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?!

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Modulation and regulation of creatine transport

Little effect on creatine uptake rates has been observed with PCr, creatinine, ornithine, glycine, glutamic acid, histidine, alanine, arginine, leucine, methionine or cysteine (Fitch, 1988 Loike et al., 1988 M ller and Hamprecht, 1989). The sodium-dependent uptake of creatine in culture is sensitive to extracellular creatine concentration (Loike et al., 1988). Myoblasts maintained for 24 h in a medium containing 1 mM creatine exhibited one-third of the uptake activity of cells bathed for the same duration in a medium lacking creatine. The downregulation was slowed by inhibitors of protein synthesis. From this observation one can conclude that extracellular creatine regulates the induction of the expression of a protein that decreases the sodium-dependent uptake activity only after the creatine enters the cell. No alteration in the efflux rate for creatine was observed in studies of the effects of changes in extracellular creatine concentrations (Loike et al., 1988). If creatine was...

Creatine uptake

Most studies on creatine transport have focused on creatine influx and several tissues have been examined (Ku and Passow, 1980 Loike et al., 1986a M ller and Hamprecht, 1989 Odoom et al., 1993). This saturable active transport is highly specific for creatine, sodium dependent, concentrative and sensitive to metabolic inhibitors (Fitch et al., 1968b Fitch and Chevli, 1980 Ku and Passow, 1980 Loike et al., 1986a, 1988 M ller and Hamprecht, 1989 Bennett et al., 1991). Two sodium molecules are transported for every creatine molecule and the Km for sodium is 55 mm (M ller and Hamprecht, 1989) thus favouring Cr transport. The uptake of creatine appears to be little affected by extracellular pH over the range pH 6.9-7.9 (Syllm-Rapoport et al., 1980). The electrogenic nature of creatine transport is important in the mechanism of uptake of the molecule. The transporter exploits the negative membrane potential as well as the inwardly directed sodium gradient in order to maximize creatine...

Creatine

Creatine is a supplement claimed to increase muscle strength and increase body mass. In addition, it may have a protective effect on nerves. Both of these possible effects are relevant to MS. Creatine is made in the liver, kidneys, and pancreas. It is involved in generating energy for muscle cells and other cells in the body. Creatine is available as a dietary supplement and may be obtained in the diet by eating meat and fish. Limited clinical studies have been done on creatine. In healthy people, creatine supplements may improve performance for brief, high-intensity exercises. In one study of 16 people with MS, creatine supplements did not improve high-intensity exercise ability or increase the muscle stores of creatine (11). In people with diseases of the muscles (such as muscular dystrophy), limited studies indicate that creatine may increase strength, decrease muscle fatigue, and improve exercise capacity. Creatine usually is well tolerated when used in appropriate doses. Rarely,...

Brief Review of the Sections

Section I Basic Biochemistry of Creatine and Creatine Phosphate This section covers aspects of the basic metabolism of creatine and creatine phosphate with particular emphasis on the enzyme creatine kinase, the creatine phosphate shuttle hypothesis, recent observations in animal and cellular models, on the high energy phosphate changes in physiological studies, 3-GPA feeding, and some muscle disorders. The regulation of oxidative phosphorylation is discussed and findings relating to creatine kinase gene manipulation models are summarized. Section II Biochemical Basis for a Therapeutic Role of Creatine and Creatine Phosphate In this section the mechanism underlying the mode of action by which creatine and creatine phosphate are thought to act as therapeutic agents is presented. A detailed description of the biophysical actions of creatine phosphate is given as well as in vitro observations on heart cells. This is a transition section between the basic and clinical science sections....

Historical Introduction To Phosphagen Kinases

Lohmann is credited with the discovery of creatine kinase (CK) in 1934. He believed that the reaction of adenosine monophosphate (AMP) with two phosphocreatine (PCr) molecules gave adenosine triphosphate (ATP) and creatine (Cr) and that the observed orthophosphate (P,) released from PCr in contracting muscle was due to ATP hydrolysis Creatine kinase was first purified by Kuby et al. (1954) from rabbit muscle and its properties reported by Kuby and Noltman (1963). Creatine and Creatine Phosphate In general, CK is characteristic of vertebrates and arginine kinase is characteristic of invertebrates. However, although arginine kinase has never been reported from vertebrates, CK is found in various invertebrate phyla (e.g. Porifera, Annelida, Echinodermata and Chordata) (Watts, 1971). In most cases a single species has one phosphagen but there are examples of more than one kinase occurring in some species of annelids and echinoderms. Phosphagens and their kinases are not restricted to...

Cardiac and skeletal muscle

Myocardial gene expression of CK is developmentally regulated (Lamers et al., 1989 Hasselbaink et al., 1990). In the mouse BB-CK alone is expressed during prenatal development, until the last week, when MM-CK increases dramatically whilst the BB-CK isoform decreases concomitantly. Associated with the co-expression of M-CK and B-CK gene peripartum, and during the first 3 weeks postnatally, there is up to a maximum of 35 MB-CK activity (Hall and DeLuca, 1975 Ingwall, 1991). The mitochondrial isoform does not get expressed until several days postnatally (Hall and DeLuca, 1975 Ingwall, 1991). In several diseased states with altered cardiac function, alteration of CK gene expression also occurs. In pressure overload or volume overload induced cardiac hypertrophy of both humans (Jansson et al., 1987 Ingwall, 1991) and experimental animals (Meerson and Javich, 1982 Younes et al., 1984 Schuyler and Yarbrough, 1990 Field et al., 1992), alteration of the CK isozyme expression develops. In the...

Catalytic and substrate binding domain

Kinetic studies suggest separate but synergistic binding of MgATP and creatine. Recently, using site-directed mutagenesis, Lin et al., (1994) and others (Furter et al., 1993) tried evaluating further the role of cysteine-283. In Lin et al.'s study of mitochondrial CK expressed by the Escherichia coli system,

Subcellular localization domain

A specific domain exists for sarcoplasmic reticulum localization or association with other sarcoplasmic reticulum proteins has not been established. Recently, Rojo et al. (1991) showed association of the CK to model membrane preparation. The mitochondrial CK interacts with a phospholipid, cardiolipin of the inner mitochondrial membrane (Ottaway, 1967 Schlame and Augustin, 1985 Cheneval and Carafoli, 1988), and with a model phospholipid membrane (Rojo et al., 1991). Further delineation of the subcellular localization domain is important to the understanding of the creatine phosphate shuttle and awaits analysis by site-directed mutagenesis through domain-deletion or domain-switching experiments.

Transgenic animal model

Over-expression of B-CK by transgenic mice has been reported (Brosnan et al., 1993). Under the control of a skeletal muscle actin promoter, the transgene was expressed and produced MB-CK (22-32 ), which is normally absent in adult skeletal muscle. Over-expression of CK, however, did not alter ATP, creatine phosphate, or creatine levels, supporting the generally held belief that CK-catalysed skeletal muscle reactions are normally in equilibrium. A transgenic model with liver-specific expression of B-CK has also been reported (Brosnan et al., 1990). The hepatocytes of the liver do not normally express any detectable CK.

Jaliashvilf Eugeny A Konorev2 Sergi A Kryzkanovsky2 and Ettore Strumia1

Creatine and Creatine Phosphate transplantation (Hearse, 1980 Semenovsky et al., 1987). One agent which shows promise in this respect is creatine phosphate (Neoton). Creatine phosphate (PCr) was discovered by Eggleton and Eggleton in 1927 (see Ennor and Morrison, 1958, for review), and the discovery predated that of ATP. It has taken more than 50 years of intensive study to understand various aspects of the physiological function of this molecule. It is now accepted that PCr has at least a dual role in cells with high energy turnover such as in the heart, skeletal muscle, brain, retina, spermatozoa and nerve endings (Saks et al., 1978 Bessman, 1985 Jacobus, 1985 Wallimann et al., 1989). The intracellular PCr content is high and ranges from 2 to 30 mM (Dawson, 1983 Gard et al., 1985). Evidence to date suggests that it acts as an energy (ATP) buffer (Mommaerts, 1969) and also as an intracellular energy carrier (Saks et al., 1978 Bessman, 1985 Jacobus, 1985 Wallimann et al., 1989). The...

Theodore J Lampidis Yufang Shi and Luigisilvestro1

Protection by creatine phosphate against Adriamycin 117 Key words creatine phosphate, muscle, cardiac, hypoxia, arrhythmia, adriamycin, phosphocreatine, phosphoarginine, cardiotoxicity Creatine and Creatine Phosphate Copyright 1996 Academic Press Limited With the ability to maintain functionally active cardiac cells in culture for prolonged periods, we began to develop this system as an in vitro model to study cardiopathogenesis produced in patients treated with the potent anti-tumour agent Adriamycin (ADM). ADM-induced cardiomyopathy is a cumulative dose-limiting toxicity which prevents a more efficacious use of this drug as an antitumour agent. We have previously shown that ADM and a number of other anthracycline analogues which are positively charged (at physiological pH) are accumulated preferentially in cardiac muscle cells as opposed to co-cultured cardiac fibroblasts (Lampidis et al., 1981). It has also been observed with compounds other than the anthracyclines (xanthene dyes)...

Michael A Conway Ronald Ouwerkerk Bheeshma Rajagopalan and George K Radda

Creatine phosphate changes in tachycardia and rhythm disorders 150 11. Changes in creatine phosphate the effects of drug therapy and diagnostic potential 152 Key words creatine phosphate, magnetic resonance spectroscopy, myocardium aortic stenosis, aortic incompetence, hypertrophy, heart failure

The Normal Heart Resting Metabolism

Human and animal cardiac spectra are composed of peaks derived from phosphates at different chemical shifts. On reading the spectrum from left to right, 2,3 diphosphoglycerate (2,3 DPG), inorganic phosphate (P,), phospho-diester (PDE), creatine phosphate (PCr) and three peaks for ATP can be identified. Blood, heart and skeletal muscle contain P PDE and ATP. Creatine phosphate is present in skeletal and cardiac muscle and absent from blood. The presence of a prominent 2,3 DPG peak indicates that the sample volume has a significant amount of blood present. Figure 9.1. Cardiac spectrum from a control acquired using the phase-modulated rotating frame imaging technique (PMRFI) (2,3 DPG+P,, 2,3 diphosphoglycerate and inorganic phosphate PDE, phosphodiester PCr, creatine phosphate ATP, adenosine triphosphate, y, a and phosphates ppm, frequency in parts per million). Figure 9.1. Cardiac spectrum from a control acquired using the phase-modulated rotating frame imaging technique (PMRFI) (2,3...

Oxidative Phosphorylation

Schematic representation of creatine-stimulated respiration at the inner mitochondrial membrane of a saponin-skinned cardiac fibre. Excess creatine (Cr) shifts the local Mi-CK reaction in favour of an increase in local ADP. ADP is then transported via the adenine nucleotide translocase into the mitochondrial matrix to stimulate respiration. IMM, inner mitochondrial membrane OMM, outer mitochondrial membrane SL, sarcolemma mit-CK, mitochondrial creatine kinase bound to the IMM. causes an increased sensitivity of mitochondrial respiratory control to changes in ADP. Through this mechanism Cr stimulates respiration (Veksler et al., 1988, 1991 Saks et al., 1991a, 1993). Creatine shifts the local Mi-CK equilibrium (Eqn 1, page 52) towards the production of PCr and ADP (ADP in turn stimulates respiration). Thus creatine and Mi-CK can lower the Km, or increase the sensitivity, for respiratory control of oxidative phosphorylation with respect to ADP (Fig. 4.3). For further details...

Metabolism

Clinical Experience with Creatine Phosphate Therapy 185 Paola Fault tto and Ettore Sirumia 12. Creatine Phosphate Added to St Thomas' Cardioplegia 199 David J. Chambers 13. Uses of Creatine Phosphate and Creatine Supplementation for the Athlete 217 Joseph F. Clark 2. Experimental creatine supplementation 218 3. Oral creatine supplementation 219 5. Creatine phosphate 221 14. Creatine and Creatine Phosphate Future Perspectives 227 Michael A. Conwy and Joseph F. Clark Assay for Creatine and Creatine Phosphate 233

Acknowledgements

Creatine and Creatine Phosphate Scientific and Clinical Perspectives was compiled with the support of a large number of contributors who undertook to complete their manuscripts within a very short period of time. We are very grateful to them for their enthusiastic support.

CNS neurons

Neurons of the central and peripheral nervous system are morphologically polarized cells, being highly specialized for the reception and transmission of (synaptic) information at the axon and dendrites, respectively. We have found that B-CK and mitochondrial creatine kinase are co-expressed in the same Golgi Type I (large) neurons, and not by the vast majority of central nervous system (CNS) interneurons and glia (Friedman and Roberts, 1994). Furthermore, these two isoforms of CK are expressed at morphologically distinct parts of the cell. The mitochondrial isoform of CK is localized primarily in the cell body of all Golgi Type I neurons. In contrast, B-CK mainly localizes within the cell processes, and to a lesser extent within the cell body. The distinct spatial arrangement of CK isoforms occurs throughout the brain including cerebral cortex, hippocampus, cerebellum and brainstem. Thus, the creatine phosphate shuttle of brain neurons serves to transfer metabolic energy from...

Photoreceptors

Is converted to PCr, which then diffuses into the outer segments to regenerate ATP for visual cycle events (i.e. regeneration of cGMP and phosphorylation reactions). The creatine phosphate shuttle then serves to supply energy from the inner to the outer segments and nerve terminals for the rapid regeneration of ATP at the point of energy consumption. These results have been confirmed and extended by studies of bovine retina (Hemmer et al., 1993). Using specific antisera and light and electron microscopy, two distinct isoforms of CK (BB-CK and mitochondrial CK) were shown to be separately compartmentalized in the outer and inner segments of the photoreceptors. Furthermore, the ATP-generating potential of the CK system was sufficiently large to regenerate the entire ATP pool during a photic cycle (Hemmer et al., 1993).

Excretory epithelia

Creatine kinase immunoreactivity is most intense in the inner stripe of the outer medulla of the kidney. Both mitochondrial and BB-CK isoforms are specifically localized to the distal nephron, especially in the thick ascending limb. The pattern of renal expression of CK correlates with the region of greatest oxygen consumption, ATP utilization and sodium transport (Friedman and Perryman, 1991). In the very specialized sodium excretory (rectal) gland of the shark, there are also high levels of expression of multiple CK isoforms and PCr (Epstein et al., 1981 Friedman and Roberts, 1992). Stimulation of this excretory epithelial gland with cAMP causes PCr levels to rapidly decrease with no change in the levels of ATP (Epstein et al., 1983). Both the mitochondrial CK and BB-CK are expressed at high levels, equivalent to that measured in mammalian myocardium. Localization of the two isoforms is restricted to the basal but not the apical aspect of the tubules, consistent with the energy...

Intestinal epithelia

Cance of an intestinal epithelial cell creatine phosphate shuttle. In vitro studies support the shuttle hypothesis and demonstrate that, at the brush border, locally CK generated ATP with PCr as substrate, is used selectively for myosin filament shortening at the same location (Gordon and Keller, 1992).

Future Applications

There is ample ultrastructural, biochemical as well as physiological experimental evidence for the presence of the creatine phosphate shuttle pathway. It is also clear that during organ development and in certain disease states, the alteration of CK isoform expression occurs. The question, therefore, is no longer whether there is a functional role for CK in cell metabolism, but to what extent the compartmentalization of CK isozymes is important in the homeostasis of the specialized cells and in response to environmental cues. This question can be investigated by several of the newly developed recombinant DNA technologies, including gene targeting and dominant negative modulation.

GPA feeding

In an attempt to develop an animal model that might identify biochemical changes and pathology associated with creatine and PCr depletion, Chevli and Fitch fed rats an analogue of creatine 3-guanidinopropionic acid ( 3-GPA) (Fitch et al., 1968b, 1974 Chevli and Fitch, 1979). This agent has been used to compete with creatine for entry into the skeletal muscle cells (1 of their diet w w) as a means to study creatine transport (Fitch et al., 1968b). Further work by Shields and Whitehair (1973) showed that rats receiving diets containing 3-GPA had abnormal creatine metabolism, with chronically reduced levels of muscle creatine combined with increased levels of excreted creatinine. Fitch et al. (1974) demonstrated that 3-GPA feeding resulted in a decrease in muscle PCr with concomitant replacement by the phosphorylated analogue, 3-GPA-P. Muscles from animals fed 3-GPA were found to have decreased 3-GPA-P during hypoxic contraction indicating that, like PCr, 3-GPA-P could serve with CK in a...

Summary

All cells use ATP as the immediate energy source. Cellular ATP is generated by oxidative metabolism and by glycolysis. Many specialized cells in an organism require fast and constant energy utilization to maintain specialized cellular function. However, most cellular ATPases utilize ATP and therefore rapid accumulation of end-product ADP and AMP will significantly alter the equilibrium kinetics around the cellular ATPase it may be myosin ATPase, sarcolemmal ion-stimulated ATPase, SR calcium ATPase, or other regulatory ATPases. Compartmentalized isoforms of CK provide an adaptive mechanism which can rephosphorylate ADP to ATP, using creatine phosphate, thus maintaining the free ADP concentration at an appropriately low level. Another compartmentalized mitochondrial CK at the site of mitochondrial ATP generation catalyses the phosphorylation of creatine to creatine phosphate, thus completing the two components of a creatine phosphate shuttle pathway. It is now evident that many cells...

Valdura Saks

Key words adenine nucleotides, cardiomyocytes, compartmentation, creatine kinase, diffusion, free energy exchange, mitochondria, oxidative phosphorylation, regulation The creatine kinase (CK) isoenzymes function, in vivo, coupled to intracellular structures (mitochondria, myofibrils and cellular membranes). They operate at equilibrium in the cytoplasm as part of the intracellular creatine phosphate (PCr) pathway, or phosphocreatine circuit for energy channelling (Saks et al., 1978, 1991a Bessman and Geiger, 1981 Bessman and Carpenter, 1985 Jacobus, 1985 Wallimen et al., 1992 Wegmann et al., 1992 Wyss et al., 1992 Aliev and Saks, 1993). Chapters 1,2 and 4 provided an introduction to the CK system. We will now see how compartmentalization of CK enzymes are involved in cardiac energy metabolism. Creatine and Creatine Phosphate Figure 5.1. (A) The dependence of the rate of respiration of the skinned cardiac fibres on the external ADP concentration in the absence (curve 1) and in the...

Joseph F Clark

Key words creatine, creatine kinase, creatine phosphate, 3-guanidinopropi-onic acid, mutation, NMR Many functions have been assigned to the creatine phosphate (PCr) creatine kinase (CK) system and some of these are described in Chapters 2, 4, 5 and 7. Little work has been performed, however, to determine how essential the CK system is in the normal function of the entire organism. Basically, there are two ways in which one can evaluate the requirement for a functioning CK system in vivo. The first method involves altering the intracellular substrates in order to short-circuit the system. This has been done using various creatine analogues such as 3-guanidinopropionic acid ( 3-GPA), cyclocreatine and 3-guanidinobuteric acid (Zweier et al., 1991 Clark et al., 1994 Boehm et al., 1995). Creatine analogues act as competitive CK inhibitors owing to their different kinetics and affinities (Wallimann et al., 1992 Clark et al., 1994). Another technique for examining the CK system in vivo is to...

Shuttle

One of the central tenets regarding the regulation of mitochondrial oxidative metabolism is that ADP produced in the cytoplasm diffuses back into the mitochondria to stimulate the production of more ATP (i.e. respiratory control). Alternatively Jacobus and Lehninger (1973) proposed that ADP produced by high metabolic activity is immediately rephosphorylated to ATP through the action of creatine kinase (CK), using the phosphate from creatine phosphate (PCr). The respiratory signal to the mitochondria, in this Creatine and Creatine Phosphate hypothesis, is creatine. The creatine, produced at sites of high metabolic activity, diffuses back into the mitochondria to be rephosphorylated to PCr through the action of a different CK isoenzyme, the mitochondrial CK. The location of mitochondrial CK facilitates this reaction since it is bound to the outer surface of the inner mitochondrial membrane. Such a cycle, in which creatine and PCr serve as the diffusible intermediates connecting sites of...

Formation of phosphate conjugates

Phosphate conjugates are rare compared to sulfates, yet they are of primary significance in the metabolism of anticancer and antiviral agents impacting on endogenous nucleotides. Indeed, phosphorylation is an essential metabolic step in the bioactivity of these agents, and numerous in vitro and in vivo studies document their stepwise phosphorylation to mono-, di-, and triphosphates. Such reactions are sometimes, and correctly, labeled as anabolic (i.e., biosynthetic) ones.68'69 They are known or postulated to be catalyzed by some among the very many phosphotransferases (EC 2.7), for example adenosine kinase (EC 2.7.1.20), thymidine kinase (2.7.1.21), uridine kinase (2.7.1.48), deoxycytidine kinase (EC 2.7.1.74), deoxyadenosine kinase (EC 2.7.1.76), nucleoside phosphotransferase (EC 2.7.1.77), creatine kinase (EC 2.7.3.2), adenylate kinase (EC 2.7.4.3), nucleoside-phosphate kinase (EC 2.7.4.4), guanylate kinase (EC 2.7.4.8), and (deoxy)nucleoside-phosphate kinase (EC 2.7.4.13).

Tests of glomerular filtration

* Serum creatinine creatinine is a metabolic product of both creatine and phosphocreatine. It has a molecular weight of 113 daltons, is freely filtered at the glomerulus and undergoes variable tubular reabsorption. The plasma creatinine level is related to muscle mass and body weight, being derived primarily from synthesis in skeletal muscle. 98 of the total creatine pool is in muscle, with about 1.6 -1.7 being converted to creatinine daily. Glomerular filtration rate in ml min per 1.73 m2 body surface area is equal to 40 multiplied by height (cm) plasma creatinine (mmol l).

Findings that elevate suspicion of MI

Laboratory values a patient with a possible MI should have serial determinations of creatine kinase (the MB isoenzyme) or troponin I P (usually drawn every 8 hours times 3 before MI is ruled out), lactate dehydrogenase (I.HI I) elevation and flip (I.DHt > LDH7) also may be used, especially if the patient presents after 24 hours. Aspartate aminotransferase is also elevated but not used clinically for MI. X-ray may show cardiomegaly and or pulmonary congestion echocardiography may show ventricular wall motion abnormalities.

New Research Areas

Antiapoptotic agents (e.g., caspase inhibitors), anti-inflammatory agents (e.g., minocycline 87), bioenergetic enhancers antioxidants (e.g., creatine, coenzyme Q, lipoic acid, dicholoroacetate, cystamine), excitotoxic anatgonists (e.g., riluzole 88, remacemide 89), histone deacetylase inhibitors (sodium butyrate and suberoylanilide hydroxamic acid), and transcriptional inhibitors (e.g., mithramycin 90) have all been examined in the R6 2 mouse model of HD and have shown some benefit.84 Some of these agents have been advanced to clinical trials (Table 2). Aggregation inhibitors are also a target.85

Acute vs Chronic Amphetamine Toxicity

Labs Hyperglycemia, leukocytosis, elevated liver function tests (LFTs), elevated creatine phosphokinase (CPK) from rhabdomyolysis with myoglobinuria. False-positive urine drug screens may result from ephedrine, pseudoephedrine, or phenylpropanolamine (PPA), often found in over-the-counter (OTC) cold medications.

Unmet Medical Needs

Since the approval of riluzole, at least 10 therapeutic approaches which showed promise in preclinical models have been tested in the clinic but have failed or shown equivocal results (such as for insulin-like growth factor-1). These include neurotrophic factor replacement strategies (ciliary neurotrophic factor, BDNF glial-derived neurotrophic factor, and insulin-like growth factor-1), glutamate NMDA receptor antagonists (topiramate, dextromethorphan) or putative glutamate modulators (gabapentin, lamotrogine, N-acetylcysteine), antioxidants (vitamin E), MAO glyceraldehyde phosphate dehydrogenase inhibitors (selegeline), and mitochondrial transition pore blockers (creatine).86'87'95 Insulinlike growth factor-1 has shown improvement in quality of life and benefit in ALS patients.97

Antiinflammatory agents

Minocycline 87, a tetracycline antibiotic with anti-inflammatory activity, appears to have multiple effects on cell function, including inhibition of the mitochondrial permeability transition-mediated release of cytochrome c, an event key to the initiation of the apoptotic cascade. Additional activities of minocycline include inhibition of reactive microgliosis, caspase-1, caspase-3, and nitric oxide synthase transcriptional upregulation, and of p38 MAPK activation. It protects against motor neuron loss in a mouse ALS model (SOD-1 G93A) alone or in combination with creatine.87 The COX-2 inhibitor, celecoxib 44, preclinically slowed motor neuron deterioration in an organotypic model of motor neuron disease and improved survival up to 30 following oral administration in an ALS transgenic model.87 COX-2 is upregulated in both the transgenic SOD-1 G93A mouse model and in the CNS of ALS patients.86 COX-2 catalyzes the conversion of arachidonic acid to prostaglandin E2, a proinflammatory...

Site Analysis Using Docking and Minimization

Figure 2 Site analysis of trypsin (1ppc) using docking and clustering. The surface of trypsin is in gray ligand (NAPAP) is in gray sticks too. Fragment of NAPAP is docked. The most distant cluster representatives are shown as green creatine phosphokinase models. The cluster representative closest to the position of the fragment in NAPAP is in light-green sticks other members of the same cluster are in a darker shade of green. Figure 2 Site analysis of trypsin (1ppc) using docking and clustering. The surface of trypsin is in gray ligand (NAPAP) is in gray sticks too. Fragment of NAPAP is docked. The most distant cluster representatives are shown as green creatine phosphokinase models. The cluster representative closest to the position of the fragment in NAPAP is in light-green sticks other members of the same cluster are in a darker shade of green.

Musculoskeletal System

Acute alcoholic myopathy (rhabdomyolysis) may cause painful, tender swelling of one or more large muscle groups. Diagnosis depends on a high index of clinical suspicion, elevation of serum creatine phosphokinase, and myoglobinuria. Chronic alcoholic myopathy may accompany alcoholic polyneuropathy, presenting as painless, progressive muscle weakness and wasting.

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome is usually thought of as a syndrome of fever and catatonic rigidity, with increased serum creatine phosphokinase levels in the setting of neuroleptic administration. The etiology of this disorder is obscure, and lack of consistent case definitions has hampered fuller study of this syndrome. The initial description of neuroleptic malignant syndrome referred to it as pallor and hyperthermia with isolated primary symptoms of fever, akinesia or stupor with hypertonicity, and pulmonary congestion. Since then, a number of diagnostic criteria have been proposed as summarized at length by Adityanjee, Mathews, and Aderibigbe in their 1999 review. In essence, the syndromic definitions stress the presence of rigidity, fever, and autonomic changes in the presence of neuroleptic exposure. Alteration in sensorium is also a common feature of several of these criteria.

General Approach to Laboratory Testing

When a dermatologist, family practitioner, internist, or rheumatologist first sees a patient with CLE, their principal concern should be to rule out evidence of systemic disease. After all, 15 of patients with CLE progress to SLE in 10-15 years of observation (Rowell 1984). In addition to a complete medical history and physical examination, clinical laboratory findings can be very helpful in this regard. Specifically, a blood chemistry panel allows screening for renal or hepatic involvement. Creatine phosphokinase testing assists in ruling out muscle inflammation. Evidence for autoimmune hemolytic anemia or thrombocytopenia is looked for in the complete blood cell count as well as in the lactic dehydrogenase, reticulocyte count, Coombs' direct antibody testing, serum haptoglobin, and antiplatelet antibodies. A routine urinalysis free of cellular casts or protein makes it highly unlikely that the kidney is involved. Specific autoantibodies, almost never observed in CLE, if found, can...

Safety concerns with statins

The most important adverse effect has been the incidence of muscle pain or weakness (myopathy) and, in its severest manifestation, rhabdomyolysis, observed with all statins. Rhabdomyolysis can lead to hospitalizations and, in rare cases, renal failure. While these skeletal muscle effects occur fairly rarely (< 0.1 ), sizable numbers of patients have experienced these effects because of the large treated patient population. The incidence of skeletal muscle side effects is more pronounced at higher doses, particularly with higher potency inhibitors, which raises additional concerns as more aggressive lipid lowering is utilized to improve clinical outcomes. Patients who complain of muscle soreness are monitored for excessive plasma levels of creatine phosphokinase (CPK), and elevations in CPK 10 times above the

Miscellaneous complications

The most frequently encountered renal abnormality among drug abusers seen today is myoglobinuric nephrosis secondary to cocaine-induced rhabdomyolysis. These are frequently seen in victims of drug-induced excited delirium accompanied by hyperpyrexia and intense muscular activity.1 Survival for several days reveals, at autopsy, massive necrosis of skeletal muscle which is easily identified because of its distinctive yellow (instead of dark brown) coloration.2 These deaths are invariably marked by pronounced elevations in serum creatine kinase, profound hypotension, and disseminated intravascular coagulation. Abuse of stimulant drugs has also been associated with renal artery thrombosis and infarction, and renal vasculitis.1 Maternal cocaine abuse has been associated with a plethora of fetal anomalies, most notably urogenital abnormalities such as hydronephrosis and atresia of the distal ureters.1

Pathological features

Depending on the results of the laboratory tests, those patients meeting the criteria above are classified into groups listed below. The following studies are suggested complete blood count, erythrocyte sedimentation rate, chemistry profile, creatine kinase, antinuclear antibody, thyroid functions, serum and urine immunoglobulin studies (to include either immunofixation electrophoresis or immunoelectrophoresis, and HIV and hepatitis serology. The list of laboratory studies is not comprehensive. For instance, in certain clinical circumstances, other studies may be indicated, such as phytanic acid, long-chain fatty acids, porphyrins, urine heavy metals, a-lipoprotein, p-lipoprotein, glucose tolerance test, imaging studies of the central nervous system, and lymph node or bone marrow biopsy. Classification of CIDP

The Blood Analysis Method for Assessing Kidney Function Using Naturally Occurring Substances

Creatinine is produced continuously in the body by the spontaneous breakdown of creatine (a constituent of muscle) to creatinine. It is scarcely broken down at all in the body (at least in normal subjects) and is excreted unchanged in the urine. An increase in plasma or serum creatinine concentration is undoubtedly the most commonly used screening test for early kidney impairment. Furthermore, a doubling of serum cre-atinine concentration does indicate that renal function is reduced by approximately half a five-fold increase indicates that renal function is reduced to approximately one-fifth and so forth similar to the idealized relationship described earlier. Normal serum creatinine concentrations are less than 1.5 mg per ml (in men) or 1.4 mg per ml (in women). First, creatinine is derived not only from the spontaneous breakdown of muscle creatine but also from the diet. For example, meat contains creatine, and if the meat you eat is well cooked, some or all of this creatine will be...

Muscular and Musculotendinous Rheumatism Syndromes

Medial Epicondylitis Elbow Radiograph

Generation, and regeneration of muscle fibers (Armbrustmacher 1988). When muscle fibers disrupt, myoglobin escapes into the extracellular fluid and plasma, resulting in myoglo-binemia, frequently causing acute renal failure. Plasma creatine kinase is elevated. In contrast to myositis ossificans, in which perimysial connective damage prevails, myocytes are mainly affected in rhabdomyolysis. Clinically, half of the cases are indolent, and in the majority of cases objective symptoms and signs are absent (Gabow 1982).

Cell Free Protein Expression

Vrrp Write

All elements involved in gene expression and protein synthesis have to be added to the RM where transcription and translation takes place (Figure 2). Components like DNA, a highly processive RNA polymerase like the enzyme encoded by the T7 bacteriophage, NTPs, mRNA, tRNA, aminoacyl tRNA synthetases (ARSs), ribosomes, transcription and translation factors as well as amino acids have to be combined in an optimal pH and salt environment. The required high amounts of free energy for the transcription and translation processes are provided by hydrolysis of the triphosphates ATP and GTP. Crucial for each CF system is therefore an efficient ATP regenerating energy system in order to maintain the NTP concentrations over a long period of time. Conventional energy systems are based on high-energy phosphate donors such as phosphoenol pyruvate in combination with pyruvate kinase,211,239 creatine phosphate and creatine kinase,234 or acetyl phosphate with acetate kinase.240

Coq As A Cardioprotective Drug

Blood perfusate was collected at the preischemic baseline and during reperfusion to estimate creatine kinase (CK) and malonaldehyde (MDA) contents. At the end of the experiments, myocardial infarct size was measured by TTC staining methods. Separate groups of pigs (CoQ10-fed and unfed) were used to assess CoQ10 content. The CoQ10 fed group revealed higher content of CoQ 10 (21.5 0.7 vs. 28.0 0.5 pg g heart) indicating bioavailability of CoQ10 in heart. Postischemic left ventricular contractile function was better recovered in the CoQ10 group as compared with the control group of pigs. For example, at the end of 2 hours of reperfusion, developed pressure (DP) (92 3.9 vs. 131 4.2 mmHg) and maximum first derivative of DP (LVmaaxdp dt) (1110 98 vs. 1976 85 mmHg sec) were higher for the hearts of CoQ10-fed pigs. CoQ10-fed pigs revealed smaller myocardial infarctions and lesser CK release from the coronary effluent compared to those for the non-CoQ10-fed animals. The CoQ10...

How is kidney function measured

Electron Microscopy Kidney

Blood, for example, creatine and urea accumulate. Creatine is a waste product of muscle metabolism that is normally excreted through the kidneys. Healthy people (Table 2.1) have a creatine serum concentration of between 0.6 and 1.2 mg 100 ml. The normal value in an individual depends on the muscle mass. In someone with less muscle, it is lower in 'muscle men', it is higher. If kidney function fails, the creatine concentration in the blood gradually rises. Generally, though, mild kidney impairment does not lead to a noticeable change in serum creatine concentration. It rises only when kidney function has decreased by more than half. In people with little musculature, the low starting point for the creatine concentration can mean that it stays within the normal range for a long time, even when kidney function is seriously compromised. A more exact picture of kidney function is given by the so-called creatine clearance rate. To measure this, the urine must be collected for 24 hours or...

Medications for High Cholesterol

Also, muscle damage can occur from statins and can lead to the release into the blood of a protein from damaged muscle, myoglobin, that can cause the kidneys to shut down entirely. This form of acute renal failure has caused the deaths of a number of patients and recently has led to the withdrawal from the market of one of the statins, Baycol. Muscle pain is the first sign of this condition. It also can be detected by monitoring the blood level of an enzyme from muscle called creatine kinase, but this test is not used much for monitoring purposes muscle pain is more likely to signal this problem.

Detection of microalbuminuria

Measurement of the albumin concentration is often imprecise because it depends on the amount of urine as well as the amount of excreted albumin. For example, in people who have drunk a lot of liquid before giving a urine sample, there will be a dilution effect, such that the measured albumin concentration will be too low. To compensate for this, the albumin concentration can be compared with the amount of creatine excreted in the urine. According to the rate of creatine excretion For women 20-300 mg g urinary creatine 2.5-35 mg mmol urinary creatine For men 20-200 mg g urinary creatine 2.5-25 mg mmol urinary creatine

Clinical Manifestations

Skeletal muscle Muscular hyperactivity and rigidity leading to muscle damage, high creatine phosphokinase (CPK) levels, rhabdomyolysis myoglobinuria may lead to acute tubular necrosis (ATN) and acute renal failure (ARF). Gastrointestinal vasoconstriction Gut ischemia and mesenteric thrombosis may lead to bowel necrosis with pneumatosis intestinalis. Uteroplacental and fetal Spontaneous abortion, abruptio placenta, intrauterine growth retardation (IUGR), limb autoamputation, microcephaly, and low birth weight.

Figure

Most enzyme biosensors use either membrane-based enzyme entrapment, or the enzyme is covalently bound to the inside of a nylon tube. The stability of the electrode is dependent on the stability of the enzyme, which is partially dependent on the method of immobilization. Many enzyme electrodes are available to detect, for example, glucose, urea, creatine, and pyruvate in clinical samples. However, only the glucose biosensor has been widely commercialized.

Toxicities

Gastrointestinal Increased gastric acidity leads to peptic ulcer, nausea and vomiting. Central nervous system (CNS) Agitation, restlessness, tremors, seizures. Metabolic Reduced serum K and Ca (chronic osteoporosis 2 cups day, 100 mg day). Muscle Increased contractility, high creatine phosphokinse (CPK), rhabdomyolysis.

Multicenter Trial

As indicated by Ebbeling and Clarkson (1989), muscle soreness and elevations in serum creatine kinase (CK) can be used as a biochemical marker for skeletal muscle injury. Recently a study was conducted to evaluate the hypothesis that exposure of skeletal muscle to exercise-induced stress in combination with prior administration of a study drug (e.g., drug A) will produce a greater increase in CK than the effects of exercise alone. This

Laboratory Testing

In general, the diagnostic workup should include complete blood count with differential, CD4 lymphocyte count, HIV-1 viral load, serum chemistries (including liver and renal function tests, fasting glucose and creatine phosphokinase), chest X-ray, electrocardiogram, blood and urine cultures (if indicated), toxicology screen, and psychotropic medication serum levels (when available). Based on the clinical presentation,

In Diabetes

As mentioned above there is circumstantial evidence that nitrosative stress and peroxynitrite formation importantly contribute to the pathogenesis of diabetic cardiomyopathy both in animals and humans. We have tested a novel metalloporphyrin peroxynitrite decomposition catalyst, FP15, in murine models of diabetic cardiovascular complications (92). We hypothesized that neutralization ofperoxynitrite with FP15 would ameliorate the development of cardiovascular dysfunction in a STZ-induced murine model of diabetes. To ensure that the animals received the FP15 treatment at a time when islet cell destruction was already complete and hyperglycemia has stabilized the treatment was initiated 6 weeks after the injection of STZ. Although FP15 did not affect blood glucose levels, it provided a marked protection against the loss of endothelium-depen-dent relaxant ability of the blood vessels (Fig. 1A) and improved the depression of both diastolic (Fig. 1B) and systolic function of the heart (92)....

Neuroimaging

A reduction in N-acetylaspartate (NAA), a marker for neuronal loss, using in vivo proton 1H MRS in patients with advanced HIV disease (Chang et al., 1999a, 1999b). The ratio of NAA to creatine (CR) reflects neuronal density and correlates with cognitive impairment in HIV-1-associated cognitive dysfunction (Becker et al., 1997). 1H MRS has also demonstrated progressive neuronal loss over time in HIV-infected individuals, and the degree of neuronal loss observed correlates with neurological impairment (Swindells et al., 1995, 1999). Similarly, the ratio of both choline (CHO) and myoinositol (MI) to CR reflects glial density, and both are elevated in HAD (McConnell et al., 1994 Jarvik et al., 1996 Tracey et al., 1998). Increased CHO levels reflect glial membrane turnover indicative of the astrocytosis that follows HIV encephalitis (HIVE).

Potential causes

1 Hypokalemic or hyperkalemic form. 2 Table 66. 3 Hypothyroidism or hyperthyroidism, acromegaly, Cushing disease, hyperparathyroidism, Conn syndrome, Cushing syndrome. 4 Myopathia distalis tarda hereditaria. 5 Elevation of creatine kinase (CK) levels in serum without clinical evidence of myopathy risk of malignant hyperthermia (related to general anesthesia, see p. 346).