How To Take Creatine

Creatine Practical Guide.

Creatine: A practical guide evolved from the thousands of questions asked by professional and amateur athletes from around the globe. Learn How To Most Effectively Combine Exercise, Nutrition And Smart Creatine Use For Explosive Muscle Growth And Improved Overall Health. Here is just a small sampling of the many questions addressed by this e-book How long can I keep creatine on the shelf? Will I lose muscle after I stop supplementing? Not all creatine brands recommend the same amount. What gives? Is mixing creatine with protein powder a bad idea? Why do so many creatine brands contain so much dextrose? Is loading really necessary? Im currently taking Accutane for nodular acne. Is it safe for me to supplement? Will creatine stunt my growth? Im training twice as much these days and Im still not making any gains! Why? If creatine isnt a steroid, then how come it gave me a positive doping result? Will creatine shrink my package?!

Creatine Practical Guide Overview

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Creatine

Historical note Creatine was first discovered in 1832 when it was identified in meat. The word creatine is derived from the Greek kreasior flesh, similar to the word 'creature'. About 1 5 years later, the meat from foxes killed in the wild were found to have 1 0-fold more creatine than meat from domesticated foxes, suggesting that physical exercise must influence the amount of creatine that accumulates in muscles. Early last century orally consumed creatine was shown to be partly retained in the body and able to increase creatine content in muscles, leading some to suspect this could influence the performance of muscles. Nowadays, creatine monohydrate enjoys enormous popularity as a sports supplements and is being recommended to elite athletes by respected sporting bodies such as the Australian Institute of Sport (AIS).

Background And Relevant Pharmacokinetics

Creatine is a naturally occurring nitrogenous compound produced in the human liver, pancreas and kidneys at a rate of 1-2 g daily. It is synthesised from the amino acids glycine, arginine and methionine and stored primarily in skeletal muscle, where it is in dynamic equilibrium with phosphocreatine and is a precursor to adenosine triphosphate (ATP), the main source of energy for muscle activity and many other biological functions. Orally ingested creatine is absorbed from the small intestine, then distributed via creatine transporters around the body to muscles and nerves (Persky et al 2003). These transporters also serve as a clearance mechanism because of creatine 'trapping' by skeletal muscle. It is ultimately converted to creatinine and excreted by the kidneys.

Congestive Heart Failure

Muscle fatigue due to loss of skeletal muscle mass and strength, decreased oxidative capacity and other abnormalities of muscle metabolism have been associated with congestive heart failure. As a result, creatine supplementation has been suggested as a possible therapeutic agent in this condition. A dose of 10 g creatine daily for 7 days significantly increased exercise capacity and muscle strength compared to placebo in a double-blind study involving 17 men with congestive heart failure (Gordon et al 1995). However, creatine supplementation did not alter ejection fraction at rest or at work. Muscle endurance during handgrip exercises was also seen to improve in another double-blind, crossover study of 20 men given 5 g creatine four times daily for 5 days (Andrews et al 1998).

Neurological Degenerative Diseases

Over the past few years, a considerable body of scientific evidence has given support to the idea that creatine supplementation may alleviate some of the clinical symptoms of neurological disease and delay disease progression (Wyss & Schulze 2002). Studies conducted in both animal models of neurodegenerative disease and humans have produced mixed results. Huntington's disease A number of studies conducted with experimental animal models of Huntington's disease have identified a possible role for creatine supplementation (Andreassen et al 2001, Dedeoglu et al 2003, Ferrante et al 2000). Creatine was shown to increase survival, delay onset of symptoms and exert neuroprotective effects in vivo. Motor neuron disease A preliminary study demonstrated that creatine supplementation of 20 g daily for 7 days followed by 3 g daily for 3 and 6 months produced temporary increases in maximal isometric power in patients with MND (Mazzini et al 2001). More recently, two randomised, double blind,...

MR Spectroscopy Quantification and Analysis

There is no agreement on which method should be employed in which cases, but use of a reference has become an established method, at least as a significant set of results. There are several signals that can be used as a reference historically, creatine has been used as a reference, as in the majority of the neurological diseases studied with 1H-MRS the Cr concentration has been shown to be constant up to the reliability of the method. On the other hand, a mounting body of findings where Cr is not constant is leading to the exploration of further reference markers. One of these markers is the internal water signal. Since the mmol concentration of water from healthy brain tissue is known, the metabolite signal can be normalized using the water signal as a reference. This method has disadvantages, as it does not take atrophy into consideration, even though there

Specific Enzymes Act As Markers Of Compartments Separated By The Mitochondrial Membranes

Mitochondria have an outer membrane that is permeable to most metabolites, an inner membrane that is selectively permeable, and a matrix within (Figure 12-1). The outer membrane is characterized by the presence of various enzymes, including acyl-CoA synthetase and glycerolphosphate acyltransferase. Adenylyl kinase and creatine kinase are found in the intermembrane space. The phospholipid cardiolipin is concentrated in the inner membrane together with the enzymes of the respiratory chain.

The MEF2 Transcription Factors

The interaction of the class IIa HDACs with members of the MEF2 family of transcription factors is by far the best characterized in terms of biological significance. The fairly well-defined roles thought to be played by the class IIa HDACs in myogenesis, cardiac hypertrophy, and T-cell development are all mediated by MEF2 family molecules. In vertebrates, there are four MEF2 family members, MEF2A, -B, -C, and -D. In an intriguing parallel to the evolution of the class IIa HDACs, only one member of the MEF2 family occurs in Drosophila and C. elegans (reviewed in ref. 10). They were originally isolated from skeletal muscle as factors binding to AT-rich DNA motifs in the promoter of the muscle creatine kinase (MCK) gene (11). Whereas MEF2A, -B, and -C are all restricted to some degree in their expression patterns, MEF2D appears to be ubiquitously expressed (reviewed in ref. 12). The MEF2 family members share a highly conserved MADS domain, as well as a unique MEF2 domain. These two...

Regulation And Posttranslational Modifications Of Class Iia Hdac Activity

The most important feature of the class IIa HDACs is their extensive non-catalytic domains that comprise multiple distinct targeting and regulatory modules. These modules allow extracellular signals to regulate the association with and repression of specific promoters by class IIa HDACs (Fig. 3). By far the best understood instance of this regulatory function is the activation of MEF2 target genes through signal-dependent dissociation of class IIa HDACs. These genes include molecules involved in multiple signal-dependent pathways of cellular differentiation. Genes regulating muscle differentiation (e.g., myogenin, muscle creatine kinase, and MRF4), genes involved in thymic selection of T cells (e.g., Nur77), and genes involved in the regulation of Epstein-Barr virus (EBV) latency (e.g., ZEBRA), are all regulated through MEF2-binding sites in their promoters (reviewed in ref. 10). Although the biological contexts and significance of the regulation of each of these target genes are...

Forensic and Chemical Warfare Toxicology

An example from the drug-doping arena is a report on the use of 1H NMR for measuring creatine in urine samples as a biomarker for the use ofillegal dietary supplements by French athletes 41 . Creatine is not typically measured in clinical laboratories, and common methods such as LC-MS and capillary electrophoresis require much sample preparation. The detection limits by NMR were 1.31 mg L-1, and the analysis of untreated urine samples took less than 10 min. Although forensic toxicology reports are scarce, it is evident that some forensic laboratories have access to conventional NMR systems.

Metabolic and Genetic Profiling

Publications on metabolic markers relating to genetic strain differences and disorders in rodents have been reported 11, 52 , and these applications will increase rapidly in the next decade, particularly with the integration of genomic, proteomic, and metabonomics techniques. 1H NMR and pattern recognition was used to examine the mdx mouse as a model of the muscle-wasting disease Duchenne muscular dystrophy (DMD) in which the muscle protein dystrophin is not expressed. Dys-trophic mouse brain and cardiac tissue extracts showed distinct metabolic profiles with altered ratios of creatine, taurine, and choline-containing metabolites. It was suggested that these ratios could be used to correlate cerebral deficits with metabolic abnormalities in DMD sufferers by using NMR in vivo 52 .

Conduction System

Pulmonary Artery Azygos Vein

Acute myocardial infarction (MI heart attack) most commonly is caused by atherosclerotic disease. It results from myocardial ischemia that induces cellular necrosis. Clinical findings include onset at rest (usually) a sensation of pressure or burning in the chest that lasts longer than 30 minutes pain radiating to the arm, jaw, and neck nausea or vomiting sweating shortness of breath and tachycardia. Mis may be silent and without consequence. Complications of MI include congestive heart failure papillary muscle rupture, indicated by acute onset of congestive heart failure with holosystolic murmur and life-threatening arrhythmias, common in the first 24 hours after Ml. Electrocardiogram (ECG) findings include ST segment elevation immediately after the Ml. Later, falling ST segments are observed, and Q waves and inverted T waves appear. Cardiac enzyme levels include elevated total creatine kinase (CK) and CK-2 fraction 6-12 hours after MI elevated troponin levels 12 hours after MI and...

Challenge Questions

A common feature of many eukaryotic mRNAs is the presence of a rather long 3' UTR, which often contains consensus sequences. Creatine kinase B (CK-B) is an enzyme important in cellular metabolism. Certain cells termed U937D cells have lots of CK-B mRNA, but no CK-B enzyme is present. In these cells, the 5' end of the CK-B mRNA is bound to ribosomes, but the mRNA is apparently not translated. Something inhibits the translation of the CK-B mRNA in these cells.

Pharmacological Toxicological Effects 51 Endocrine Effects

With respect to increasing exercise performance, Hsu and colleagues reported that ginseng attenuated the formation of creatine kinase induced by submaximal exercise in subjects undergoing a treadmill test (27). However, no increase in aerobic work capacity was noted. In a related study of exercise performance effects, Siberian ginseng administration had no effect on steady-state substrate utilization or any physiological measure in individuals undergoing prolonged cycling exercise (28). The study was conducted in a

Degree of Differentiation

Biochemical assays include analysis of creatine kinase (CK) isozymes. CK is composed of two subunits (CK-B and or CK-M). In proliferating myoblasts, only the CK-BB isoform is detected, and in differentiated normal adult muscle, the muscle CK-MM is almost the only isoform present. Intermediate stages contain a mixture of both isoforms together with the heterodimer CK-MB. The assays take advantage of the fact that during embryogenesis, regeneration and in vitro differentiation, the levels of the individual CK dimers present in the muscle cells gradually change 114, 136-138 . The percentage of CK-MM is a marker for the maturation grade. The highest percentages of CK-MM reported in aneurally cultured human myotubes and using optimized media were over 60 51, 139 , while in cultures with standard culture media, CK-MM percentages of 15 to 20 are usually reached 51 . The activity of CK and other enzymes such as cytochrome c oxidase, phosphorylase, citrate synthase and AMP deaminase also...

T Imaging of Brain Tumours

Proton MR spectroscopic imaging ('H-MRSI) is a non-invasive technique that provides metabolic information from living tissues 3, 4 . Of the main metabolites of interest, choline (Cho) is found to be increased in areas of active membrane turnover, as in brain gliomas N-acetylaspartate (NAA) is regarded as a marker of neuronal damage, destruction and or dysfunction, and it is decreased whenever neurons are replaced by other cells creatine (Cr) comprises signals from both phosphocreatine and creatine and is involved in energy metabolism and lactate and or lipids (LL) usually indicate necrosis 3, 4 . Several studies have demonstrated that 1H-MRSI can be used to guide surgical resection or biopsies, to define radiotherapy planning and monitor treatment effects, and to identify recurrence and progression of brain gliomas 3-10 .

Cardiac Protein Gene Expression

Biochemical markers of myocardial tissue, including creatine kinase mass and activity, CK-MB subunit mass and activity, and myoglobin levels can be used for identification of cultured cells, as well as the evaluation of cell de-differentiation. Spherical cardiomyocytes isolated from pediatric and adult myocardium are differentiated and can grow in vitro. Although these cells do not demonstrate spontaneous contractile activity in vitro, they possess many of the characteristics of normal cardiomyocytes in vivo. The properties include immunohistochemical staining, Northern blot analysis of cardiomyocyte-specific contractile proteins and biochemical assays of creatine kinase MB fraction activity and mass 21, 32 . These cultured cells do, however, undergo phenotypic modulation compared to their in vivo counterparts. In addition to the morphological changes, which include the formation of pseudopods and development of a stellate appearance, the intracellular contractile apparatus becomes...

Several Mechanisms Replenish Stores Of Atp In Muscle

The ATP required as the constant energy source for the contraction-relaxation cycle of muscle can be generated (1) by glycolysis, using blood glucose or muscle glyco-gen, (2) by oxidative phosphorylation, (3) from creatine Creatine Phosphate Constitutes a Major Energy Reserve in Muscle Creatine phosphate prevents the rapid depletion of ATP by providing a readily available high-energy phosphate that can be used to regenerate ATP from ADP. Creatine phosphate is formed from ATP and creatine (Figure 49-16) at times when the muscle is relaxed and demands for ATP are not so great. The enzyme catalyzing the phosphorylation of creatine is creatine kinase (CK), a muscle-specific enzyme with clinical utility in the detection of acute or chronic diseases of muscle.

Proton MRS in Neuroradiology

Proton magnetic resonance spectroscopy of the brain reveals specific biochemical information about cerebral metabolites, which may support clinical diagnosis and enhance the understanding of neurological disorders. Analysis of the resonance signals of low-molecular weight brain metabolites (concentrations in mmol) provides information on metabolite concentrations and makes it possible to correlate their modifications with various pathological conditions. The high diagnostic specificity of MRS enables the biochemical changes that accompany various diseases to be detected, as well as disease characterization, sometimes diagnosis, and monitoring. At 1.5 T the main metabolites detected vary according to the acquisition parameters (TR, TE) and type of pulse sequence adopted (STEAM, PRESS). 1.5 T brain MRS currently has a number of clinical applications, including the characterization of cerebral tumours and the monitoring of their treatment (e.g., radiation necrosis versus recurrence...

Other White Matter Diseases

In patients, the N-acetyl group (NA) creatine + phosphocreatine (Cr) ratios were decreased in both the GM of the posterior cingu-late gyrus and the precuneus, and the parieto-occipital WM regions. A decrease in the glutamate + glutamine (Glx) Cr ratio and a correlation between the NA Cr and Glx Cr ratios were detected in the GM, but not in the WM. NA and Glx metabolism are simultaneously affected in AD however, metabolic changes in Glx are more profound in the GM than in the WM Detection of early neurochemical changes in lesion formation prior to detection of abnormalities by conventional MRI. Creatine and choline containing compounds were the weakest markers of cerebral disease while N-acetylaspartate, glutamine, and lipids + lactate were the strongest

Brief Review Of Basic Aspects Of Nonconventional Mr Techniques

Magnetisation Transfer Weighted Images

Water-suppressed proton MR spectra of normal human brain at long echo times reveal four major resonances one at 3.2 ppm from tetramethylamines mainly from choline-containing phospholipids (Cho) , one at 3.0 ppm from creatine (Cr) and phosphocreatine, one at 2.0 ppm from N-acetyl groups (mainly NAA), and one at 1.3 ppm from the methyl resonance of lactate (Lac). NAA is a marker of axonal integrity, while Cho and Lac are considered as chemical correlates of acute inflammatory demyelinating changes (30). An immunopathologic study of MS (31) has indeed shown that a decrease in NAA levels is correlated with axonal loss, and an increase in Cho correlates with the presence of active demyelination and gliosis. 1H-MRS studies with shorter echo times can detect additional metabolites, such as lipids and myoinositol (mI), which are also regarded as markers of ongoing myelin damage. Therefore, 1H-MRS can complement conventional MRI in the assessment of MS patients by defining simultaneously...

Ginseng And The Cardiovascular System

Several Chinese workers have indicated that various ginseng saponins can reduce the size of myocardial infarction, the area of dead tissue developed after coronary occlusion has obstructed the blood flow to the cardiac muscles or myocardium. Experimentally this can be achieved by ligation of the left descending coronary artery (ca 40 min) and subsequent reperfusion (ca 120 min). In various animals (dogs, guinea pigs, rats and mice) Chen et al. (1981) observed that ginsenosides increased myocardial tolerance to hypoxia (oxygen deficiency), a decrease in myocardial oxygen consumption apparently occurring during hypoxia. The survival times for mice given ginseng extract intraperitoneally and subjected to hypoxia were prolonged (Lu et al., 1987). Ginsenosides have also been reported by other workers to protect mice against metabolic disturbances and myocardial damage associated with severe anoxia and anoxaemia (lack of oxygen in the tissues) (Yunxiang and Xiu, 1987). Myocardial necrosis...

Deficiency Signs And Symptoms

Several rare inborn errors of metabolism that result in a lack of creatine and phosphorylcreatine in the brain and severe mental retardation have been identified. Other symptoms and signs, such as involuntary extrapyramidal movements, speech People involved in intense physical activity, vegetarians and those with muscle diseases may have lowered creatine levels.

Crush Injurycrush Syndrome

Globin as opposed to hemoglobin, a microscopic examination of the brown urine will reveal an absence of red blood cells. The direct renal toxic effect of myoglobin and its secondary obstructive effects as it precipitates in the renal tubules play a critical role in the development of acute renal failure. An estimated 50 of the crush-injured patients with severe rhabdomyolysis will develop acute renal failure secondary to myoglobinemia. It is important to note that the degree of creatine phosphokinase elevation and the presence of myoglobinemia do not predict those who will go on to develop ARF. Other important factors include hypovolemia, metabolic acidosis, and age.

Abortive Complexes

Early product inhibition studies of Aerobacter aerogenes ribitol dehydrogenase5 demonstrated the formation of the E-NAD+-d-ribulose and E-NADH-d-ribitol complexes. In the lactate dehydrogenase reaction, the E-NADH-lac-tate and E-NAD+-pyruvate complexes are stable6, and determination of the Kd values indicates that the E-NAD+-pyruvate ternary complex is physiologically relevant7. Abortive complexes have been reported for a wide variety of enzymes. isotope exchange at equilibrium is used to identify the E-NADH-malate abortive with bovine heart malate dehydrogenase7. Creatine kinase forms an E-MgADP-creatine complex8. Inhibition at high substrate-product concentrations may arise from factors other than abortive complexes for example, the inhibition observed in an equilibrium exchange experiment may be related to high ionic strength of reaction solutions9.

Spectroscopy

MR spectroscopy (MRS) is becoming more commonplace in the routine evaluation of patients with intracranial masses as the software becomes more widely available and user-friendly on MR machines. Proton MRS can be practically implemented on any 1.5T MR system with clinically useful exam times, signal-to-noise, and spatial resolution. Higher field systems (e.g., 3.0 Tesla T ) provide the theoretical advantages of improved signal to noise, shorter exam times, and improved spectral resolution (peak separation). The actual improvements in signal-to-noise are closer to 20-50 resulting from greater line width at 3.0T as a result of greater field inhomogeneities and shorter T2 and T2* relaxation times (104,105). Certainly, most studies are performed at 1.5T. The most practical considerations affecting the visibility of metabolites in MR spectra are the relaxation times of the metabolites and the sequence parameters. In single voxel techniques, chemical-shift imaging, or 3D multivoxel...

Energy Production

Although the exact mechanism is unknown, much is known about the biochemistry of endogenous creatine. In skeletal muscle tissue, it is used for the production of phosphocreatine, an important form of high-energy phosphate. Phosphocreatine is broken down into phosphate and creatine during high intensity exercise lasting 1 5-30 seconds. During the process, energy is released and is used to regenerate ATP, the primary source of energy. Supplemental creatine Oral supplementation with creatine has been shown to increase phosphocreatine levels in muscles, and as such, has been described as 'fuelling up' natural energy stores. Increased creatine stores leads to faster regeneration of ATP, thereby making more energy immediately available to muscles. Theoretically, increased free creatine allows depleted stores to replenish more quickly, thus shortening recovery times during repeated bouts of intense exercise. Increased muscle creatine may also buffer the lactic acid produced during exercise,...

Neuroprotective

Creatine supplementation has displayed neuroprotective effects in several animal models of neurological disease, such as Huntington's disease, Parkinson's disease, or motor neurone disease (MND) (also known as amyotrophic lateral sclerosis) (Andreassen et al 2001, Dedeoglu et al 2003, Ferrante et al 2000, Wyss & Schulze 2002) and is currently being evaluated in early stage trials in Parkinson's disease and MND (Beal 2003). A number of theories of a possible mechanism for neuroprotection have been put forward. One theory proposes that creatine exerts antioxidant activity and mitochondrial stabilising effects, two mechanisms of benefit in neurodegenerative diseases, which are characterised by mitochondrial dysfunction and Creatine 331 oxidative damage (Shefner et al 2004).

Muscular Dystrophy

A number of muscle diseases are associated with a decrease in intracellular creatine concentration, which could theoretically contribute to muscle weakness and degeneration of muscle tissue (Wyss et al 1998). As a result, testing with creatine supplementation in a variety of muscle diseases has started. One double-blind, crossover study of 36 patients with various muscle diseases found that creatine supplementation over 8 weeks produced a mild but significant improvement in muscle strength and daily-life activities on Medical Research Council scales and the Neuromuscular Symptom Score (Walter et al 2000). A single-blind placebo-controlled trial of 21 volunteers with different neuromuscular disorders found that creatine supplementation (10 g daily for 5 days followed by 5 g daily for 5-7 days) produced significant improvements in body weight, handgrip, dorsiflexion, and knee extensor strength (Tarnopolsky et al 1997).

Case Analysis

On clinical grounds, was there sufficient information to support the diagnosis of an acute myocardial infarction The acute onset of heart failure with chest pain is presumptive evidence however, unstable angina pectoris may be associated with ventricular failure due to stunned myocardium (e.g. ischemia-induced contractile dysfunction without myocardial necrosis), and cannot be used as an absolute indicator of infarction. The electrocardiographic findings of ST elevation in the anterior leads V2-V5 are supportive of acute ischemia, but whether the ischemia was transient or associated with actual tissue damage cannot be determined from this information. The creatine kinase (CK) was within normal limits (22 U L). Does this mean there was no myocardial necrosis, or was the enzyme drawn too early in the course of events to be abnormal Creatine kinase is an intracellular enzyme that is only released into the interstitium from necrotic cells. It is then mobilized in the cardiac lymph, where...

Clinical Summary

S was 45 years old at the time of his death. He had smoked cigarettes for 25 years, had hypertension, and was a known non-insulin dependent diabetic (type II) controlled with oral hypoglycemic drugs. He was moderately obese, weighing 105 kg and 175 cm length (BMI 34 kg m2). He also had a history of illicit intravenous drug use with scarred veins in the antecubital fossa. He had clinical evidence of diabetic neuropathy, and peripheral vascular disease (intermittent claudication and sexual dysfunction). He was admitted to the hospital because of complaints of indigestion and progressive discomfort radiating to both arms. The presumptive diagnosis was acute inferior wall myocardial infarction, and he was treated with tissue plasminogen activator (TPA). The patient slowly became clinically stable after his creatine kinase (CK) peaked at 1555 U L. On medication, and 3 days later, he had a low level stress exercise ECG, which was negative for ischemia. He was discharged home with a plan...

Coenzyme

Synthesis of S-adenosyl-L-methionine (SAMe) A THF derivative is critical for the regeneration of methionine from homocysteine. The methyl group donated in this process is taken up by SAMe, which provides it with the ability to become a carbon donor in multiple transmethylation reactions throughout the body including the synthesis of adrenaline, melatonin and creatine (Hendler & Rorvik 2001). Amino acid metabolism Folate is involved in the synthesis of some of the nonessential amino acids such as serine and glycine. It is also required for the conversion of histidine into glutamate (Gropper et al 2005).

Antiinflammatory

Both a crude and a standardised extract (G11 5) of ginseng varying in saponin concentrations have been found to protect against muscle fibre injury and inflammation after eccentric muscle contractions in rats on a treadmill. The oral ginseng extracts significantly reduced plasma creatine kinase levels by about 25 and lipid peroxidation by 1 5 . Certain markers of inflammation were also significantly reduced (Cabral de Oliveira et al 2001). In a later study, pretreatment with ginseng extract (3, 10, 100 or 500 mg kg) administered orally for 3 months to male Wistar rats resulted in a 74 decrease in lipid peroxidation caused by eccentric exercise (Voces et al

Dose Escalation

Magnetic resonance spectroscopy (MRS) is a noninvasive imaging tool that can distinguish between tumor bearing regions, normal tissues, and necrosis based on the metabolic profile of the tissue. The three main cerebral metabolites are choline-containing compounds (Cho), the total creatine pool, and A-acetylaspartate (NAA). An increase in Cho containing compounds relative to NAA correlates closely with tumor infiltration a corresponding increase in creatine predicts for a malignant neoplastic process such as GBM. Researchers at the University of California San Francisco (UCSF) compared radiotherapy planning based on standard MRI to MRS for 34 patients with HGG (12). In their study, they found that metaboli-cally active tumor extended outside the T2 region in 88 of patients. Additionally, defining the boost volume as the T1-contrast enhancing region with a 2-cm margin missed metaboli-cally active tumor by as much as 2.8 cm.

Organ Toxicity

The main organ toxicities studied by NMR have been hepatotoxicity 2, 3, 9, 10 and nephrotoxicity 2, 3, 10 . Early studies identified taurine as a biomarker for liver damage and creatine for testicular damage 35 . Nicholson and coworkers have argued that it is not any single biomarker but rather a combination of altered metabolites which are significantly changed over time that constitutes a more predictive model of toxicity 2, 3, 9, 10 . Building on the above studies, one of the most systematic programs to date using NMR to construct databases and metabolic models of drug toxicity has been the COMET program, as outlined in Section 8.3.3.

Info

The side effects of intramuscular administration include pain, elevation of serum creatine phosphokinase as a result of trauma, and often sciatic nerve damage following gluteal injections. Other complications include skin pigmentation, hemorrhage, septic or sterile abscesses, cellulitis, muscular fibrosis, tissue necrosis, and gangrene.

MRI Studies

New Gd enhancing lesions mainly occur during the early relapsing phase of the disease, whereas Gd-enhancing lesions occur less frequently during the slowly progressive phase of the disease, characteristic of PPMS and SPMS without relapses (94). There are also progressive signal abnormalities in the so-called normal appearing'' white matter of MS patients. MRS reveals reduced NAA and elevated creatine levels in the NAWM of primary progressive MS (95,96), and magnetic transfer ratios are reduced in the NAWM of chronic versus relapsing disease (97). These changes have been interpreted as evidence of axonal destruction in the white matter plaques leading to secondary (Wallerian) degeneration (92,98,99). However, brain atrophy in MS is, in part, independent of T2 lesion load, suggesting that NAWM pathology not only reflects Wallerian degeneration of axons traversing macroscopic lesions, but also reflects microscopic or diffuse lesions not detected by MRI (100). Diffuse white matter damage...

Daptomycin

Although the antibiotic is reasonably well tolerated in current clinical studies, early experience with the antibiotic when administered every 8 hours suggested skeletal muscle toxicity. However, using a dosing schedule from every 12 to every 24 hours, elevated serum concentrations of creatine phosphokinase occur in only 2.8 of prospectively studied adults, compared to 1.8 of vancomycin-treated control patients. The mechanism of muscle toxicity is unknown, but current guidelines suggest following CPK concentrations on a weekly basis. Adverse events which occurred in greater than 5 of adults include constipation, nausea, headache, diarrhea, vomiting, and injection site reactions, although these side effects occurred in control patients with a statistically similar frequency (Stein, 2005 Tedesco and Rybak, 2004).

Case report

Examination revealed a heart rate of 90 beats min and a blood pressure of 92 70mmHg. The results of hematological and other blood chemical tests (Fig. 1) showed both liver and cardiac dysfunction (WBC, 10,800 mL asparate aminotransferase (AST), 1015IU L alanine aminotransferase (ALT), 829IU L lactate dehydrogenase (LDH), 2,691 IU L (LDH5> LDH1) and creatine kinase (CK), 284 IU L), and mild pericardial effusion was also detected by echocardiography. On December 22, the patient was diagnosed to have acute hepatitis, severe type (PT (prothrombin time), 14 HGF (hepatocyte growth factor), 20.5ng ml). He was treated with steroid pulse therapy (methylprednisolone 500 mg day for three days). In addition, plasma apheresis was also performed. On December 25, the symptoms disappeared and a chest X-ray revealed only mild cardiomegaly with neither pleural effusion nor congestion. On December 29, the CK level became elevated again (348 IU L) and an electrocardiogram (ECG) showed marked ST-T...

Calmodulin

Selected entries from Methods in Enzymology vol, page(s) Calmodulin purification and fluorescent labeling, 102, 1 assay of calmodulin by Ca2+-dependent phosphodiesterase, 102, 39 myosin light chain phosphorylation in smooth muscle and nonmuscle cells as a probe of calmodulin function, 102, 62 spectroscopic analyses of calmodulin and its interactions, 102, 82 Ca2+ binding to calmodulin, 102, 135 preparation of fluorescent labeled calmodulins, 102, 148 techniques for measuring the interaction of drugs with calmodulin, 102, 171 detection of calmodulin-binding polypeptides separated in SDS-polyacrylamide gels by a sensitive 125I calmodulin gel overlay assay, 102, 204 use of calmodulin affinity chromatography for purification of specific calmodulin-depen-dent enzymes, 102, 210 chemical approaches to the calmodulin system, 102, 296 13C chemical shift, 239, 369 contamination in creatine phosphokinase, 238, 76 removal of endogenous calmodulin, 238, 77 heteronuclear relaxation studies, 239,...

Glial Neoplasms

In recent years, the combination of 1H-MRSI, DWI and or PWI in addition to conventional MRI has improved the ability to differentiate solid tumour from other intratumoral or peritumoral components 33-36 . Most of these studies have been performed at a magnetic field strength of 1.5 T. We applied such a multiparametric MR approach using a 3 T MR scanner to better characterize the large heterogeneity of brain gliomas. We evaluated 30 patients, 20 with high- and 10 with low-grade gliomas, before undergoing surgery and histologic confirmation. Normalized metabolite signals, including choline (Cho), N-acetylaspartate (NAA), creatine (Cr) and lactate lipids (LL), were obtained by 'H-MRSI apparent diffusion coefficient (ADC) by DWI and relative cerebral blood volume (rCBV) by PWI. We carefully examined the regions of interest (ROIs) surrounding the enhanced margins of tumours (perienhancing ROIs) and those surrounding the non-enhancing tumours (peritumoral ROIs), identifying peculiar...

Critical Issues

Used to establish the feasibility of carrying out BNCT, based on the uptake and distribution of 18F-BPA within the tumor, and in the latter, to monitor the response to therapy. The possibility of using MRI for either 10B or 11B has been under investigation (197), and this may prove to be useful for real time localization of boron in residual tumor prior to BNCT. Magnetic resonance spectroscopy (MRS) and magnetic resonance spectroscopic imaging (MRSI) also may be useful for monitoring the response to therapy (198). Kojimoto and Miyatake et al. recently have used MRS to analyze the target specificity of BPA and the effects of BNCT in a group of 6 patients using multivoxel proton MRS (199). There was a reduction in the choline creatine ratio without a reduction of the N-acetlylaspartate creatine ratio at 14 d following BNCT, strongly suggesting that there was selective destruction of tumor cells and a sparing of normal neurons (199). Noninvasive procedures such as MRSI may be a powerful...

Reperfusion Injury

Picture Reperfusion Arrythmias

Indirectly accomplished by hemodynamic monitoring (pressures, cardiac outputs, echocardiography) and examining blood levels of cardiac enzymes (creatine kinase-MB fraction CK-MB , troponin I, lactate dehydrogenase LDH , and or aspartate transferase AST ). Ideally, left ventricular end-diastolic pressure-volume measurements would provide functional and quantitative information relative to the degree of reperfusion injury however, clinically such data are difficult and rarely feasible to obtain. On the other hand, myocardial viability can be assessed with inotropic stimulation as the postischemic stunned or the potentially reversibly injured myocardium will display an increased heart rate and contractility the irreversibly injured (necrotic) myocardium exhibits little to no response to the inotrope (e.g., by dopamine stress echocardiography). Note that, by definition, myocardial stunning is reversible therefore, within days, a depressed cardiac function caused by stunning should recover...

Genitourinary System

Considering the frequency of urinary disorders in older men, it is not surprising that the majority of urology patients are in their fifties or older. Shrinkage of the kidneys, loss of elasticity and capacity by the bladder, and enlargement of the prostate gland combine to increase the frequency of urination, cause urination to be less complete and bladder control to be lost, as well as other urological disorders. Reductions in the number of functioning excretory units (glomeruli) and, consequently, lower renal blood flow and a lower filtration rate of the kidney's result in body toxins and wastes being excreted less efficiently. Not only is less urine excreted and excreted less efficiently with aging, but it also contains more creatine. Like older men, older women sometimes experience problems with bladder control and incontinence. Urinary problems are not as common in older women as in older men, but cancer of the genitourinary tract is no respecter of gender. Prostate cancer occurs...

Figure 911

The initial source of energy available to regenerate ATP from ADP and phosphate is creatine phosphate. Like ATP, creatine phosphate contains a high-energy phosphate bond, and it is actually four to six times more abundant in muscle fibers than ATP. Creatine phosphate, however, cannot directly supply energy to a cell's energy-utilizing reactions. Instead, it stores excess energy released from mitochondria. Thus, whenever sufficient ATP is present, an enzyme in the mitochondria (creatine phosphokinase) promotes the synthesis of creatine phosphate, which stores the excess energy in its phosphate bond (fig. 9.13). As ATP is decomposed to ADP, the energy from creatine phosphate molecules is transferred to these ADP molecules, quickly converting them back into ATP. The amount of ATP and creatine phosphate in a skeletal muscle, however, is usually not sufficient to support maximal muscle activity for more than about ten seconds during an intense contraction. As a result, the muscle fibers in...

Spectral Editing

In vivo measurements of cerebral GABA for example are limited by its low concentration and by the presence of the significantly overlapping resonances at GABA-2 (2.3 ppm) from Glx, at GABA-3 (1.9 ppm) from NAA and at GABA-4 (3.0 ppm) from the methyl group of creatine. Fortunately, the methyl group of creatine is not subject to the effects of J-coupling. This allows it to be suppressed or separated using a variety of spectroscopic techniques, such as J-editing 43-47 , 2D J-resolved spectroscopy 48 , longitudinal scalar order difference editing 49 , and multiple quantum filtering 50, 51 . These methods selectively prepare GABA-3 and GABA-4 into a steady state while suppressing the dominant overlapping creatine signal at 3.0 ppm. The GABA-4 can be made visible by further advanced processing, which can include signal averaging or subtraction. The result is a single signal assigned to GABA as shown in Fig. 6.8, even though a significant amount of co-edited resonances from macro-molecules,...

Case

This patient had an apparently successful procedure carried out in the LAD and RCA on separate days. He allegedly had good coronary flow with widely patent vessels and no residual stenosis. He did have bleeding complications at his arteriotomy site, but this is not unusual. He also had minor elevations of creatine kinase (CK), with a significant increase of his Clearly, this embolic biologic and foreign material was secondary to the two atherectomy procedures. The dating of the focal myocytolysis associated with the emboli, provides a temporal relationship to the coronary intervention occurring 3 weeks before death. It is noteworthy, that at the time of the atherectomy, the patient developed an abnormally elevated creatine kinase, with a positive MB fraction. This was not considered to be significant clinically. Yet, in retrospect, the elevated CK enzyme was due to multi-focal small areas of reperfusion myocardial necrosis secondary to coronary micro-emboli. Whether it was the...