycle. Acetyl-CoA flows into TCA cycle and ATP is produced and this ATP is provided to urea cycle. Propionyl-CoA or valproyl-CoA inhibits NAGS activity and suppresses the urea cycle and induces hyperammonemia. Free carnitine acts as an antidote of these harmful acyl-CoA by excreting these acyl groups into urine as acylcarnitines. In the case of carnitine deficiency or fatty acid oxidation disorders, the coordination of carnitine cycle and urea cycle is disturbed, and this lack of coordination between carnitine cycle and urea cycle is supposed to be leading to hyperammonemia. ARG arginase, ASL arginosuccinate lyase, ASS arginosuccinate synthetase, CACT carnitine acylcarnitine translocase, CPS1 carbamyl phosphate synthetase 1, CPT carnitine palmitoyltransferase, NAGS N-acetylglutamate synthase, OCTN2 carnitine transporter, ORNT1 ornithine citrulline antiporter (also called as mitochondrial ornithine transporter), OTC ornithine transcarbamylase
911.Fig. 5.7: Chemical structures of γ-butyrobetaine, N-trimethyl-hydrazine-3-propionate (THP, meldonium, MET-88, mildronate), and L-carnitine
912.Fig. 6.1: Chemical structure of bicarnesine (dicarnitine, carnitine carnitate). (Modified from Ref. [1])
913.Fig. 6.2: Body weight changes during 4 months in severe frail patients (left) and early-stage TB patients (right) after bicarnesine administration or control. BW: body weight, y: years, TB: tuberculosis. (Modified from Ref. [8])
914.Fig. 6.3: Changes in duodenal fluid volume after intravenous administration of L-carnitine (0.2 g/kg, I: solid line), D-carnitine (0.2 g/kg, II: broken line), NaCl solution (0.9%, III: dotted line) and Cecekin (0.8 mg/kg, IV: dash-dotted line). (Modified from Ref. [10])
915.Fig. 6.4: Changes of enzyme secretion in duodenum fluid after administration of L-carnitine (I), D-carnitine (II), Cecekin (IV). The horizontal dotted lines indicate the levels of 0.9% NaCl solution (100%). (Modified from Ref. [10])
916.Fig. 6.5: Changes in duodenal fluid volume, activities of lipase, amylase and trypsin after administration of L-carnitine D-carnitine (2 g, intra-duodenum) in 13 digestive diseases patients without pancreatic diseases. Solid line: duodenum fluid volume, broken line: lipase, dotted line: amylase, dash-dotted line: trypsin. (Modified from Ref. [11])
917.Fig. 6.6: Correlation between constipation severity score and blood free carnitine concentration in patients with severe motor and intellectual disabilities. Constipation severity score: frequency of defecation/a day +Bristol stool score. (From Ref. [18])
918.Fig. 6.7: Frequency of defecation/a day (left) and Bristol stool score (right) before and after supplementation of L-carnitine (10–50 mg/kg/day) in patients with severe motor and intellectual disabilities. (From Ref. [18])
919.Fig. 7.1: General concept of NF-κB pathway and mechanisms of increased expression of inflammatory cytokines and adhesion molecules. In normal conditions, NF-κB is localized in cytoplasm and binds with IκB and inactivated. However, various inflammatory ligands bind with their receptors, IKK complex is activated, and then IκB is ubiquitinated and degraded in proteasome. Released from inhibitory molecules, free NF-κB migrates into nucleus and increases the expression of target molecules such as inflammatory cytokines or adhesion molecules. Among the increased expression molecules, there is IκB, and this IκB binds to NF-κB and inactivates it. NF-κB signal is oscillatory system. LPS lipopolysaccharide, LBP LPS binding protein, AGEs advanced glycation end products, RAGE AGE receptor, AT1 type 1 angiotensin IIreceptor, TLR toll-like receptor, IKK IκB kinase, IκB NF-κB inhibitory molecule, Bcl-3 B cell lymphoma/leukemia 3, TNF-α tumor necrolysis factor α, IL-1 interleukin 1, IL-2 interleukin 2, VCAM-1 vascular cell adhesion molecule 1, ICAM-1 intercellular adhesion molecule 1. (Modified from ref. [1])
920.Fig. 7.2: Simplified schematic diagram of Nrf2-Keap1 system and stress response. In normal conditions, transcription factor Nrf2 is bind with Keap1 and degraded in proteasome after ubiquitination. However, when cells are exposed to oxidative stress or electrophiles, these substances react with highly reactive SH-groups on Keap1, then conformational change of Keap1 occurs, and Nrf2 is released and migrated into nucleus, binds with sMaf and forms heterodimer, and binds to ARE/EpRE. Then the expression of downstream antioxidant enzymes genes, detoxification enzyme genes, and cytoprotective molecule genes are enhanced. Nrf2 nuclear factor erythroid 2-related factor 2, Keap1 Kelch-like ECH associated protein 1, ARE/EpRE antioxidant/electrophile responsive element, HO-1 heme oxygenase 1, NQO1 NAD(P)H quinone reductase, CAT catalase, SOD superoxide dismutase, GSH-Px glutathione peroxidase, TrxR thioredoxin reductase, HSP70 heat shock protein 70
921.Fig. 7.3: Function of Nrf2 protein after its activation and binding to ARE/EpRE based on their downstream cardioprotective genes and cross talk. The downstream genes were revealed by microarray or RNA-seq as transcripts increased or reduced due to Nrf2 activation of deficiency or are targets of Nrf2 binding as determined by DNA sequencing following ChIP. Underlines indicate the genes, expression of which has been found in cardiomyocytes in culture or in mouse myocardium related to Nrf2 status. Color shade reflects the ratio of genes in the functional group under control of Nrf2 in the myocardium and the amount of literature validating the function by Nrf2 inducers or Nrf2 knockout in experimental animals. ARE antioxidant response element, EpRE electrophile responsive element, ChIP chromatin-immunoprecipitation, Cat catalase, c/EBP CCAAT-enhancer-binding protein, GPx glutathione peroxidase, GSH-R glutathione reductase, GST glutathione S transferase, HbEGF heparin-binding epidermal growth factor-like growth factor, HO-1 heme oxygenase 1, MT metallothionein, NF-κB nuclear factor kappa B, NO1 NAD(P)H quinone oxidoreductase 1, Pdx peroxiredoxin, PGC1α peroxisome proliferator-activated receptor gamma activator 1 alpha, PINK1 PTEN-induced kinase 1, SOD superoxide dismutase, Srxn sulfiredoxin, TGF transforming growth factor, Trx thioredoxin, TrxR thioredoxin reductase, VEGF vascular endothelial growth factor. (From ref. [7])
922.Fig. 7.4: Chemical structures of main compounds which activate Nrf2. Among them, there are many electrophilic substances from plant origin such as curcumin in turmeric, resveratrol in red wine, carnosic acid in rosemary, sulforaphane in broccoli sprouts, methyl fumarate in shepherd’s purse, quercetin in onion/apple/buck wheat. However, it is proved that astaxanthin in salmon, carnitine/acetylcarnitine/carnosine in meat also activates Nrf2. As others, there is bardoxolone methyl which is a drug candidate compound developing as a Nrf2-activator
923.Fig. 7.5: Outline of proposed cross-talk between Nrf2 and NF-κB systems. Nrf2 activation induces intracellular events that concur to NF-κB suppression and vice versa. Namely, Nrf2 activation induces enhanced HO-1 expression and reduced environment and inhibits breakdown of IκBα, an inhibitory protein of NF-κB, resulting in suppression of NF-κB system. On the other hand, NF-κB activation reduces CBP, suppresses gene expression of cytoprotective genes located in downstream of ARE, enhances the binding of HDAC3 to ARE, and acetylation of ARE is also reduced by interaction of HDAC3 with CBP or MafK, resulting in reduction in gene expression of the downstream of ARE. HO-1 heme oxygenase 1, MAPK mitogen-activated protein kinase, CBP CREB binding protein, ARE antioxidant responsive element. HDAC3 histone deacetylase 3. (Modified from ref. [32])
924.Fig. 7.6: Effects of L-carnitine on protein expression of Nrf2, Keap1, HO-1, and γ-GCS in cultured retinal ganglion cells under high glucose conditions. Comparison of expression of Nrf2 (a), Keap1 (b), HO-1 (c) and γ-glutamyl cysteine synthetase (γ-GCS, D) proteins in the control, high glucose stimulation (Glu, 30 mM) and L-carnitine (LC) treatment group under high glucose stimulation (L): 50 μM, LC(M): 100 μM, LC(H): 200 μM) in cultured retinal ganglion cells. The vertical axes show relative expression ratio to proliferating cell nuclear antigen (PNCA) in the case of Nrf2, and to β-actin in the cases of Keap1, HO-1 and γ-GCS. (From ref. [34])
925.Fig. 7.7: Effects of L-carnitine (5 mM) on reactive oxygen species (ROS) production and expression of anti-oxidant enzymes in human hepatoma HepG2 cells under high fructose condition (5 mM). (a): H2O2 stimulation of HepG2 cells enhanced ROS production (CNT), and addition of L-carnitine lowered ROS production (LC). High fructose treatment further enhanced ROS production (F), but addition of L-carnitine suppressed the ROS production (LCF). (b): Expression of SOD2 and Nrf2 in HepG2 cells. CNT control, F high fructose (5 mM), LC L-carnitine (5 mM), LCF high fructose (5 mM) + L-carnitine (5 mM). (c) Effect of AMPK inhibitor, compound C on the action of L-carnitine. Addition of compound C cancelled the action of L-carnitine. *: P≦0.05, **: P≦0.01, ***: P≦0.001. (From ref. [35])
926.Fig. 7.8: Effects of L-carnitine on angiotensin II (AngII) induced superoxide anion (O2−) production and NADPH oxidase activity in NRK-52E cells derived from normal rat kidney. (a) Dose-responsive curve for Ang II-dependent O2− production. NRK-52E cells were incubated with AngII (0.1–100 nM) for 24 h. (b): Time course of O2− production induced by AngII (100 nM). (c): Effects of oxypurinol (OXI, an inhibitor of xanthine oxidase), rotenone (ROT, an inhibitor of mitochondrial electron transport system), diphenyleneiodonium (DPI, an inhibitor of flavoprotein), and superoxide dismutase (SOD, 100 U/mL, scavenger enzyme of O2−) on AngII-induced O2− production in NRK-52E cells. (d) Effects of L-carnitine (0.001–10 mM) on NADPH oxidase activity. *: P < 0.05 vs control, #: P < 0.05 vs AngII. (From ref. [36])
927.Fig. 7.9: Effects of L-carnitine on Ang II-induced PKC activation in NRK-52E cells. (a): Activation of PKC by Ang II (100 nM). This activation of PKC was suppressed by L-carnitine (1 mM, ALC). (b): The time course of migration of NF-κB into nucleus by Ang II. (c): Effects of L-carnitine (ALC) on migration of NF-κB into nucleus by Ang II. (d): Effects of L-carnitine (ALC) on phosphorylation of I κB induced by Ang II. *: P < 0.05 vs other groups. PKC: protein kinase C. (From ref. [36])
928.Fig. 7.10: Reduction of SOD (a), catalase (b), glutathione peroxidase (Gpx, c), and total anti-oxidant capacity (TOC, d) by H2O2 in HK-2 cells, and effects of L-carnitine (10, 50, 100 μM) on them. #: P < 0.05 vs non-treated cells, *: P < 0.05 vs H2O2 alone-treated cells. SOD superoxide dismutase, CAT catalase, Gpx glutathione peroxidase, TOC total anti-oxidant capacity. (From ref. [38])
929.Fig. 7.11: Effects of L-carnitine on expression of Bax, Bcl-2 and Bax/Bcl-2 ratio (a) and caspase 3 activity (b) in HK-2 cells during H2O2-induced cellular injury. #: P < 0.05 vs non treated cells, *: P < 0.05 vs H2O2 alone-treated cells. NAC N-acetylcysteine. (From ref. [38])
930.Fig. 7.12: Inhibition of MPP+ (500 μM)-induced neurotoxicity by L-carnitine and dose-response studies as measured by MTT assay (a) and cell death ELISA that measures nucleosomes (b). *: P < 0.05 vs control. M: 500 μM MPP+, C: L-carnitine (From ref. [39])
931.Fig. 7.13: Quantitative assessment of TUNEL-positive cells (apoptosis) in the forebrain cultures following control, 500 μM MPP+, and 500 μM MPP+ + 30 μM L-carnitine for 24 h. *: P < 0.05 vs control. (From ref. [39])
932.Fig. 7.14: Western blot analysis of the effect of MPP+ and L-carnitine on the regulation of BCL-XL and Bax protein expression (a) and a ratio of BCL-XL to Bax by densitometry measurements (b). *: P < 0.05 vs control. (From ref. [39])
933.Fig. 7.15: Effects of various reagents on Pal-CoA-induced cytochrome c release (Western blot). Addition of palmitoyl-CoA (Pal-CoA, 5 μM) induces cytochrome c release from mitochondria (M) to soluble fraction (cytosol, S). Carnitine (1 mM), cyclosporin A (1 μM, CsA), BSA (100 μg/mL) suppressed the cytochrome release. (From ref. [43])
934.Fig. 7.16: L-carnitine reduced oxidative stress and apoptosis of rat cardiomyocytes in vivo. Expression of SOD1, SOD2, caspase8, Bcl-2, and Bax in the 3 groups was detected by Western blot (a) and qRT-PCR (b–g). ROS level (h) and cell apoptosis level (i) induced by DCFH-DA were determined by flow cytometry. Control control group, IRI ischemia–reperfusion group, LC L-carnitine administration group (150 mg/kg/day for 1 month) with ischemia–reperfusion. *: P < 0.05 vs Control, #:P < 0.05 vs IRI DCFH-DA: 2′, 7′-dichlorodihydrofluorescein diacetate, an oxidant-sensing probe. (Modified from ref. [53])
935.Fig. 7.17: L-carnitine increased the activity of Nrf2/HO-1 signaling pathway in rat myocardial tissue and H9c2 cells. A-C: Expression of Nrf2 and HO-1 in rat myocardial tissue was determined by Western blot (a) and qRT-PCR (b, c). D-F: Expression of Nrf2 and HO-1 in H9c2 cells was determined by Western blot (d) and qRT-PCR (e, f). *: P < 0.05 vs control, #: P < 0.05 vs IRI group or hypoxia-reoxygenation group. IRI ischemia–reperfusion injury, HO-1 heme oxygenase 1, LC L-carnitine. (From ref. [53])
936.Fig. 7.18: Protective effects of l-carnitine in cardiomyocytes injury model irradiated with γ-ray. (a): The captured images from the TUNEL assay of cardiac tissue from Ctrl, Irrad, Treat 1, Treat 2, and Treat 3, respectively, and the quantification results. *: P < 0.05, **: P < 0.01 and ***: P < 0.001. (b): The expression of apoptosis facilitating factor Bax, active caspase3 (cleaved-caspase3 or c-caspase3) and caspase3. Ctrl: control (without irradiation), Irrad: irradiation (3 Gy/day, for 5 days), Treat 1: before irradiation, L-carnitine administration (100 mg/kg/day, i. p.), then irradiation. Treat 2: before irradiation, L-carnitine administration (200 mg/kg/day, i. p.), then irradiation. Treat 3: before irradiation, L-carnitine administration (200 mg/kg/day, i. p.) and p38 MAPK inhibitor SB203580 (15 mg/kg, i. p), then irradiation. GAPDH glycelaldehyde-3-phosphate dehydrogenase. (Modified from ref. [54])
937.Fig. 7.19: Expression of NQO1, HO-1, pNrf2, Nrf2 and p-p38 MAPK in irradiated rat cardiomyocyte, and effects of L-carnitine and p38 MAPK inhibitor on them. Each group of horizontal axes are the same as Fig. 7.18a, b *: P < 0.05, **: P < 0.01, ***: P < 0.001. C: ***: P < 0.001 vs Ctrl, **: P < 0.01 vs Irrad, #: P < 0.05 vs treated 1, ##: P < 0.01 vs Treated 2. (From ref. [54])
938.Fig. 7.20: The mRNA expression of NF-κB (a), Nrf2 (b) and PPARα (c) in Wistar rat kidney cortex after administration of L-carnitine, L-NAME and L-NAME + L-carnitine. L-NAME: NG-nitro-L-arginine methyl ester (25 mg/kg, 10 weeks, in drinking water), LC: L-carnitine (400 mg/kg, in drinking water, 2 weeks before L-NAME administration and total 10 weeks). *: P < 0.05 vs Wistar, ***: P < 0.001 vs Wistar, #: P < 0.05 vs L-NAME, ##: P < 0.01 vs L-NAME, ###: P < 0.001 vs L-NAME. (From ref. [55])
939.Fig. 7.21: Activation of NF-κB and migration into nucleus after sunitinib administration suppress effects of L-carnitine on it. LC L-carnitine (400 mg/kg, in drinking water, 10 weeks), Su sunitinib (25 mg/kg, in drinking water, 8 weeks), LC + Su: L-carnitine, in drinking water, before 2 weeks of sunitinib administration and more 8 weeks, and sunitinib for 8 weeks). ***: P < 0.001 vs Control, ###: P < 0.001 vs Su. (From ref. [58])
940.Fig. 7.22: Change in L-carnitine levels, oxidative stress marker, and antioxidant enzymes activities after L-carnitine supplementation in patients with coronary artery disease. L-carnitine (LC, 1000 mg) was administered for 12 weeks. White bar: 0 week, Blue bar 12 weeks. *: P < 0.05 in same group after intervention, #: P < 0.05 between placebo and LC groups, a, b: P < 0.05 between different two groups. MDA malondialdehyde, CAT catalase, SOD superoxide dismutase, GPx glutathione peroxidase. (From ref. 71, modified)
941.Fig. 7.23: Forest plot of the effect of L-carnitine supplementation on serum CRP. WMD weighted mean difference, CI confidence interval. (Modified from ref. [87])
942.Fig. 7.24: Forest plot of effect of L-carnitine supplementation on serum IL-6. WMD weighted mean difference, CI confidence interval. (Modified from ref. [87])
943.Fig. 7.25: Forest plot of the effect of L-carnitine supplementation on serum TNF-α. WMD weighted mean difference, CI confidence interval. (Modified from ref. [87])
944.Fig. 7.26: L-carnitine suppressed NF-κB pathway in patients with rheumatic valvular heart disease (RVHD) undergoing valve replacement surgery. (a): p65 activity in the nuclear extract of heart tissue was determined. (b, c): Nuclear p65 and cytosolic IκB-α protein in heart tissue was detected by Western blot analysis. Control: St. Thomas’IIcardioplegic solution only, Experimental group 1: same cardioplegic solution +6 g/L of L-carnitine, Experimental group 2: same cardioplegic solution +12 g/L of L-carnitine. Data were presented as the mean ± SD (n = 43). *: P < 0.05, ***: P < 0.001 vs preoperation of the same group, #: P < 0.05, ##: P < 0.01 vs the corresponding control group, preoperation;, postoperation;. (From ref. [90]
945.Fig. 7.27: L-carnitine activated Nrf2 pathway in patients with rheumatic valvular heart disease (RVHD) undergoing valve replacement surgery. (a): Nrf2 activity in the nuclear extract of heart tissue was determined. (b): Nuclear Nrf2 protein in heart tissue was detected by Western blot analysis. (c, d): Nrf2-regulated genes including HO-1 (c) and NOQ1 (d) mRNA in heart tissue were determined by real-time PCR. Control: St. Thomas’IIcardioplegic solution only, Experimental group 1: the same cardioplegic solution +6 g/L of L-carnitine, Experimental group 2: the same cardioplegic solution +12 g/L of L-carnitine. Data were presented as the mean ± SD (n = 43). *: P < 0.05, **: P < 0.01, ***: P < 0.001 vs preoperation of the same group, #: P < 0.05, ##: P < 0.01, ###: P < 0.001 vs the corresponding control group, preoperation;, postoperation;. HO-1 heme oxygenase-1, NOQ1 NAD(P)H quinone oxidoreductase. (From ref. [90]
946.Fig. 7.28: Potential pathogenetic relationships between carnitine deficiency and geriatric frailty (Crentsil’s hypothesis). OCTN2 organic cation transporter 2, CPT II carnitine palmitoyltransferase II. (Modified from ref. [102]
947.Fig. 7.29: Hypothetical model of mechanisms underlying the anti-wasting effects of carnitine supplementation under pathologic conditions. IGF-1 insulin-like growth factor 1, ROS reactive oxygen species, PGC-1α peroxisome proliferator-activated receptor γ coactivator-1α, NF-κB nuclear factor κB, PiF proteolysis inducing factor, mTOR mechanistic target of rapamycin, FoxO forkhead box O transcription factor, MuRF1 muscle-specific RING finger protein 1, AIF apoptosis-inducing factor, EndoG endonuclease G. (Modified from ref. [110])
948.Fig. 7.30: Action mechanism of L-carnitine on cancer cachexia. (Modified from ref. [111]
949.Fig. 7.31: L-carnitine increased phosphorylated high molecular weight neurofilament (pNFH) and myelin binding protein (MBP) after chronic hypoperfusion in rats with ligation of the bilateral common carotid artery (LBCCA). L-carnitine (LCAR, 600 mg/kg/day, oral route) was administration for 28 days after LBCCA. (a–c): pNFH and MBP levels were measured using Western bolts. β-actin was used as an internal control. N = 5/group. Values are expressed as Mean ± S.E., #: P < 0.05 vs vehicle-treated rats. (d): Quantitation of GST-pi+ cell numbers in the corpus collosum. N = 4/group. Values are expressed as Mean ± S.E., *: P < 0.05 vs sham-operated rats. GST-pi+ Glutathione-S-transferase pi (a marker of mature oligodendrocytes). (From ref. [116])
950.Fig. 7.32: L-carnitine increased myelin sheath thickness after chronic hypoperfusion by LBCCA. (a) Quantification of the diameter of MBP+ processes in the corpus collosum. N = 4/group. (b) Quantification of average myelin sheath thickness in sham-operated rats, and at 14 and 28 days after LBCCA in vehicle-treated and LCAR-treated rats. N = 4/group. (c): Quantification of pNFH+ axons colocalized with MBP+ processes in the corpus collosum. N = 4/group. Values are expressed as Mean ± S.E. *: P < 0.05, ***: P < 0.001 vs the sham-operated rats, and ###: P < 0.001 vs the vehicle-treated group. Abbreviations are same as Fig. 7.31. (Modified from ref. [116])
951.Fig. 8.1: Basic reactions of enzyme method. (I) Carnitine in the sample is reacted with acetyl-CoA in the presence of carnitine acyltransferase (CAT) purified from porcine heart and producing acetylcarnitine and CoASH. (II) CoASH react with DTNB and produce thiophenolic acid which has an absorption peak at 412 nm and is measured by spectrophotometrically. Notes: “CoASH” means free CoA. In reaction formula, sometimes “CoASH” is used instead “CoA” to show the presence of highly reactive SH-group in CoA molecule. CAT carnitine acetyltransferase, DNTB 5′,5′-dithiobis-nitrobenzoic acid
952.Fig. 8.2: Basic reaction of radioenzyme method. Carnitine in the sample reacts with 14C-acethyl-CoA in the presence of CAT as Fig. 8.1 and produces 14C-acetyl-L-carnitine and CoASH. Remaining un-react 14C-acethyl-CoA is removed by anion exchange resin column, and the eluent radioactivity is measured. CAT carnitine acetyltransferase
953.Fig. 8.3: Measurement method of carnitine fractions with radioenzyme method. RI method radioenzyme method, FC free carnitine, AC acylcarnitine, TC total carnitine, SCAC short-chain acylcarnitine, LCAC long-chain acylcarnitine
954.Fig. 8.4: Principle of enzyme cycling method for free and total carnitine measurement. ACE: acylcarnitine esterase, CDH: carnitine dehydrogenase, Thio-NAD+ thionicotinamide adenine dinucleotide, Thio-NADH thionicotinamide adenine dinucleotide reduced form. (Modified from refs. [13, 16])
955.Fig. 8.5: Pharmacokinetic 3 compartment model of disposition of L-carnitine and rate constants. (From ref. [1])
956.Fig. 9.1: Relationship between plasma carnitine concentration and CVD risk. (a–c): Forest plots of Relationship between odds ratios of CAD, PAD, CVD and quartiles of plasma carnitine concentrations before (closed circles) and after (open circles) logistic regression adjustments with traditional cardiovascular risk factors, including age, sex, history of diabetes mellitus, smoking, systolic blood pressure. Bars represent 95% confidence intervals. (d): Relationship of fasting plasma carnitine concentrations and angiographic evidence of CAD. Boxes represent the 25th, 50th and 75th percentile of plasma carnitine concentrations, and bars represent the tenth and 90th percentiles. (e): Forest plot of the hazard ratio of MACE and quartiles of carnitine unadjusted (closed circle) and after adjusting for traditional cardiovascular risk factors (open circles), or traditional cardiac risk factors plus creatinine clearance, history of myocardial infarction, history of CAD, burden of CAD (one-, two- or three-vessel disease), left ventricular ejection fraction, baseline medications (angiotensin-converting enzyme inhibitors, statins, beta blockers and aspirin) and TMAO levels (open squares). Bars represent 95% confidence intervals. (f): Kaplan-Meire plot and hazard ratios with 95% confidence intervals for unadjusted model, or following adjustments for traditional risk factors as in E. Median plasma concentration of carnitine (46.8 μM) and TMAO (4.6 μ) within the cohort were used to stratify subjects as having ‘high’ (≥median) or ‘low’ (<median) values. CVD cardiovascular diseases, CAD coronary artery diseases, PAD peripheral artery diseases, MACE major adverse cardiac events, TMAO trimethylamine-N-oxide. (From ref. [13])
957.Fig. 9.2: A working hypothesis by Koeth et al. Carnitine and choline in foods are metabolized and degraded to γBB and further converted into TMA by bacterial flora in the intestine of Clostridium order. TMA go to liver via blood stream and converted into TMAO by flavin-containing monooxygenase (FMO). Their hypothesis claims that this TMAO induces atherosclerosis, and causes heart failure, heart attack, stroke, etc. Koeth et al. describes that vegetarian who don’t eat meats have little intestinal bacterial flora which convert γBB into TMA, so that TMA is very low. γBB γ-butyrobetaine, TMA trimethylamine, TMAO trimethylamine-N-oxide, FMO flavin-containing monooxygenase. (From ref. [13])
958.Fig. 9.3: A correlation analysis between the thoracic aorta % lesion area and very low (<0.05 ppm), low (0.1 ppm), moderate (0.1–0.2 ppm), and high (>0.2 ppm) TMAO levels was conducted in hCETP expressed male Apoe−/− mouse administered L-carnitine for 12 weeks. The results were rather low thoracic aorta % lesion area in low, moderate and high groups compared to very low group (P < 0.01). (From ref. [24])
959.Fig. 9.4: Forest plot of odds ratios for all-cause mortality. IV inverse variance, CI confidence interval. (From ref. [38])
960.Fig. 9.5: Forest plot of risk ratios for the development of heart failure (6 studies, n = 3214). IV inverse variance, CI confidence interval. (From ref. [38])
961.Fig. 9.6: Forest plot of risk ratios for ventricular arrhythmia (5 studies, n = 229). IV inverse variance, CI confidence interval. (From ref. [38])
962.Fig. 10.1: Pathogenic mechanisms of main organic acidemias and role of carnitine supplementation. Deficiency or mutation of amino acid (isoleucine, leucine, lysine, etc.) metabolism enzymes cause accumulation of metabolic intermediates at the upstream and causes cell damage. Free carnitine is utilized to detoxify these intermediate toxicity and large amount of these disease specific acylcarnitine is excreted as related acylcarnitines and causes secondary carnitine deficiency. Carnitine supplementation therapy prevents, treats and normalizes these abnormalities
963.Fig. 10.2: Summary of propionic acidemia. (Created using as Refs. [2, 6, 7])
964.Fig. 10.3: Summary of methylmalonic acidemia. (Created using as Refs. [2, 6, 7])
965.Fig. 10.4: Summary of isovaleric acidemia. (Created using as Refs. [2, 6, 7] and others)
966.Fig. 10.5: Summary of glutaric acidemia type 1. (Created using as Refs. [2, 6, 7] and others)
967.Fig. 10.6: Summary of fatty acid β oxidation disorders. SCAD short chain acyl-CoA dehydrogenase, MCAD medium chain acyl-CoA dehydrogenase, LCAD long chain acyl-CoA dehydrogenase, VLCAD very long chain acyl-CoA dehydrogenase. (Created using as Refs. [2, 6, 7])
968.Fig. 10.7: Conventional spiral schema of long chain fatty acid β-oxidation. Acyl-CoA of a long-β chain fatty acid, becomes enoyl-CoA by dehydrogenation by acyl-CoA dehydrogenase (ACD), and then by the reaction of enoyl-CoA hydratase (EH) to 3-hydroxyacyl-CoA, and by the reaction of hydroxyacyl-CoA dehydrogenase (HAD) to produce 3-ketoacyl-CoA. Finally, the reaction of 3-ketoacyl-CoA thiolase (KAT) results in a long-chain acyl-CoA with two fewer carbons than at the start. These reactions are repeated in a spiral shape, and acetyl-CoA is produced and enters the TCA cycle, and the H+ generated by the ACD reaction enters the electron transport chain via electron transfer flavoprotein (ETF), and NADH produced by the HAD reaction also enters the electron transport chain and energy is produced. These reactions were supposed to take place in the mitochondrial matrix, but now it was revealed that the long chain acyl-CoA dehydrogenase reactions take place in mitochondrial inner membrane (See, text). (From Ref. [10])
969.Fig. 10.8: Enzymology of mitochondrial fatty acid oxidation. Detailed overview of the enzymes involved in the sequential reactions that compose mitochondrial fatty acid oxidation. LC long-chain, MC middle-chain, SC short-chain, CPT carnitine palmitoyltransferase, CACT carnitine acylcarnitine translocase, MOM mitochondrial outer membrane, MIM mitochondrial inner membrane, TCA tricarboxylic acid, VLCAD very-long-chain acyl-CoA dehydrogenase, MTP mitochondrial trifunctional protein, ETF electron transfer flavoprotein, EFTDH electron transfer flavoprotein dehydrogenase, MCAD middle-chain acyl-CoA dehydrogenase, SCAD short-chain acyl-CoA dehydrogenase, SCEH short-chain enoyl-CoA hydratase (crotonase), SCHAD short-chain 3-hydroxyacyl-CoA dehydrogenase, MCKAT middle-chain 3-ketoacyl-CoA thiolase, OXPHOS mitochondrial oxidative phosphorylation system. (From Ref. [15], with permission from The Korean Society of Lipid and Atherosclerosis)
970.Fig. 10.9: Overall scheme of urea cycle. Urea cycle localize in liver and consist of enzymes such as NAGS, CPS1, OTC, ASS1, ARG1, and transporter/carrier protein such as ORNT1, citrin (aspartic acid/glutamic acid carrier). NAGS, CPS1 and OTC localize in mitochondria, and ARG1, ASS1 and ASL localize in cytosol. Ammonia is converted to urea by urea cycle and detoxified. NAGS N-acetylglutamate synthase, CPS1 carbamyl phosphate synthetase 1, OTC ornithine transcarbamylase, ORNT1 mitochondrial ornithine/citrulline antiporter, ASS1 argininosuccinate synthetase, ASL argininosuccinate lyase, ARG1 arginase 1. (Modified from Ref. [9])
971.Fig. 10.10: Lipid and protein oxidative damage in plasma from phenylketonuric (PKU) patients (n = 18) and effects of L-carnitine (LC) and selenium (Se) treatment on them. (a) Thiobarbituric acid-reactive species (TBARS). (b) Sulfhydryl content. TNB: A yellow derivative which is generated when 5, 5′-dithio-bis (2-nitrobenzoic acid) (DTNB) is reduced by sulfhydryl-group and has an absorption peak at 412 nm. (c) Carbonyl formation. Data represent mean ± S.D., *: P < 0.05, **: P < 0.01 vs controls. (From Ref. [43])
972.Fig. 11.1: Serum total carnitine concentration (a), serum-free carnitine concentration (b), and serum acylcarnitine concentrations (c) in enteral nutrition users without carnitine (Group A: 36 cases), carnitine-supplemented enteral nutrition users(Group B: 8 cases), and oral foods users(Group C: 34 cases). (a) Total carnitine concentration (normal range: 46–91 μmol/L), Group A: 16.8 ± 8.9, Group B: 64.2 ± 23.5 μmol/L), Group C: 38.2 ± 12.1 μmol/L. (b) Free carnitine concentration (normal range: 36–71 μmol/L), Group A: 13.9 ± 7.5, Group B: 48.2 ± 15.9 μmol/L), Group C: 32.1 ± 10.7 μmol/L. (c) Acylcarnitine concentration (normal range: 6–23 μmol/L), Group A: 2.9 ± 1.6, Group B: 16.2 ± 11.0 μmol/L), Group C: 6.1 ± 1.9 μmol/L. **: P 0.01, ***: P 0.001. [20])
973.Fig. 11.2: Comparison of free carnitine concentration by valproic acid (VPA) and phenobarbital (PB) administration in enteral nutrition users without carnitine (Group A). **: P < 0.01, ***: P < 0.001. (From Ref. [20])
974.Fig. 11.3: Comparison of serum-free carnitine concentration by the species of anti-epileptics in oral foods users(Group C). (a) Comparison by multi-agents, single agent and without anti-epileptics. (b) Comparison by with or without valproic acid (VPA) and phenobarbital (PB). **: P < 0.01, ***: P < 0.001. (From Ref. [20])
975.Fig. 12.1: Chemical structure and chemical name of sodium valproate
976.Fig. 12.2: Relationship of valproate administration on plasma-free carnitine and blood ammonia concentrations in 25 children with severe physical and mental disabilities. (a) Relationship of plasma-free carnitine concentration and valproate dose in 14 children with severe physical and mental disabilities who received valproate administration. (b) Relationship of blood ammonia and plasma-free carnitine concentrations in 25 children with severe physical and mental disabilities. (Modified from Ref. [40])
977.Fig. 12.3: Relationship between hepatic survival rate and time of carnitine administration (a), and comparison of efficacy of intravenous or oral carnitine on hepatic survival (b) in VHT cases. (a) Non-carnitine-supplemented group (white bar) showed lower hepatic survival compared to carnitine-supplemented group (blue bar) regardless of time of carnitine administration. Among carnitine supplemented group, administration of carnitine within 0–5 days after onset of symptoms showed high efficacy. *P < 0.001 vs. non carnitine-supplemented group. (b) Intravenous carnitine-supplemented group (blue bar) showed high efficacy on hepatic survival compared to oral carnitine-supplemented group (white bar), but it is important that carnitine is administered as soon as possible same as (a). *P < 0.001 vs. oral carnitine-supplemented group. (From Ref. [102])
978.Fig. 12.4: Ammonia levels in 2724 adult epilepsy patients receiving VPA. (From Ref. [113])
979.Fig. 12.5: Blood ammonia level stratified by the number of combined anti-epileptic drugs (AEDs) other than valproate. *P < 0.001 vs. 1, 2. 3, 4, and 5 AEDs. **P < 0.001 vs. 2, 3 and 4 AEDs; P < 0.05 vs. 5 AEDs, ***P < 0.001 vs. 3 AEDs; P < 0.01 vs. 4 AEDs (analysis of variance (ANOVA) and Scheffe’s multiple comparison test). (From Ref. [113])
980.Fig. 12.6: Changes of ammonia levels after carnitine administration in hyperammonemic psychiatric patients receiving VPA. L-carnitine was administered 900 mg/day at first, then increased to 1800 mg/day after 2 weeks in the 3 cases (bold dashed lines). (From Ref. [133])
981.Fig. 12.7: Speculated mechanisms of carnitine deficiency and hyperammonemia by VPA. ⊖ inhibition, ⊕ activation, CPS1 carbamyl phosphate synthetase, NAGS N-acetylglutamate synthase, VPA valproic acid, TPM topiramate, OCTN2 carnitine transporter. (Created from Refs. [162, 164–167])
982.Fig. 13.1: Chemical structure of pivoxil group containing antibiotics (example of cefditoren pivoxil)
983.Fig. 13.2: Metabolism of pivalic acid and mechanism of the carnitine deficiency with pivoxil-containing antibiotics. Note: Molecular weight of pivaloyl-carnitine (245.3) is same as isovalerylcarnitine which is observed in high concentration in the urine in isovaleric acidemia, one of the inherited metabolic diseases, so that it is not possible to distinguish between pivaloyl-carnitine and isovalerylcarnitine by mass spectrometer. In the case of carnitine deficiency due to pivoxil-containing antibiotics, C5 carnitine increases in the urine but it is necessary to confirm that this C5 carnitine is isovalerylcarnitine or not by GC/MS. (Modified from Ref. [1, 2])
984.Fig. 14.1: Correlation between serum carnitine and serum creatinine in patients with non-dialyzed chronic renal disease. The black rectangle indicates normal range. The correlation coefficient: r = 0.731. (From Ref. [9])
985.Fig. 14.2: Concentrations of plasma total carnitine, free carnitine, and acylcarnitine in patients with non-dialyzed chronic renal disease. Each point indicates the data of each patient. The dotted lines indicate the normal range of each carnitine fraction. (From Ref. [10])
986.Fig. 14.3: Muscle free carnitine level in uremic patients, normal controls, and patients on maintenance hemodialysis. (From Ref. [11])
987.Fig. 14.4: Serum total carnitine (a), free carnitine (b), acylcarnitine (c), and acyl/free carnitine ratio (d) levels according to CKD stage in patients with CKD who were not on dialysis. eGFR: estimated glomerular filtration ratio, CKD: chronic kidney disease. (From Ref. [12])
988.Fig. 14.5: Relation between concentrations of carnitine in plasma and muscle. Mean concentration of carnitine in muscle was significantly less in hemodialysis patients than controls (P < 0.05, Wilcoxon two-sample test). (From Ref. [22])
989.Fig. 14.6: Changes in plasma carnitine concentration from dialysis to next dialysis. Upper panel is male patients (n = 4) and lower panel is female patients (n = 4). The blue area indicates normal range. (From Ref. [23])
990.Fig. 14.7: Mean ± SEM plasma concentrations of L-carnitine (upper panel), (middle panel), and total L-carnitine (lower panel) in patients with end-stage renal disease (ESRD) during the first 12 months of hemodialysis treatment. Mean ± SEM plasma concentrations of L-carnitine (upper panel), acetyl-L-carnitine (middle panel), and total L-carnitine (lower panel) in patients with end-stage renal disease during the first 12 months of hemodialysis treatment. *: Compared with baseline, P < 0.05. (From Ref. [27])
991.Fig. 14.8: Correlation between plasma and muscle free carnitine in a group of 14 patients on hemodialysis (P < 0.05). (From Ref. [35])
992.Fig. 14.9: Relationship between duration of hemodialysis in patients with chronic renal failure and total muscle carnitine content at rest in the vastus lateralis. Each point represents an individual patient. The duration of hemodialysis was inversely correlated with the muscle carnitine content (y = −138x + 3409; R = −0.74, P < 0.05). (Modified from Ref. [31])
993.Fig. 14.10: Plasma concentration versus time profiles for L-carnitine in 12 end-stage renal disease patients under baseline conditions and after a single intravenous dose of L-carnitine (20 mg/kg). The symbols (●) represent pooled concentrations from 12 patients, and the continuous line represents the concentrations predicted by the fitted model with three compartment model simulation. The inserted figure indicates 10-folds scale of vertical axis. (Modified from Ref. [37])
994.Fig. 14.11: Simulated amounts of L-carnitine in the three compartments (a: Plasma, b: liver, and c: muscle) of the pharmacokinetic model in patient 5 undergoing intermittent hemodialysis three times per week. (From Ref. [37])
995.Fig. 14.12: The predicted and observed muscle contents of L-carnitine when an individual with normal carnitine pools is placed on dialysis. The symbols show the muscle carnitine contents estimated from measures of muscle carnitine concentration in dialysis patients before and during continuous dialysis for up to 17 years. The lines show the muscle content predicted using the model with initially normal carnitine pools and with parameter values and dialysis condition set at either 2, 4, 6, or 8 μmol h−1. The extent of depletion of the muscle carnitine depended on the balance between the loss of carnitine via dialysis and the rate of inputs (from diet, endogenous synthesis, and supplement). (From Ref. [37])
996.Fig. 14.13: (a) Histogram showing serum free carnitine concentrations in 150 patients on dialysis. (b) Histogram showing serum acyl/free carnitine ratio in these patients. (From Ref. [48])
997.Fig. 14.14: Scatter plots with trend lines between acylcarnitine acyl chain length and strength of relationship (as represented by partial correlation coefficient) to outcome measures: (a) C-reactive protein, (b) 6-min walk distance, (c) sit-to-stand maneuver count, (d) Medical Outcomes Trust SF-36 PCS, and (e) ESA dose. Medical Outcomes Trust SF-36 PCS: Questionary of Medical Outcomes Trust short form physical composite score. (From Ref. [53])
998.Fig. 14.15: Relationship between mean (±SEM) ratio of post-dialysis/pre-dialysis acylcarnitine concentration and carbon chain length of the acyl group. (From Ref. [56])
999.Fig. 14.16: Significant correlation between carnitine deficiency (acyl carnitine/free carnitine ratio) and the erythropoietin resistance index in patients (n = 60) who underwent peritoneal dialysis. (From Ref. [69])
1000.Fig. 14.17: The effect of L-carnitine on serum triglyceride (a random model analysis) and on total cholesterol (b fixed model analysis). Open boxes indicate the effects of each individual trial, and the closed boxes the overall effect of treatment. The P value is given for overall treatment effect and is significant for values ≦ 0.01. Heterogeneity of treatment effect among trials is present if H test value is <0.10. (From Ref. [1])
1001.Fig. 14.18: Difference of free carnitine levels (left panel) and AC/FC ratio (right panel) between patients with symptoms (group A) and patients without symptoms (group B). This figure shows the mean ± SD of data in each group. *: denotes P < 0.05 for comparison with group B. **: denotes P < 0.0005 for comparison with group B. Statistical significance was determined be student’s t-test. (From Ref. [49])
1002.Fig. 14.19: Improvement in dialysis-associated muscle symptoms by oral L-carnitine substitution. (a) Effects on muscle weakness, fatigue, and cramps/aches after 12 weeks of treatment. (b). Improvement index in muscular symptoms during the course of the study. Approximately two-thirds of patients showed some improvement in each symptom. *: P < 0.005 for comparison with the baseline; **: P < 0.05 for comparison with the baseline. Statistical significance was determined by Scheffe’s test. (From Ref. [49])
1003.Fig. 14.20: Maximal oxygen consumption during progressive work exercise test at baseline and repeated at 24 weeks in patients receiving L-carnitine (N = 14) and those receiving placebo (N = 23). The comparisons between baseline and 24 weeks were made by paired t-test. Values are mean (SEM). (From Ref. [96])
1004.Fig. 14.21: Proposed pathogenic mechanism of muscle cramps in dialysis patients. (From Refs. [106, 107])
1005.Fig. 14.22: Correlation between plasma carnitine levels and the cardiothoracic ratio (CTR). (From Ref. [127])
1006.Fig. 14.23: Results of BMIPP myocardial scintigraphy of patients before and after carnitine supplementation compared with normal control. (a) H/M ratio, (b) myocardial washout rate of BMIPP. Data are expressed as means ± SD, *P < 0.005 vs. control, #P < 0.05 vs. before, ##P < 0.001 vs. before. H/M: Heart to mediastinal ratio, BMIPP: 125I-labeled β-methyl-p-iodophenyl-pentadecanoic acid. (From Ref. [118])
1007.Fig. 14.24: Effect of carnitine supplementation on cardiac symptoms (dyspnea on exertion, palpitation, chest pain), cardiac hypertrophy (CTR and LV mass), and cardiac function (EF) in patients on hemodialysis. CTR: cardiothoracic ratio, EF: ejection fraction, LV mass: left ventricular mass. (From Ref. [119])
1008.Fig. 14.25: The relationship between EF and FC before carnitine supplementation therapy in 16 dialysis patients (P < 0.02). EF: ejection fraction, FC: free carnitine concentration. (From Ref. [122])
1009.Fig. 14.26: Effect of carnitine supplementation (intravenously, 1000 mg/3 times a week, after dialysis session) in 11 dialysis patients whose LVEF were low. There was significant improvement from 2 months treatment (P < 0.05 vs. baseline). LVEF: left ventricular ejection fraction. (From Ref. [125])
1010.Fig. 14.27: Effect of carnitine supplementation (oral. 900 mg/day, for 3 months) on LVEF (a) and hypotensive episodes during dialysis (b) in 18 dialysis patients. LVEF: left ventricular ejection fraction. (From Refs. [126, 127])
1011.Fig. 14.28: Effect of carnitine supplementation (oral, 20 mg/kg/day, for 12 months) on LVEF (a), change in LVEF (b) and change in LVMI (c) in dialysis patients. (a) Ejection fraction(EF)data are expressed as mean ± SD, (b) Change in EF (ΔEF) is expressed as mean ± 95% confidence interval, (c) Change in left ventricular mass index (ΔLVMI) is expressed as mean ± 95% confidence interval. *P<0.001 vs. baseline, †P<0.01, ‡P<0.001 vs. the levocarnitine subgroup of patients without left ventricular hypertrophy (LVH). LVEF: left ventricular ejection fraction, LVMI: left ventricular mass index. (From Ref. [128])
1012.Fig. 14.29: Image of chest X-ray of a heart failure dialysis patient with significant effect after intravenous carnitine administration (intravenous, 1000 mg/after dialysis session, 2 times a week (total 2000 mg/week), for 1 year). After 1 year, CTR improved from 71.3 to 51.4%. CTR: cardiothoracic ratio. (Modified from Ref. [130])
1013.Fig. 14.30: Changes in BMIPP score, LVEF, LVMI, and BNP in heart failure dialysis patient with significant effect after intravenous carnitine administration (intravenous, 1000 mg/after dialysis session, 2 times a week (total 2000 mg/week), for 1 year). After carnitine supplementation for 1 year, BMIPP score decreased from 20 to 6 and BNP level from 8257 to 378 pg/mL, and LVEF improved from 50.6 to 71.2 and LVMI from 214 to 144 g/m2. BMIPP: 125I-labeled β-methyl-p-iodophenyl-pentadecanoic acid, LVEF: left ventricular ejection fraction, LVMI: left ventricular mass index, BNP: brain natriuretic peptide. (From Ref. [130])
1014.Fig. 14.31: Serum C-reactive protein (CRP) levels in maintenance hemodialysis patients with baseline levels <3 mg/dL (solid lines) or ≥3 mg/dL (dotted lines), treated with L-carnitine 20 mg/kg or placebo thrice weekly for 6 months. (Modified from Ref. [142])
1015.Fig. 14.32: Serum albumin concentrations (g/dL) in maintenance hemodialysis patients treated with L-carnitine or placebo for 6 months. (Modified from Ref. [142])
1016.Fig. 14.33: Correlation between ∆skin advanced glycation end products (AGEs) and ∆free carnitine in L-carnitine-treated hemodialysis patients (n = 32). (From Ref. [148])
1017.Fig. 14.34: Relationships among skin AGE, hsCRP, and carotid PI in hemodialysis patients. Low hsCRP: log ≦ 2.42, high hsCRP: log ≧ 2.43, low AGEs: ≦2.84, high AGEs: >2.85. AGE: advanced glycation end products, hsCRP: high-sensitive C-reactive protein, PI: pulsatility index. (From Ref. [151])
1018.Fig. 14.35: Proposed mechanisms of progression of CVD via oxidative stress-AGEs system by carnitine deficiency. CVD: cardio-vascular diseases, AGEs: advanced glycation end products. (From Ref. [152])
1019.Fig. 14.36: Changes in baPWV following L-carnitine treatment (oral, 20 mg/kg/day, for 12 months) in hemodialysis patients. *P < 0.05, **P < 0.001 vs. pre value, baPWV: brachial-ankle pulse wave velocity. (From Ref. [153])
1020.Fig. 14.37: Effect of carnitine supplementation (oral, 1.6 g/day, for 12 months) on hematocrit in dialysis patients. (Modified from Ref. [157])
1021.Fig. 14.38: Relationship between rHuEPO dose and serum total carnitine concentration in 16 hemodialysis patients. (From Ref. [160])
1022.Fig. 14.39: Relation between maintenance rhEPO dose and serum carnitine levels. (a and b) Maintenance rhEPO dose was correlated with serum total carnitine (TC) and free carnitine (FC) levels. (c) Maintenance rhEPO dose was not correlated with serum acylcarnitine (AC) levels. (From Ref. [161])
1023.Fig. 14.40: Values for rHuEPO requirements in L-carnitine group (n = 13) and placebo group (n = 11). L-carnitine (intravenously, 1000 mg, 3 times a week) or placebo were administered for 6 months. (Modified from Ref. [163])
1024.Fig. 14.41: The effect of L-carnitine on anemia (hematocrit: Ht) control (above the dotted line; fixed model analysis) and erythropoietin (EPO) dose reduction (below the dotted line; random model analysis). Open boxes indicate the effect of each individual trial, and the closed boxes indicate the overall effect of treatment. The P value is given for overall treatment effect and is significant for values ≤0.01. Heterogeneity of treatment effect among trials is present if H test value is <0.10. (Modified from Ref. [1])
1025.Fig. 14.42: The effect of L-carnitine on erythropoietin resistance index (ERI) in control (left) and L-carnitine-treated (right) groups. ERI was defined as the ratio of EPO dose divided by the patient’s hemoglobin level. Data were available in four trials. The numbers in parenthesis indicate the reference numbers in Chap. 14 of this book, and Altmann’s data are from a meeting abstract. (Modified from Ref. [1])
1026.Fig. 14.43: Serum free carnitine (left), serum total carnitine (center), and RBC total carnitine (right) concentrations in normal controls and patients receiving 9000 U/week of EPO (group A and B). Results are expressed as mean ± SD. Serum carnitine levels in both group A and group B were significantly decreased compared to controls, while no difference was observed between group A and group B. RBC carnitine levels showed no obvious difference among three groups. Control: adults healthy subjects (n = 15), group A: patients with Ht < 27.5% when treated with EPO 9,000 U/week, group B: patients with Ht > 30 5 when treated with EPO 9000 U/week. Ht: hematocrit, RBC: red blood cells. (From Ref. [167])
1027.Fig. 14.44: Effect of L-carnitine treatment on hematocrit levels in the poor responders to EPO (group A). Hematocrit levels were measured before a dialysis session. The change of hematocrit levels in each patient of group A. Solid or dotted lines indicate patients with or without efficacy, respectively. (From Ref. [167])
1028.Fig. 14.45: Effect of L-carnitine supplementation (oral, 600 mg/day, divided 2 times, for 24 weeks) on hemoglobin (Hb) and on erythropoiesis stimulating agents (ESA) dose in dialysis patients who were low-responsive to ESA treatment. (From Ref. [101])
1029.Fig. 14.46: Change in ERI after carnitine treatment in dialysis patients with ESA-resistant anemia. ERI: erythropoietin resistance index = ESA dose (units/week)/hemoglobin (g/dL). (Modified from Ref. [101])
1030.Fig. 14.47: Change of quantity of ESA from baseline to month 6 in carnitine-treated and control groups. In the carnitine-treated group, 20 mg/kg/day (oral, maximum 1200 mg/day) of carnitine was administered for 6 months. *: P < 0.05 vs. ESA doses after 6 months of control group, ESA: erythropoiesis stimulating agent. (Modified from Ref. [168])
1031.Fig. 14.48: Change of ERI from baseline to months 3 and 6 in treated and control groups and comparison between two groups. *: P < 0.05 vs. ERI after 3 months of control group, **: P < 0.001vs. ERI after 6 months of control group. ERI: erythropoiesis resistance index = weekly ESAs dose/kg/g Hb/dL. (From Ref. [168])
1032.Fig. 14.49: Changes in the total ESA dose per week from baseline to 6 and 12 months in the L-carnitine- treated and control groups with comparison between the 2 groups. In the L-carnitine-treated group, L-carnitine was administered for 12 months (intravenous, 1000 mg, 3 times a week after each dialysis session). *P < 0.0001 vs. Pre, †p < 0.05 vs. ESA dose at the same time point in the control group. ESA: erythropoiesis-stimulating agent. (Modified from Ref. [171])
1033.Fig. 14.50: Changes in ERI from baseline to 6 and 12 months in the L-carnitine treated and control groups with a comparison between the 2 groups. *P < 0.0001 vs. Pre, †P < 0.05 vs. ERI at the same time point in the control group. In the L-carnitine-treated group, L-carnitine was administered intravenously (1000 mg, 3 times a week after each dialysis session). ERI: erythropoiesis resistance index. (Modified from Ref. [169])
1034.Fig. 14.51: Change in EPO dose with or without zinc supplementation in dialysis patients with ESA resistant anemia and zinc deficiency. Zinc supplementation: Polaprezinc 2 bags (containing 34 mg/day) for 12 months. (From Ref. [176])
1035.Fig. 14.52: Changes in ESA dosage (upper part) and erythropoietin responsiveness index (ERI, lower part) during the study period with or without zinc supplementation (34 mg/day). Data are expressed as mean ± SD. *P < 0.05 vs. baseline, †P < 0.05 vs. control group. (Modified from Ref. [177])
1036.Fig. 14.53: Proportion of who could control hemoglobin (Hb) without rHuEPO between vitamin D3 pulse therapy group (A, n = 27) and non-vitamin D3 pulse therapy group (B, n = 46) in maintenance hemodialysis patients. VD3-P: vitamin D3 pulse therapy. (Modified from Ref. [188])
1037.Fig. 14.54: Proportion of patients who had acquired renal cysts in vitamin D3 pulse therapy group (a) and non- vitamin D3 pulse therapy group (b) in maintenance hemodialysis patients. No: patients who had not acquired renal cysts, Yes: patients who had acquired renal cysts. VD3-P: vitamin D3 pulse therapy. (Modified from Ref. [188])
1038.Fig. 14.55: Changes in monthly proportion of dialysis patients whose hemoglobin could control within target range without ESA (bar graph), and changes in monthly proportion of zinc supplementation (blue circle and dotted line) and L-carnitine supplementation (black circle and solid line) from January 2011 to May 2012. Most of patients received vitamin D3 supplementation, and along with increase of the proportion of zinc and L-carnitine supplementation, the proportion of patients whose hemoglobin could control within target range without ESA gradually increased and finally reached around 60 %. The numbers indicate the percentage of each month. (Modified from Ref. [189])
1039.Fig. 14.56: An image figure for carnitine deficiency, zinc deficiency, and vitamin D3 deficiency in maintenance dialysis patients. In dialysis patients, carnitine deficiency, zinc deficiency, and vitamin D3 deficiency are common and sometimes they overlap each other, two or three of these deficiencies. LC: L-carnitine, Zn: zinc, VD3: vitamin D3
1040.Fig. 14.57: Schematic synopsis of the mode of action of selected hormonal adjuvants that are potentially applicable to increase erythropoiesis in chronic kidney disease patients. Closed arrows represent stimulatory, open arrows inhibitory influence. Note that data on the effect of zinc largely stem from experimentally induced states of zinc deficiency. EPO: erythropoietin, GH: growth hormone, IGF-1: insulin-like growth factor-1, PTH: parathyroid hormone; Zn: zinc. (Modified from Ref. [191])
1041.Fig. 14.58: Analogy of heart failure and anemia in dialysis patients between Liebig’s law of the minimum. Liebig’s law of the minimum (Dobeneck’s barrel, or pail) says multiple nutrients are required for plant growth, but the growth is determined (rate-limited) by the scarcest (least) amount of nutrient. To treat pathophysiology such as anemia and heart failure in dialysis patients, we have to always consider multiple nutrients deficiencies and supplementation therapy for corresponding deficiencies. EPO: erythropoietin, Fe: iron, VD3: vitamin D3, Zn: zinc, Se: selenium, LC: L-carnitine
1042.Fig. 14.59: Total cross-sectional area and average blood flow velocity of blood vessels in systemic circulation. Blood flow volume is equal in each blood vessel, and blood flow velocity is high in aorta and vena cava where the cross-sectional area is smallest. In the capillaries, the cross-sectional area is largest, but the blood flow velocity is smallest which contributes to exchange of substrates, waste substances, and gases between capillaries and the tissues. The dotted line: total cross-sectional area of blood vessels; The solid line: average blood flow velocity. (From Ref. [202])
1043.Fig. 14.60: Potential metabolic (a) and biophysical (b) interventions of L-carnitine on circulating red blood cells. Membrane phospholipid repair (A): When oxidative challenge of a polyunsaturated fatty acid esterified in membrane phospholipid (PLP) generates a phospholipid hydroperoxide (PLP-OOH), the deacylating activity of a phospholipase A2 (PLA) hydrolyzes the fatty acid hydroperoxide (FA-OOH), which in turn may be further reduced to the corresponding non-reactive fatty acid alcohol (FA-OH) by a glutathione peroxidase (GSH-Px). This is followed by a parallel increase of lysophospholipid acyl-CoA transferase (LAT), which would regenerate the original PLP and limit the accumulation of the potentially toxic lysophospholipid (LPL). The increased LAT activity requires an increased supply of activated acyl units (acyl-CoA) from the activity of the ATP-dependent enzyme acyl-CoA synthetase (ACS). The combined activities of LAT and ACS generate a cycle, whose efficiency is strictly dependent on the extent of the enzymatic rates of LAT and ACS. Thus, the presence of a rate-coupler, carnitine palmitoyltransferase (CPT), would allow the ACS-LAT cycle to keep the acyl-CoA/free CoA ratio constant. Indeed, given the kinetic properties of CPT, any alteration of the acyl-CoA/free CoA ratio would be promptly buffered by the fully reversible and mass action-sensitive CPT reaction. The presence of supraphysiological concentration of carnitine (Cn) would support the buffering action of CPT. In addition, acyl-carnitine (acyl-Cn) represents a reservoir of acyl-CoA units at no ATP cost. Membrane viscoelastic properties (B): Major determinants of the viscoelastic properties of RBC membrane are the cytoskeletal network and membrane phospholipid bilayer. The cytoskeletal network is an organization of supramolecular proteins lying beneath the inner monolayer of erythrocyte membrane bilayer. LC may improve the viscoelastic properties of RBC by exerting a stabilizing effect on the membrane via a specific interaction with certain cytoskeletal components (spectrin/actin as indicated in the figure by right red circle). LC would also affect the viscoelastic properties of RBC membrane by strengthening the polar head packing of membrane phospholipids (left red circle). (From Ref. [192])
1044.Fig. 14.61: Potential anti-apoptotic intervention of L-carnitine. (a) Schematic representation of negative regulation of erythropoiesis triggered by death receptor activation or erythropoietin deprivation/resistance: Both these conditions induce the apoptotic cascade, which the consequent activation of caspase 3 that cleaves the transcription factors GATA-1. The cleavage of GATA-1 is responsible for either the maturation arrest or apoptosis of erythroid cells. By inhibiting caspase 3, L-carnitine would favorably affect the maturation of erythroid cells. EPO: erythropoietin, FADD: FAS-associated death domain, Bcl: antiapoptotic protein, JAK: Janus kinase, CFU: colony forming unit. (b) Ceramide- and caspase 3-dependent cell death pathways are also operative in circulating red blood cells and known as erythro apoptosis: Indeed, activation of such cell death pathways leads to phosphatidylserine (PS) exposure at the surface of the erythrocyte membrane, a well-known signal for the elimination of RBCs by macrophages in vivo. L-carnitine may counteract PS exposure by either preventing ceramide production or inhibiting caspase-3. SCR: scramblase, AMT: aminophospholipid translocase, SM: sphingomyelinase, PLA: Phospholipase A2, PAF: platelet activating factor. (From Ref. [192])
1045.Fig. 14.62: Multiple mode of action through which L-carnitine may affect the number and quality of red blood cells in the circulation. Inhibition of apoptosis by L-carnitine (a) is expected to increase red cell number. On the other hand, by promoting phospholipid remodeling (b) and improving viscoelastic properties (c), L-carnitine is expected to affect red blood cells quality, and hence, increase their lifespan. EPO: erythropoietin, FADD: FAS-associated death domain, Bcl: antiapoptotic protein, JAK: Janus kinase, CFU: colony forming unit. (From Ref. [192])
1046.Fig. 14.63: The regulation and physiology of membrane phospholipid asymmetry. This model describes how membrane phospholipid asymmetry is generated, maintained, and perturbated as a prerequisite to various phosphatidylserine-related pathophysiologies. Membrane lipid asymmetry is regulated by the cooperative activities of three transporters. The ATP-dependent aminophospholipid-specific translocase, which rapidly transports PS and PE from the cell’s outer-to-inner leaflet; the ATP-dependent nonspecific lipid floppase, which slowly transports lipids from the cell’s inner-to-outer leaflet; and the Ca2+-dependent nonspecific lipid scramblase, which allows lipids to move randomly between both leaflets. The model predicts that the translocases are targets for Ca2+ that directly regulate the transporter’s activities. The figure shows that elevated intracellular Ca2+ induces PS randomization across the cell’s plasma membrane by providing a stimulus that positively and negatively regulates scramblase and translocase activities, respectively. At physiologic Ca2+ concentrations, PS asymmetry is promoted because of an active translocase and floppase but inactive scramblase. Depending on the type of cell, elevated intracellular Ca2+ can be achieved by cellular activation that generally results in the concomitant influx and accumulation of extracellular Ca2+ and by its release from intracellular stores. Increased cytosolic Ca2+ can also result in calpain activation, which facilitates membrane blebbing and the release of PS-expressing procoagulant microvesicles. Exposure of PS at the cell’s outer leaflet. The appearance of PS at the cell’s outer leaflet promotes coagulation and thrombosis by providing a catalytic surface for the assembly of the prothrombinase and tenase (not shown) complexes and marks the cell as a pathologic target for elimination by phagocytes. Recognition of the PS-expressing targets can occur by both antibody-dependent and direct receptor-mediated pathways. β2-Gp: β2-glycoprotein-1, rec: receptor, PS: phosphatidylserine, PE: phosphatidylethanolamine. (From Ref. [232])
1047.Fig. 14.64: PS exposure rates of RBC in chronic renal failure patients. PS exposure rates were studied using FITC-labeled Annexin V which bound to PS on RBC surface. Normal: healthy subjects, CRF: non-dialyzed chronic renal failure patients, CAPD; chronic renal failure patients treated with CAPD, HD: chronic renal failure patients treated with hemodialysis. PS: phosphatidyl serine, RBC: red blood cells, FITC: fluorescein isothiocyanate (a fluorescence probe). *: P < 0.05 vs. healthy subjects, °: P < 0.05 vs. CAPD patients. (From Ref. [233])
1048.Fig. 14.65: Hospitalization rate (a) and hospital days (b) in dialysis patients (n = 2967) who received carnitine supplementation therapy more than 3 months. (From Ref. [240])
1049.Fig. 14.66: Recommended approach to the evaluation and treatment of a patient with possible dialysis-related carnitine disorder (DCD) by “Carnitine Consensus Conference” panel in National Kidney Foundation. DCD: dialysis-related carnitine disorder, ESA: erythropoiesis stimulating agents, Hb: hemoglobin, Hct: hematocrit, NYHA: New York Heart Association, ACC: American College of Cardiology, AHA: American Heart Association, QOL: quality of life. (From Ref. [243])
1050.Fig. 15.1: Plasma carnitine and acylcarnitines in hepatic cirrhosis. The blue box represents the mean ± 1S.D. of values for carnitine and its metabolites for 30 healthy subjects. The solid dots are individual values for each of the 20 cirrhotic patients. The horizontal bar is the mean value for the cirrhotic patients. (From ref. [4])
1051.Fig. 15.2: Contents of acylcarnitines and free carnitine in CLD and HCC. (a): Acylcarnitines with long chain; (b): free carnitine and acylcarnitines with a medium or short chain. CLD chronic liver diseases, CHB chronic hepatitis B, HCC hepatocellular carcinoma, CIR hepatic cirrhosis, N healthy control. *: Peak area in corresponding liver disease group was significantly different from that in the control (p < 0.05), +: Peak area in CIR or HCC was significantly different from that in CHB, #: peak area in HCC was significantly different from that in CIR. (From ref. [14])
1052.Fig. 15.3: Effects of L-carnitine on the latency to the first seizure (min, a), and number of the seizures during 10 min observation (b) Each mouse was injected with saline solution with or without L-carnitine and then with 15 mmol ammonium acetate/kg body weight. Bars indicate the mean values of each group (n = 7) and an asterisk significant difference (P < 0.01) from the untreated group (0 mmol/L-carnitine/kg body weight), (Wilcoxon test). (From ref. [39])
1053.Fig. 15.4: Effect of L-carnitine (16 mmol/kg, i.p.) (●) and vehicle (○) on plasma (a) and CSF (b) concentration of ammonia in PCS rats administered ammonium acetate (NH4OAc) to precipitate severe sign of encephalopathy. Precoma stage defined as stage at which animals lost their righting reflex; coma stage defined as loss of corneal reflex. Data points represent mean ± SD of duplicate determination from n = 6 per treatment group. Values significantly different from vehicle-injected controls indicated by ★★. P < 0.01 by Student’s t-test with Bonferroni correction. CSF cerebrospinal fluid, PCS rats Portacaval shunted rats. (From ref. [40])
1054.Fig. 15.5: The “Trojan horse hypothesis” in neurotoxicity of ammonia. Left: Diagrammatic sketch illustrating the synthesis of glutamine (①); its transport into mitochondria via the glutamine carrier (②); its hydrolysis by phosphate-activated glutaminase (PAG) resulting in glutamate (GLU) and ammonia (③); the generation of reactive oxygen species (ROS) from ammonia (④). Right: General scheme by which ammonia and glutamine lead to mitochondrial failure resulting in astrocyte dysfunction and clinical development of hepatic encephalopathy. GS glutamine synthetase, GLU-Tx glutamine transporter, MPT mitochondrial permeability transition, ROS reactive oxygen species. (From ref. [52])
1055.Fig. 15.6: Change in plasma ammonia level after carnitine or placebo administration in cirrhotic patients with hepatic encephalopathy. L-carnitine was administered orally (2 g, 2 times a day) for 90 days. (Created from Table 15.2. in ref. [61], with permission)
1056.Fig. 15.7: Change in score of trail making test-A after carnitine or placebo administration in cirrhotic patients with hepatic encephalopathy. L-carnitine was administered orally (2 g, 2 times a day) for 90 days. (Created from Table 15.2. in ref. [61], with permission)
1057.Fig. 15.8: Clinical course of case 1. (Male, 70 years old, cirrhosis type C, hepatocellular carcinoma). ALB albumin, T. Bil total bilirubin, AFP α-fetoprotein, TACE transcatheter arterial chemoembolization. (From ref. [70])
1058.Fig. 15.9: Ammonia levels and clinical courses of case 1 (a) and case 2 (b) with severe hepatic encephalopathy. At the early stage of treatment, L-carnitine injection was administered, and judging the responsiveness of the treatment, dose of oral L-carnitine was determined. (From ref. [74])
1059.Fig. 15.10: Change in the number of hospital admissions for hepatic encephalopathy for 3 years before and after L-carnitine administration. This difference is statistically significant (P < 0.001). (From ref. [76])
1060.Fig. 15.11: Comparison of NIRS data between the L-carnitine and no treatment groups at baseline and 8 weeks post-treatment. (a) All patients. The box plot includes the stratified analysis according to the L-carnitine dose. (b) Patients with hyperammonemia. (c) Patients with normal ammonia levels at baseline. NIRS near-infrared spectroscopy. (From ref. [79])
1061.Fig. 15.12: Clinical course of a significant improvement case of severe muscle cramps of patient with hepatic cirrhosis (72 years-old, female, Child-Pugh B, cirrhosis of hepatitis virus type C) by L-carnitine administration. VAS visual analogue scale, RFA radiofrequency ablation, SBP spontaneous bacterial peritonitis, TACE transcatheter arterial chemoembolization. (From ref. [83])
1062.Fig. 15.13: Efficacy of L-carnitine treatment for the reduction or disappearance of muscle cramps. Percentages of (a) reduction and (b) disappearance of muscle cramps are shown. Muscle cramping was reduced in 88.1% and disappeared in 28.6% of patients after 8 weeks of therapy. The dose of L-carnitine was an important factor associated with disappearance of muscle cramps. L-carnitine was administered 900 mg/day (300 mg × 3 times/day) or 1200 mg/day (300 mg/day × 3 times/day). (From ref. [84])
1063.Fig. 15.14: Scores of VAS before and after 8 weeks of L-carnitine treatment. (a): Changes in VAS score for pain due to muscle cramps before and after L-carnitine administration (900 mg/day, black dotted lines, and 1200 mg/day, blue lines, n = 31). The VAS score of all cases significantly decreased from 69.9 ± 22.5 to 26.2 ± 29.1 (black bold line, P < 0.0001). (b): Changes in VAS scores for pain due to muscle cramps before and after L-carnitine administration by dose (900 mg/day, blue dotted line, 1200 mg/day, black line). The VAS score significantly decreased in 1200 mg group than in 900 mg group (P = 0.003). VAS visual analogue scale. (From ref. [84])
1064.Fig. 15.15: Outline of measurement of energy metabolism using indirect calorimetry. REE resting energy expenditure, RQ respiratory quotient, V̇O2 oxygen consumption per minute, V̇CO2 CO2 exhaled per minute, UN nitrogen excretion per 24 h. (Created as refs. [88, 89])
1065.Fig. 15.16: Relative oxidation rates of carbohydrate (% CHO), fat (% FAT), and protein (% PRO) in controls and in patients with liver cirrhosis of modified Child’s grade (m-Child) A, B, or C. Values are expressed as mean (SE). *: P < 0.05, **: P < 0.01, ***: P < 0.001 (Dunnett t test). (From ref. [88])
1066.Fig. 15.17: L-carnitine effects on CP score and serum albumin. (a):L-carnitine effects on mean CP score changes from baseline in study patients overall. (b):L-carnitine effects on mean CP score changes from baseline in BCAA+ patients. (c):L-carnitine effects on mean serum albumin changes from baseline in study patients overall. (d):L-carnitine effects on mean serum albumin changes from baseline in BCAA+ patients. Error bars represent standard errors. CP Child-Pugh, TACE transarterial chemoembolization. (From ref. [95])
1067.Fig. 15.18: L-carnitine effects on PT and total bilirubin. (a): L-carnitine effects on mean PT changes from baseline in study patients overall. (b): L-carnitine effects on mean PT changes from baseline in BCAA+ patients. (c): L-carnitine effects on mean total bilirubin changes from baseline in study patients overall. (d): L-carnitine effects on mean total bilirubin changes from baseline in BCAA- patients. Error bars represent standard errors. PT prothrombin time, TACE transarterial chemoembolization. (From ref. [95])
1068.Fig. 15.19: Patient flow chart. Of 158 patients with liver cirrhosis who were screened, 44 were excluded due to inadequate clinical information or lack of paired CT imaging. Thus, 35 patients who were administered-carnitine and 79 control patients who were not administered L-carnitine were enrolled. After propensity score matching for age, sex, presence of HCC, and supplementation of BCAAs, 35 patients who received L-carnitine supplementation were selected as cases and 35 patients who did not receive carnitine supplementation were selected as matched controls. HCC hepatocellular carcinoma, BCAA branched chain amino acids. (From ref. [100])
1069.Fig. 15.20: Comparison of ∆PMI/month in patients with L-carnitine supplementation and controls. Left: overall cohort, middle: males, right: females. L-carnitine supplementation significantly suppressed loss of skeletal muscle mass. Data were analyzed with the Mann-Whitney U test, and shown as mean ± SD. Asterisk indicates a statistically significant difference (*P < 0.05, **P < 0.01). PMI psoas muscle mass index (cross-sectional area of psoas muscle at L3 level of CT image). (From ref. [100])
1070.Fig. 15.21: Comparison of ∆PMI/month in patients with L-carnitine supplementation and controls in subgroup stratified according to BCAA supplementation. PMI psoas muscle mass index (cross-sectional area of psoas muscle at L3 level of CT image), BCAA branched chain amino acids. (From ref. [100])
1071.Fig. 15.22: Comparison of ∆PMI/month in patients with L-carnitine supplementation and controls in subgroup stratified according to patients with L-carnitine who did not experience an ammonia decrease (left), and patients with L-carnitine who experienced an ammonia decrease (right). Data were analyzed with the Mann-Whitney U test, and shown as mean ± SD. Asterisk indicates a statistically significant difference (*P < 0.05. **P < 0.01). PMI: psoas muscle mass index (cross-sectional area of psoas muscle at L3 level of CT image). (From ref. [100])
1072.Fig. 15.23: Carnitine deficiency and liver cirrhosis. (From ref. [101])
1073.Fig. 15.24: Effects of L-carnitine and α-tocopherol on preventing hepatocarcinogenesis. (a) Control group developed numerous tumors on the liver surface, while groups receiving L-carnitine or α-tocopherol developed fewer tumors. (b) Number of tumors was significantly lower in the L-carnitine group. In the α-tocopherol group, the average tumor number and size were not reduced. (c) Histological findings showed that the tumors are hepatocellular carcinoma. Data are expressed as means ± SD. *P < 0.05. (from ref. [119])
1074.Fig. 15.25: Treatment with L-carnitine (CAR) prevents hepatic steatosis following high-fat diet (HFD) feeding in KK-Ay mice. Representative photomicrographs of liver histology in mice after 4 weeks of feeding with control chow (a), 4-week HFD (b), and 8-week HFD (c). (d) Eight-week HFD with L-carnitine for the latter 4 weeks (hematoxylin-eosin staining, original magnification × 100). Liver/body weight ratio (e), and the average levels of serum aspartate aminotransferase (AST) (f) and alanine aminotransferase (ALT) (g) are plotted (mean ± standard error of mean) (n = 5; *P < 0.05 vs. controls; †P < 0.05 vs. 4 week HFD; #P < 0.05 vs. 8 week HFD alone, by analysis of variance (ANOVA) on ranks and Student-Newman-Keuls post-hoc test). (From ref. [121])
1075.Fig. 15.26: Carnitine and carnitine ester hepatic contents. Total liver carnitine (TC), free carnitine (FC), long-chain acylcarnitine (LCAC), and short-chain acylcarnitine (SCAC) in liver specimens of 16 control subjects and 26 patients with NASH. NS not significant. (From ref. [130])
1076.Fig. 15.27: Activity of the mitochondrial respiratory complexes (MRC) in liver specimens of 11 control subjects and 18 patients with NASH. Enzyme activities are expressed as nmol × min−1 × mg protein −1 × 100/nmol × mg protein−1 CS ([complex/CS] × 100). CS citrate synthase. (From ref. [130])
1077.Fig. 16.1: Change in end-diastolic volume (left) and end-systolic volume (right) from baseline (hospital admission) to hospital discharge (3, 6, and 12 months) in the two treatment groups. Both groups received conventional treatment, and carnitine group was treated with intravenous carnitine infusion (9 g/day, for 5 days) and then oral carnitine (6 g/day, for 12 months). Mean ± 95% confidence interval. (From Refs. [30, 31], modified)
1078.Fig. 16.2: A typical case of ventricular premature beats during hemodialysis in a 40-year-old female with 2.7-year history of hemodialysis (Case 4). Ventricular premature beats during hemodialysis were shown on a histogram as the number per minute (a part of the trend chart automatically analyzed by DYNA-GRAM Holter scanner Model 6000). HR heart rate, VPB ventricular premature beat, FFA free fatty acid. (From Ref. [43])
1079.Fig. 16.3: Effects of L-carnitine on arrhythmias during hemodialysis. Values were represented as mean ± SD. A Student’s t-test was used for the significance of changes, compared with the control. X: number of ventricular or supraventricular premature beats during hemodialysis. Cont control. (From Ref. [43])
1080.Fig. 16.4: Metabolite profiling identifies markers of cardiovascular death in end-stage renal disease (ESRD). (a) The mean ratio of each analyte for cases (n = 100) vs. controls (n = 100) in baseline plasma, with P values plotted on the y axis. The four metabolites that reached the Bonferroni significance threshold of P < 0.0003 are shown in black circles. (b) Median peak areas for oleoylcarnitine, linoleylcarnitine, palmitoylcarnitine, and stearoylcarnitine for cases and controls. Box plots show 75th and 25th percentiles; whiskers show 95th and 5th percentiles. (From Ref. [57])
1081.Fig. 16.5: Plasma levels of free L-carnitine, carnitine precursors, and derivatives (μmol/L) in HF patients (n = 183) and healthy controls (CTR, n = 111). In HF patients, the carnitine composition is also given in relation to clinical disease severity as assessed by NYHA classification and etiology (CAD vs. DCM). Data are given as mean ± SEM. *p < 0.001 vs. controls and adjusted by age. BMI and gender distribution. †p < 0.05, ††p < 0.01, and †††p < 0.001 vs. NYHA II. ‡P < 0.05 vs. NYHAIII. The p-value to the left denotes the result of the Kruskal–Wallis test comparing NYHA II/III/IV. (Note: original reference described “†p < 0.05, ††p < 0.01, and †††p < 0.01 vs. NYHA II” but the italic part supposed to be a mistake of “†††p < 0.001 vs. NYHA II”). HF heart failure, CRT control, CAD coronary artery disease, CMP dilated cardiomyopathy (DCM), NYHA New York Heart Association classification for heart failure. (From Ref. [58], modified)
1082.Fig. 16.6: Association between plasma levels of the carnitine derivative palmitoylcarnitine and serious adverse events (i.e., all-cause mortality and heart transplantation, n = 49) in patients with heart failure. Kaplan–Meier curves showing cumulative incidence of serious adverse events during the entire study (mean follow-up 34 ± 16[SD] months), according to dichotomized palmitoylcarnitine levels (cut-off median: 0.09 μmol/L). (From Ref. [58])
1083.Fig. 16.7: The glucose/fatty acid cycle. Glucose and fatty acid are the major sources of cardiac energy production. The glucose/fatty acid cycle describes the reciprocal relationship between fatty acid and glucose metabolism. Acetyl-CoA and NADH produced from fatty acid β-oxidation can inhibit the pyruvate dehydrogenase (PDH) complex (1). Citrate derived from fatty acid β-oxidation-derived acetyl-CoA inhibits phosphofructokinase-1 (PFK-1), the rate determining step of glycolysis, which in turn can lead to an inhibition of hexokinase by glucose-6-phosphate (G-6-P) (2). Increasing the contribution of glucose oxidation to the generation of acetyl-CoA decreases fatty acid β-oxidation via feedback inhibition of 3-ketoacyl-CoA thiolase; in addition, NADH derived from glucose oxidation can decrease fatty acid β-oxidation via feedback inhibition of both acyl-CoA dehydrogenase and 3-hydroxyacyl-CoA dehydrogenase reaction (3). (From Ref. [62])
1084.Fig. 16.8: Alterations in myocardial energy substrate metabolism in ischemia/reperfusion. During ischemia, glycolysis becomes an important source of ATP production in response to a decrease in supply of oxygen, or in the absence of oxygen (1). Fatty acid dominate as the substrate for residual oxidative metabolism due to increased plasma level of fatty acids (2) as well as the activation of 5′-adenosine monophosphate activated protein kinase (AMPK) which decreases the production of malonyl-CoA, the endogenous inhibitor of carnitine palmitoyl-transferase-1 (CPT1) (3). During reperfusion, glycolysis rates remain high, while fatty acid oxidation dominates over glucose oxidation as the main source of oxidative metabolism. The dominance of fatty acid oxidation during reperfusion inhibits glucose oxidation (4). The uncoupling of glycolysis from glucose oxidation leads to increased proton production, which ultimately leads to myocardial acidosis and calcium overload (5). (From Ref. [62])
1085.Fig. 16.9: (a) Efficacy evaluated as change in NYHA class in low AC/FC patients (left) and high AC/FC patients (right). Median values were measured at baseline for the whole study cohort. Data are shown as n (%). (b) Efficacy evaluated as 6-min walk distance (m) in low AC/FC patients and high AC/FC patients. 6-min walk distance changes are shown as mean ± SE. P-values calculated by logistic regression. LC L-carnitine, AC acylcarnitine, FC free carnitine. (From Ref. [70], modified)
1086.Fig. 16.10: Effect of L-carnitine on survival in the Dahl salt-sensitive rats. Kaplan–Meier survival curves in the HFpEF (closed circles, n = 16) and carnitine groups (open triangle, n = 16). HFpEF heart failure with preserved ejection fraction. (From Ref. [73])
1087.Fig. 16.11: Possible mechanism of the anti-fibrotic effect of carnitine. The beneficial effects of carnitine on left ventricular stiffening are likely provided through enhanced provision of arachidonic acid with upregulation of FADS1 and FADS2, which might be mediated through Nrf2 activation with L-carnitine (dotted arrows), and subsequent promotion of the production of prostacyclin, which suppresses pathological collagen production and prevents left ventricular stiffening. FADS fatty acid dismutase, Nrf2 nuclear factor erythroid 2-related factor 2 (see Chap. 7). (Created using as Refs. [73, 74])
1088.Fig. 16.12: Comparison of cardiac event rates according to the acylcarnitine to free carnitine ratio. Kaplan-Meier analysis for cardiac event rates. (a) All heart failure patients (n = 168); (b) heart failure with preserved ejection fraction patients (n = 79); and (c) heart failure with reduced ejection fraction patients (n = 89). (From Ref. [77])
1089.Fig. 16.13: Effect of carnitine insufficiency on clinical outcomes. Event-free survival rate in patients with or without carnitine insufficiency. Patients with carnitine insufficiency (44.4% of total patients) were defined as the lowest quantile of free carnitine level (<56.3 μmol/L) or the highest quantile of the acylcarnitine to free carnitine ratio (≥0.35). (From Ref. [79])
1090.Fig. 16.14: Prevalence of skeletal muscle weakness in patients with and without carnitine insufficiency. (From Ref. [82])
1091.Fig. 16.15: Effect of the two treatments (placebo and L-carnitine) on absolute claudication distance in intermittent claudication patients during the entire study period. The effects of placebo or L-carnitine(oral administration, 2 g/day, divided 2 times, for 3 weeks) were studied in double-blind, cross-over manner. Note the sharp increase in walking capacity whenever L-carnitine is given. Data are expressed as mean ± SD. *Different from baseline value, P < 0.01, B: baseline value (after washout period), C: end of L-carnitine period, P: end of the placebo period. (From Ref. [96])
1092.Fig. 16.16: Effect of placebo, L-carnitine 500 mg (LC 500) and L-propionylcarnitine 600 mg (LPC 600) on the claudication distance. (a) initial claudication distance. (b) absolute claudication distance. Note that the effect with LPC 600 is significantly greater than that with LC 500. Drugs were administered before 30 min of treadmill test (single, intravenous administration). (From Ref. [111])
1093.Fig. 16.17: Description in TASC II about L-carnitine and propionyl-L-carnitine for the treatment of claudication. TASC II: Inter-society consensus for the management of peripheral arterial disease (TASC II). (From Refs. [113–115])
1094.Fig. 17.1: Pathogenetic mechanisms of influenza encephalopathy/encephalitis and new treatment proposed by Dr. Y. Kuroda et al. Patients with influenza encephalopathy had a basis of carnitine deficiency, which was supposed to cause deterioration of energy metabolism in the brain. So, Dr. Kuroda proposed oral L-carnitine administration in addition to conventional treatments in his article because, at that time, only oral L-carnitine was available. Now, intravenous L-carnitine is available and suitable in the acute and comatose state of patients with influenza encephalopathy. CPT2 carnitine palmitoyltransferase 2, VPA valproic acid, TNF-α tumor necrosis factor-α, IL-6 interleukin 6. (Created using Ref. [6])
1095.Fig. 17.2: Effects of L-carnitine on disease progression. Non-Tg and Tg littermates were allowed free access to either tap water or L-carnitine-containing water (1 mg/mL) from the age of 16 weeks. Proportions without disease onset were plotted with Kaplan-Meier curves, and differences between Tg and Tg groups treated with L-carnitine were tested by the log-rank test (P = 0.0008). Tg: transgenic mice carrying a human SOD1 gene with the G93A mutation. (From Ref. [15])
1096.Fig. 17.3: Effects of L-carnitine on disease progression. Motor function in the hind limbs was scored at the age of 33 weeks using a rating scale. Values are means ± SD. *P < 0.01 versus Tg. (From Ref. [15])
1097.Fig. 17.4: Apoptotic cell death in hind limb muscles. Non-Tg and Tg littermates were treated as in Fig. 17.3. At the age of 33 weeks, gastrocnemius muscle samples were stained by the TUNEL method, and the number of TUNEL-positive cells was counted. Values are means ± SD (n = 4). *P < 0.01 versus Tg. (From Ref. [15])
1098.Fig. 17.5: Effects of L-carnitine on survival. Non-Tg and Tg littermates were treated as in Fig. 17.3. Proportions of survival were plotted with Kaplan-Meier curves, and the difference between Tg and Tg animals treated with L-carnitine was tested by the log-rank test (P = 0.0001). (From Ref. [15])
1099.Fig. 18.1: The flow chart of diagnosis of carnitine deficiency. Left: In this case, it is possible to diagnose by blood carnitine 2 fractions test and clinical manifestation or signs. Right: When there are time constraints, or it is impossible to diagnose with blood carnitine 2 fractions test, administer carnitine preparations and judge by the responses (therapeutic diagnosis). (From Ref. [1])
1100.Fig. 18.2: Flow chart of diagnosis and treatment of carnitine deficiency by blood carnitine 2 fractions test. AC acylcarnitine, CRRT continuous renal replacement therapy, FC free carnitine, TPN total parenteral nutrition. (From Ref. [1])
1101.Fig. 18.3: Time-course of plasma free carnitine levels in chronic hemodialysis patients (6 female, 6 male, total 12 patients) when L-carnitine was administered intravenously (20 mg/kg, 3 times a week), after each dialysis session (weeks 3–10) and for 6 weeks after cessation of L-carnitine administration (in 6 of 12 patients only). (From Ref. [23])
1102.Fig. 19.1: Scheme to promote the development of off-label drugs and unapproved drugs through “Price maintenance premium” in Japan. *Chuikyo: Central Social Insurance Medial Council, **MHLW: Ministry of Health, Labour and Welfare. (From Medical Representatives’ training materials, Distribution Optimization Committee, Japan Pharmaceutical Manufacturers Association)
1103.Table 3.1: Main B group vitamins and enzymes to which these vitamins bound
1104.Table 3.2: Structure, systematic name, common name, and acyl group of main organic acids and fatty acids
1105.Table 3.3: Biochemical and physiological functions of L-carnitine
1106.Table 3.4: Estimation of the amount of ATP consumption in human
1107.Table 3.5: Energy consumption of various organs
1108.Table 3.6: Number of ATP generated in glycolysisa
1109.Table 3.7: Enzymes inhibited by various acyl-CoA
1110.Table 3.8: Acronyms, names, subcellular localization, acyl-chain specificity, and malonyl-CoA sensitivity of various carnitine acyltransferases
1111.Table 4.1: The distribution of carnitine into the primary sites of carnitine storage in human body for a 70 kg adult
1112.Table 4.2: Carnitine contents in vegetables, potatoes, and avocado (mg/100 g of eatable parts)
1113.Table 4.3: Carnitine contents in seafood (mg/100 g of eatable part)
1114.Table 4.4: Carnitine contents in birds, animal meat, egg, cow milk, and soymilk (mg/100 g of eatable parts)
1115.Table 4.5: Carnitine contents in various animal meat (mg/100 g of eatable parts)
1116.Table 4.6: Organ distribution of activities of four biosynthesis enzymes of carnitine
1117.Table 5.1: Classification of carnitine deficiency by etiology
1118.Table 5.2: Common features of fatty acid oxidation disorders
1119.Table 6.1: Effects of bicarnesine on 22 cases of infant subjects
1120.Table 6.2: Effects of bicarnesine on 19 infant subjects older than 2 years old
1121.Table 6.3: Effects of bicarnesine on preterm infants
1122.Table 6.4: Classification of infant cases and number of cases by age
1123.Table 6.5: Changes in gastric fluid volume, free acidity, and total acidity after administration of histamine or bicarnesine in 10 subjects without gastric disorders
1124.Table 6.6: Changes in pancreatic juice volume, pancreatic lipase and trypsin activity in healthy subjects administered bicarnesine
1125.Table 6.7: Pharmaceutical products of DL-carnitine sold in Japan in the past
1126.Table 7.1: ecNOS and HO-1 gene (A) and protein expression (B) in human umbilical endothelial cells incubated with H2O2 alone and with H2O2 and L-carnitine, or acetyl-L-carnitine, or propionyl-L-carnitine
1127.Table 8.1: Carnitine content and distribution of various tissues and organs of the human body
1128.Table 9.1: Total choline content (mg) in 100 g of various foods
1129.Table 9.2: Total trimethylamine (TMA) contents in various fishes and urinary excretion rate
1130.Table 10.1: Subcellular localization, substrate specificity, and structure of acyl-CoA dehydrogenases in mitochondrial β-oxidation of long chain fatty acids
1131.Table 10.2: Characteristics of main urea cycle disorders
1132.Table 10.3: Main points of carnitine supplementation in metabolic emergency
1133.Table 10.4: Main points of L-carnitine supplementation in inherited metabolic diseases (1)
1134.Table 10.5: Main points of L-carnitine supplementation in inherited metabolic diseases (2)
1135.Table 10.6: Main points of L-carnitine supplementation in inherited metabolic disorders (3)
1136.Table 10.7: Classification of mitochondrial abnormalities by functions
1137.Table 11.1: Case reports of carnitine deficiency with specific milk and tube feeding
1138.Table 11.2: Main products of enteral nutrition in Japan and their carnitine content
1139.Table 11.3: Types of concentrated liquid foods and patient burden in Japan
1140.Table 11.4: Patient background of carnitine deficiency of 13 infants and children with severe physical and mental disabilities undergoing long-term tube feeding
1141.Table 11.5: Laboratory findings at the time of diagnosis of carnitine deficiency
1142.Table 11.6: Abnormal laboratory findings due to hypocarnitinemia
1143.Table 11.7: Background of 29 patients with intractable neurological diseases such as muscular dystrophy and ALS
1144.Table 11.8: Duration of tube feeding and serum-free carnitine concentrations in 29 patients with intractable neurological diseases such as muscular dystrophy and ALS
1145.Table 11.9: Classification of specific milk in Japan
1146.Table 11.10: Case reports of carnitine deficiency caused by Specific milks such as milk for allergies in Japan
1147.Table 12.1: History of clinical application of valproic acid
1148.Table 12.2: Clinical studies on the concentrations of total carnitine, free carnitine, and acylcarnitine in patients treated with valproate
1149.Table 12.3: Risk factors for carnitine deficiency
1150.Table 12.4: Results before and after carnitine therapy for 20 patients with two or more risk factors for carnitine deficiency
1151.Table 12.5: Hepatic survival in the L-carnitine-treated and untreated groups
1152.Table 12.6: Metabolic functions of carnitine
1153.Table 12.7: Clues favoring an underlying metabolic abnormality in patients with epileptic encephalopathies or seizures
1154.Table 12.8: Recommendations for carnitine administration
1155.Table 12.9: Prevalence of valproate-treated hyperammonemia in prospective studies (3 reports) and cross-sectional studies (14 studies)
1156.Table 12.10: Clinical characteristics of VHE cases in psychiatric patients
1157.Table 12.11: L-carnitine supplementation therapy for patients with VPA-induced hyperammonemia in psychiatric setting
1158.Table 12.12: Effect of carnitine on valproate-induced asymptomatic hyperammonemia in 12 patients with psychiatric disorder or dementia aged 65 years and older
1159.Table 12.13: Patients background of 10 psychiatric patients with hyperammonemia during valproic acid administration
1160.Table 12.14: Description of carnitine administration for hyperammonemia due to valproic acid poisoning in the Washington Manual
1161.Table 13.1: Pivoxil-containing antibiotics current and past on the market in Japan (as of April 2022)
1162.Table 13.2: Case reports of carnitine deficiency caused by pivoxil-containing antibiotics in Japan
1163.Table 14.1: Plasma carnitine concentration in patients with conserved period of renal failure, dialyzed patients with renal failure and healthy control group
1164.Table 14.2: Plasma and muscle carnitine concentration and dialysate loss in hemodialysis, peritoneal dialysis, and CAPD patients
1165.Table 14.3: Change in plasma carnitine concentration in patients with end-stage renal disease on dialysis therapy (μmol/L)
1166.Table 14.4: Change in muscular carnitine concentration in patients with end-stage renal disease on dialysis therapy (μmol/g)
1167.Table 14.5: Simple linear regression analysis to determine the association of clinical parameters with primary outcomes
1168.Table 14.6: Simple linear regression analysis to determine the association of clinical parameters with secondary outcomes
1169.Table 14.7: Major clinical studies investigating the effect of carnitine supplementation on muscle symptoms and QOL in dialysis patients
1170.Table 14.8: Effect of intravenous carnitine supplementation on hypotension, cramps, and asthenia during dialysis
1171.Table 14.9: Studies of effects of L-carnitine on cardiac function, arrhythmias, and hypotension in dialysis patients
1172.Table 14.10: rHuEPO dose, globular osmotic fragility, plasma erythropoietin, and carnitine levels in carnitine and placebo groups at the beginning (T0) and (T6) of the study
1173.Table 14.11: Proportion of patients receiving carnitine supplementation therapy for more than 3 months for dialysis patients with ESA-resistant anemia in European countries
1174.Table 14.12: Steinman’s criticism for carnitine supplementation therapy in dialysis patients and Schreiber’s rebuttal for it
1175.Table 14.13: Proportion of kidney transplantation in patients with ESRD in each country
1176.Table 15.1: Serum carnitine levels in patients with alcohol-induced liver disease
1177.Table 15.2: Proposed pathogenetic mechanisms of hepatic encephalopathy
1178.Table 15.3: Causes of hyperammonemia in patients with cirrhosis
1179.Table 15.4: Protective effect of L-carnitine on acute ammonia intoxication in mice
1180.Table 15.5: Effect of L-carnitine pretreatment on the incidence of ammonia-induced encephalopathy and on mortality in PCS rats
1181.Table 15.6: Effect of carnitine administration on cirrhotic patients with mild and moderate hepatic encephalopathy
1182.Table 15.7: Effect of L-carnitine on cramps and ammonia levels in patients with cirrhosis
1183.Table 15.8: Independent factors related to QOL and sleep disturbances
1184.Table 15.9: Therapeutic efficacy of monotherapy with L-carnitine for muscle cramps after excluding cases without data of second interviewing
1185.Table 15.10: Effects of L-carnitine in overall HCC patients who received TACE
1186.Table 15.11: Calculation of CONUT (controlling nutritional status score) score
1187.Table 15.12: Effects of L-carnitine treatment for cirrhotic sarcopenia patients on clinical variables
1188.Table 15.13: Laboratory parameters in patients treated with placebo plus diet or L-carnitine plus diet before and after 24 weeks of treatment
1189.Table 15.14: Histological data in patients treated with placebo plus diet or L-carnitine plus diet before and after 24 weeks of treatment
1190.Table 16.1: Changes in creatine kinase-MB (CK-MB) and troponin-I (TnI) after percutaneous coronary intervention
1191.Table 16.2: Premature ventricular beats and ventricular tachycardia in the placebo and L-carnitine groups
1192.Table 16.3: Number of patients with premature ventricular beats during the first and second day of treatment (placebo or L-carnitine)
1193.Table 16.4: Levels of carnitine and acylcarnitine in human left ventricular papillary muscle
1194.Table 16.5: Carnitine levels and CPT activities in normal controls and end-stage congestive heart failure patients
1195.Table 16.6: Toxic properties of long-chain fatty acid esters
1196.Table 16.7: Efficacy according to change in NYHA classification in the per protocol population
1197.Table 16.8: Changes of echocardiography indices following treatment in the control group and experimental group
1198.Table 16.9: Echocardiography indices after treatment of the control group and carnitine group for 1 year in children with dilated cardiomyopathy
1199.Table 16.10: Individual metabolites of long-chain acylcarnitine means and comparisons between HFpEF, HFrEF, and No-HF controls
1200.Table 18.1: Comparison of enzyme cycling method and tandem mass method for carnitine measurement in Japan
1201.Table 18.2: Precautions for insurance coverage of blood carnitine 2 fractions test using enzyme cycling in Japan
1202.Table 18.3: Reference values for carnitine measurement by enzyme cycling method (blood carnitine 2 fractions test)
1203.Table 19.1: History of important clinical research on carnitine and its approvals in overseas (mainly in the United States) and in Japan
1204.Table 19.2: Status of approvals of off-label drugs and unapproved drugs covered in “Formulation of Priority List of Off-Label Drugs and Unapproved Drugs in the Field of Inherited Metabolic Diseases” in Japan (as of the end of August 2022)
