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OBJECTIVE: To assess the effects of moderate exercise on plasma creatine kinase (CK) pharmacokinetics and to estimate exercise-induced muscle damage in dogs. ANIMALS: 6 untrained adult Beagles. PROCEDURE: The study was divided into 3 phases. In phase 1, dogs ran for 1 hour at a speed of 9 km/h, and samples were used to determine the area under the plasma CK activity versus time curve (AUC) induced by exercise. In phases 2 and 3, pharmacokinetics of CK were calculated in dogs during exercise and at rest, respectively. Values for AUC and plasma clearance (CI) were used to estimate muscle damage. RESULTS: At rest, values for Cl, steady-state volume of distribution (Vdss), and mean retention time (MRT) were 0.32+/-0.02 ml/kg of body weight/min, 57+/-173 ml/kg, and 3.0+/-0.57 h, respectively. During exercise, Cl decreased significantly (0.26+/-0.03 ml/kg/min), MRT increased significantly, (4.4+/-0.97 h), and Vdss remained unchanged. Peak of plasma CK activity (151+/-58.8 U/L) was observed 3 hours after completion of exercise. Estimated equivalent amount of muscle corresponding to the quantity of CK released was 41+/-29.3 mg/kg. CONCLUSION AND CLINICAL RELEVANCE: These results revealed that exercise had a minor effect on CK disposition and that the equivalent amount of muscle damaged by moderate exercise was negligible. This study illustrates the relevance for use of the minimally invasive and quantitative pharmacokinetic approach when estimating muscle damage.

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The objective of the study was to investigate the potential in-vitro and in-vivo myotoxicity of different in-situ forming biodegradable drug delivery systems, namely in-situ Microparticle (ISM) systems and polymer solutions (in-situ implant systems). The acute myotoxicity was evaluated in-vitro using the isolated rodent skeletal muscle model by measuring the cumulative creatine kinase (CK) efflux. For the in-vivo study, following intramuscular injection (i.m.) into male Sprague Dawley rats, the area under the plasma CK-curve was used to evaluate muscle damage. The formulations included ISM-systems [a poly (lactide)-solvent phase dispersed into an external oil phase] and poly (lactide) solutions (in-situ implant systems). Phenytoin and normal saline served as positive and negative controls, respectively. Poly (lactide) in different solvents (in-situ implant systems) resulted in 14.4-24.3 times higher CK-values compared to normal saline, indicating a high myotoxic potential. With the ISM-system, the CK-release was significantly lower, decreased with a lower polymer phase: oil phase ratio, and approached the values of normal saline at a ratio of 1:4. Bupivacaine HCl- and Buserelin acetate- containing ISM-systems resulted in significantly lower CK-levels when compared to the corresponding drug formulation in normal saline. The in-vivo studies confirmed the in-vitro data and showed good muscle compatibility of the ISM-systems.

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Objetivos. Proponemos que en la rata, la síntesis anaeróbica de ATP mediada por el sistema creatina cinasa/fosfocreatina (CK/PCr) es sexualmente dimórfica durante la maduración y el envejecimiento del corazón. Antecedentes. En función de género, las diferencias morfológicas y funcionales durante el envejecimiento cardiovascular parecen explicar la mayor longevidad de las hembras de los mamíferos y de la mujer. Material y Métodos. Se estudiaron 46 ratas Wistar de ambos sexos, por parejas de peso semejante de 200, 250 y 300 g de peso corporal. Resultados. No se observaron diferencias sexuales en cuanto al peso del corazón y a su contenido de proteínas del sobrenadante post 27 000 xg, en ninguno de los pesos corporales estudiados en la rata. Los cocientes peso cardíaco/peso corporal no mostraron diferencias significativas de género durante todo el estudio. Se encontraron diferencias de la actividad específica de la CK cardíaca solamente a los 257 ñ 6 g de peso corporal, debido al decremento de tal actividad en el macho. El corazón de la hembra mostró una mayor variedad de isoenzimas de la CK citosólica en todos los pesos corporales estudiados. En los corazones de rata de ambos sexos se encontraron consistentemente isoenzimas del tipo cerebral BB-CK citosólicas fuertemente teñidas catalíticamente, durante todo el estudio. Este hallazgo no está de acuerdo con la aceptada especificidad tisular de la CK cardíaca. Conclusiones. En este trabajo se encontraron diferencias significativas de género, principalmente en cuanto a los patrones y al número de isoformas catalíticas de la CK citosólica del corazón de rata. En relación con los mecanismos anaeróbicos de la producción de ATP, estas diferencias podrían explicar, en parte, la susceptibilidad diferencial sexual al compromiso hemodinámico, en respuesta al estrés cardiovascular, en favor de las hembras.

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Pharmacokinetic variables of skeletal muscle creatine kinase were determined in sheep after intravenous and intramuscular administration of the semipurified enzyme. Catheters implanted in the jugular vein were used for both intravenous injections and blood withdrawals. Blood sample collection by vacutainer and hemolysis may in fact have considerable effects on the measurement of creatine kinase activity in plasma. The change in the enzyme activity versus time in the plasma, after intravenous administration (123 +/- 38 U/kg) of creatine kinase, was fitted by a biexponential model. The mean volume of the central compartment (45 +/- 5 mL/kg) was approximately equal to the plasma volume. Plasma half-life and plasma clearance of creatine kinase were 3.7 +/- 1.7 h and 23 +/- 8 mL.kg-1.h-1, respectively. Mean plasma bioavailability of creatine kinase after intramuscular administration (357 +/- 36 U/kg) in both the loins and the gluteal mass was 42%. Maximal plasma activity was observed 4 and 5 h after injection and the half-life of the terminal phase was 7.3 or 8.6 h according to the muscle. The extent of muscle damage after intramuscular administrations of 21 veterinary drug formulations (one product per animal) was estimated from the total creatine kinase activity released in plasma during the 72 h following the injection. Equivalent weights of damaged muscle ranged from 1.4 to 83.3 g according to the irritant potency of the test formulation. Results differed only moderately between the injection sites (right and left gluteal mass) in the same animal. It can be concluded from this study that, in sheep: i) the bioavailability of creatine kinase from different injection sites (gluteal mass and loins) is comparable; and ii) the intra-individual variability in the estimation of muscle damage is moderate. Once validated, this non-invasive approach for local tolerance studies could be of value in assessing and comparing the irritant potency of veterinary drugs and in reducing the number of animals required.

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Intramuscular administration of veterinary drugs can induce severe muscle damage resulting in economic losses and residue persistence. Local tolerance is usually evaluated by macroscopic examination of the injection site requiring euthanasia of a large number of animals. A non-invasive quantitative method, based on the pharmacokinetic analysis of creatine kinase (CK) release from muscle, is proposed for the evaluation of post-injection muscle damage. Plasma CK activity is a specific and sensitive marker of skeletal muscle damage. Three disposition parameters are needed to measure the actual amount of CK released by the injured muscle: plasma CK clearance, bioavailability of CK from muscle and area under the plasma CK activity vs time curve. A CK solution from a homologous muscle extract was administered in different animal species by intravenous route and by intramuscular route for the determination of the CK disposition parameters. The general equation for the determination of the destroyed muscle equivalent (Q), following the drug intramuscular injection, is: Q = CI x AUC/F x M, with Cl, the plasma CK clearance; AUC, the area under the plasma CK vs time curve after drug administration; F, the CK bioavailability from muscle; and M, the CK content in the injected muscle. Population equations are proposed for dogs, sheep, horses and cattle and their use is illustrated. Rabbits and pigs seem inappropriate species for the pharmacokinetic approach because of stress-induced spontaneous increases in plasma CK. In cattle, for example, Q (g.kg-1 body weight) = 4.4 x 10(-6) AUC (U.h.L-1) and the estimated equivalent of muscle destroyed after a single IM injection of a chloramphenicol formulation was about 300 g. This screening approach is simple, ethical, rapid and inexpensive.

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The present study was undertaken to measure the weight of muscle destroyed by an intramuscular injection of phenylbutazone (PBZ) in horses. In six horses, CK disposition parameters were evaluated after intravenous (i.v.) and intramuscular (i.m.) administration of a CK horse preparation. The same horses received PBZ, a potentially irritating agent, by i.v. and i.m. (neck and hindquarter) routes. Data were analysed using compartmental approaches and instantaneous CK flux was calculated using a discrete deconvolution method. For a 150 U/kg CK dose, the steady-state volume of distribution was 0.050 +/- 0.0115 L/kg and the plasma half-life was 112 +/- 18 min. After CK i.m. administration, the half-life of the terminal phase was 11.8 +/- 5.3 h indicating a flip-flop process and the mean bioavailability of CK was close to 100%. After PBZ i.m. administration, the CK activity was significantly increased with peak values of 508 +/- 109 U/L after the neck administration and 873 +/- 365 U/L after the gluteal administration. By measuring the total amount of CK released from injured muscle, it was calculated that an equivalent of 0.044 +/- 0.029 g/kg of muscle was destroyed after PBZ administration in the neck. The corresponding figure was 0.118 +/- 0.048 g/kg after intragluteal PBZ administration. By deconvoluting plasma CK activity, it was shown that the CK entry rate was maximum for the first 30-60 min following PBZ administration, which then decreased slowly to return to the control value after a delay of 24-48 h after PBZ administration. It was concluded that the CK release pattern following a controlled muscular damage was a non-invasive approach useful for quantifying the amount of damaged muscle, and that the calculation of CK input rate by deconvolution was of potential interest in describing events at the muscle cell level.

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The fate of skeletal muscle-derived creatine kinase (CK) was investigated in six dogs. After i.m. and i.v. injections of 3000 g and 105,000 g supernatants of dog muscle homogenates, plasma CK activity was measured up to 48 h. There was no significant difference in pharmacokinetic parameters dependent on the type of supernatant injected. After i.v. injection, the volume of distribution of CK was equal to the plasma volume, CK clearance was relatively low (about 0.5 mL/kg/min) and its terminal half-life of elimination was about 2.5 h. After i.m. injection, the CK terminal half-life was about 6.5 h, demonstrating a flip-flop mechanism, i.e. a limiting absorption process from the site of injection. Bioavailability after i.m. injection was about 65%, and the rate of absorption from muscle injection site was relatively slow: peak activity occurred at the second hour post administration, and most CK activity had been absorbed by 24 h. These pharmacokinetic parameters can be used as a basis for a minimally invasive means of quantitating muscle damage either after intramuscular drug administration or in canine sports medicine.

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For the first time we have compared time courses of cardiac myosin light chain-1 (MLC-1), beta-type myosin heavy chain (MHC), troponin T (TnT), myoglobin, creatine kinase (CK) and CKMB in the same patients with acute myocardial infarction (AMI). Blood samples were serially collected in 23 patients with first-time AMI. All but 3 patients received intravenous thrombolytic treatment. TnT and MLC-1 time courses were biphasic in most patients and showed two distinct peaks in 13 and 8 patients, respectively. MHC time courses were usually monophasic. Only 1 patient showed a biphasic MHC time course with two distinct peak values. Although MHC and MLC were lower by about the fourth day after onset of AMI in early reperfused patients, reperfusion did not qualitatively alter MLC and MHC release (no significant influence on the first appearance in blood or on time to peak). MLC and MHC peaks correlated closely (r = 0.75, P = 0.0001), whereas TnT peaks were correlated less closely with MLC or MHC peaks (r = 0.58 each, P < 0.007). Peak values of all cardiac contractile proteins correlated closely and significantly with CKMB peaks (0.75 < or = r < or = 0.81, P < or = 0.0006). Myoglobin was the first marker to increase in blood after AMI and showed the earliest peaks, whereas MHC increased latest showing the latest peaks. TnT increased significantly (P = 0.0001) earlier than MLC and MHC. These results can be explained by the impact of the intracellular compartmentation of a cardiac protein on the rapidity with which it is released after AMI.

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Pharmacokinetic variables of skeletal muscle creatine kinase (CK) activity after IV administration of a muscle extract; CK bioavailability after IM administration of the muscle extract; and effect of IM administration of saline solution, to appreciate the possible release of CK consecutive to muscle puncture, were determined in 6 cows. A general equation for the quantitative estimation of skeletal muscle damage also was derived. Administration of saline solution IM had no effect on plasma CK activity (ANOVA, P > 0.05) in any of the cows. After IV administration of the muscle extract (150 U/kg of body weight), mean volume of the central compartment, plasma half-life, and plasma clearance of CK were 0.027 +/- 0.007 L/kg, 520 +/- 109 minutes, and 6.43 +/- 2.29 ml/kg/h, respectively. After IM administration (150 U/kg), mean bioavailability of CK was 51 +/- 17% and maximal plasma CK activity (500 +/- 97 U/L) was observed at 454 +/- 131 minutes. The rate of CK activity entry into plasma was determined by use of deconvolution analysis. Two peaks were observed; the first appeared before the 30th minute after IM administration, and the second appeared at 3.3 +/- 1.1 hours. Amplitudes were 6.31 +/- 4.45 and 6.57 +/- 3.08 U/kg/h, for the first and the second peaks, respectively. The quantity of CK liberated from control muscle was 0.69 +/- 0.12 U/kg/h, corresponding to a normal daily catabolism of 5.8 +/- 1.0 mg of muscle/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

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To quantify the extent of muscle alteration during prolonged exercise, the release rate of creatine kinase (CK) from striated muscle was measured in six horses during a rest period (6 h) and during three exercise tests (15, 30, and 60 km) at a constant speed of 200 m/min. CK clearance was measured after intravenous bolus administration (150 U/kg) of a CK solution obtained from horse muscle. The CK steady-state volume of distribution was 0.059 +/- 0.0215 l/kg, the terminal half-life was 123 +/- 28 min, and the plasma clearance was 0.36 +/- 0.10 ml.kg-1 x min-1. After an intramuscular CK administration, the CK systemic availability was 74.1 +/- 21.2% and the half time of absorption was 9.4 +/- 5.7 h, indicating a slow process for CK transit through the lymphatic system. The CK release rate was only significantly increased during the 60-km exercise test. The increase of CK plasma activity was observed after a delay of approximately 5 h and peaked after the end of the race; the estimated CK release rate was 9.92 +/- 2.62 U.kg-1 x h-1 over a mean duration period of 65.8 +/- 15.8 h. With the CK activity of horse striated muscle taken into account, a 60-km race released a quantity of CK corresponding to an equivalent of 18.8 +/- 4.3 g striated muscle. It is concluded that the equivalent amount of damaged muscle may be considered as negligible for a 60-km test and that only very high plasma CK activity levels (at least higher than 10,000 U/l) may provide some evidence of a myolysis.

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The purpose of this study was to compare the disposition parameters of creatine kinase (CK) in rabbits after intravenous bolus administration of 3 CK preparations: 1) purified CK; 2) CK obtained from a muscular extract after a 3,000 g centrifugation (ie with cell remains) (3,000 g CK); or 3) a 105,000 g centrifugation (ie the cytosolic soluble phase) (105,000 g CK). The plasma half-lives were not significantly different (approximately 9 h). In contrast, the clearance of 3,000 g CK (3.25 +/- 0.33 ml.kg-1.h-1) was significantly lower than that of the 2 others (7.00 +/- 0.49 ml.kg-1.h-1 and 4.63 +/- 0.65 ml.kg-1.h-1 for 105,000 g and purified CK, respectively). These findings suggest that purified CK preparation is not the most appropriate form for determination of enzyme pharmacokinetic parameters following muscle damage.

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A systematic study was performed to optimize the accuracy of kinetic parameters derived from magnetization transfer measurements. Three techniques were investigated: time-dependent saturation transfer (TDST), saturation recovery (SRS), and inversion recovery (IRS). In the last two methods, one of the resonances undergoing exchange is saturated throughout the experiment. The three techniques were compared with respect to the accuracy of the kinetic parameters derived from experiments performed in a given, fixed, amount of time. Stochastic simulation of magnetization transfer experiments was performed to optimize experimental design. General formulas for the relative accuracies of the unidirectional rate constant (k) were derived for each of the three experimental methods. It was calculated that for k values between 0.1 and 1.0 s-1, T1 values between 1 and 10 s, and relaxation delays appropriate for the creatine kinase reaction, the SRS method yields more accurate values of k than does the IRS method. The TDST method is more accurate than the SRS method for reactions where T1 is long and k is large, within the range of k and T1 values examined. Experimental verification of the method was carried out on a solution in which the forward (PCr----ATP) rate constant (kf) of the creatine kinase reaction was measured.

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Oxygen toxicity in the non-ischemic and non-hypoxic heart has not been reported. In an experiment on isolated rat heart lung preparation, the effects of superoxide dismutase (SOD) on oxygen toxicity during hyperoxic perfusion were evaluated with intramyocardial high energy phosphates and the release of creatine phosphokinase (CPK) in the perfusate blood. Although there were no significant differences in high energy phosphates between SOD-treated and untreated hearts, the CPK release from the SOD-treated hearts was significantly less than from the untreated hearts. SOD increased the oxygen pressure of perfusate blood, too. These results indicate that hyperoxia induced cardiac and lung cell damage which was protected by SOD.

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Release characteristics of S-LD, S-LD1, S-ASAT, S-CK and S-CK-MB were studied in 47 consecutive AMI patients. In addition, previously obtained data for serum myoglobin (S-MYO) were compared. Serum was sampled at regular intervals after admission to the Coronary Care Unit (CCU). The release rate and half lives of the enzymes were calculated according to a one-compartment kinetic model. The time to peak values, the time of total release and the half lives were interrelated in the following order: MYO less than CK-MB less than CK less than ASAT less than LD1 less than LD which coincides with the wellknown appearance and disappearance rates in serum. The ratio between mean peak values and upper reference limits followed the reverse order. The finding that the release rate of enzymes and half-lives co-vary is hypothetically suggested to be attributed to differences in rate of membrane diffusion. There is indirect evidence that a slow indicator such as LD1 reflects infarct size better than fast indicators with rapid release and removal such as MYO or CK-MB. However, these fast markers have a better signal to noise ratio, whereby they probably reflect changes in the infarction process better.

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