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PubMed2005

Compartmental pharmacokinetics of dantrolene in adults: do malignant hyperthermia association dosing guidelines work?

Dantrolene is the only drug proven effective for prevention and treatment of malignant hyperthermia (MH). Current dosing recommendations are based on noncompartmental analyses and are largely empiric. They are also divergent, as evidenced by differing recommendations from the Malignant Hyperthermia Association of the United States (MHAUS) and European Sources. We determined the compartmental pharmacokinetics of dantrolene, simulated the concentration time course based on currently recommended dosing, and suggest an optimal regimen. Nine volunteers (55-89 kg) received IV infusions of dantrolene (5 mg/kg over 30 min followed by 0.05 mg.kg(-1) . h(-1) for 5 h). Venous blood samples were drawn for up to 60 h, and dantrolene plasma concentrations were determined by reverse phase, high-performance liquid chromatography. One, two, and three compartmental models were fitted to the data, and a covariate analysis was performed. All calculations were performed with NONMEM using the population approach. The data were adequately described by a two-compartment model with the following typical variable values (median +/- se): volumes of distribution V1= 3.24 +/- 0.61 L; V2= 22.9 +/- 1.53 L; plasma clearance CL el= 0.03 +/- 0.003 L/min; and distributional clearance CL dist= 1.24 +/- 0.22 L/min. All parameters were scaled linearly with weight. Simulations of European recommendations for treatment of MH lead to plasma concentrations converging to 14-18 mg/L within 24 h. Simulating MHAUS guidelines (intermittent bolus administration) yielded peak and trough plasma concentrations ranging from 6.7-22.6 mg/L. Based on our findings, we propose an infusion regimen adjusted to the initial bolus dose(s) required to control symptoms. This strategy maintains the individualized therapeutic concentrations and improves stability of plasma concentrations.

Adult↗
PubMed2004

Compartmentalization established by claudin-11-based tight junctions in stria vascularis is required for hearing through generation of endocochlear potential.

Claudins are cell adhesion molecules working at tight junctions (TJs) that are directly involved in compartmentalization in multicellular organisms. The cochlea includes a rather peculiar compartment filled with endolymph. This compartment is characterized by high K+ concentration (approximately 150 mM) and a positive endocochlear potential (approximately 90 mV; EP), both indispensable conditions for cochlear hair cells to transduce acoustic stimuli to electrical signals. These conditions are thought to be generated by the stria vascularis, which is adjacent to the endolymph compartment. The stria vascularis itself constitutes an isolated compartment delineated by two epithelial barriers, marginal and basal cell layers. Because TJs of basal cells are primarily composed of claudin-11, claudin-11-deficient (Cld11-/-) mice were generated with an expectation that the compartmentalization in stria vascularis in these mice would be affected. Auditory brainstem response measurements revealed that Cld11-/- mice suffered from deafness; although no obvious gross morphological malformations were detected in Cld11-/- cochlea, freeze-fracture replica electron microscopy showed that TJs disappeared from basal cells of the stria vascularis. In good agreement with this, tracer experiments showed that the basal cell barrier was destroyed without affecting the marginal cell barrier. Importantly, in the endolymph compartment of Cld11-/- cochlea, the K+ concentration was maintained around the normal level (approximately 150 mM), whereas the EP was suppressed down to approximately 30 mV. These findings indicated that the establishment of the stria vascularis compartment, especially the basal cell barrier, is indispensable for hearing ability through the generation/maintenance of EP but not of a high K+ concentration in the endolymph.

Alleles↗
PubMed1982

Compartmental pressure changes during calcaneal traction in tibial fractures.

The effect of calcaneal traction on the compartmental pressure in the legs of five individuals with tibial fractures was studied. Mean resting pressures without traction were found to be 31.9 mmHg for the deep posterior compartment and 27.0 mmHg for the anterior compartment. For each kilogram weight of traction applied the deep posterior pressure rose by 5.7 per cent of the resting value and the anterior pressure by 1.6 per cent. It is suggested that the weight of traction should be only sufficient to render the patient comfortable and maintain alignment of the limb. Excessive traction is likely to increase the risk of compartmental ischaemia. The application of six kilograms of traction would raise the mean resting pressure by 34 per cent from 31.9 to 42.7 mmHg.

Ankle↗
PubMed2007

Compartmentalized self-replication: a novel method for the directed evolution of polymerases and other enzymes.

Compartmentalized self-replication (CSR) is a novel method for the directed evolution of enzymes and, in particular, polymerases. In its simplest form, CSR consists of a simple feedback loop involving a polymerase that replicates only its own encoding gene (self-replication). Self-replication occurs in discrete, spatially separate, noncommunicating compartments formed by a heat-stable water-in-oil emulsion. Compartmentalization ensures the linkage of phenotype and genotype (i.e., it ensures that each polymerase replicates only its own encoding gene to the exclusion of those in the other compartments). As a result, adaptive gains by the polymerase directly (and proportionally) translate into genetic amplification of the encoding polymerase gene. CSR has proven to be a useful strategy for the directed evolution of polymerases directly from diverse repertoires of polymerase genes. In this chapter, we describe some of the CSR protocols used successfully to evolve variants of T. aquaticus Pol I (Taq) polymerase with novel and useful properties, such as increased thermostability or resistance to the potent inhibitor, heparin, from a repertoire of randomly mutated Taq polymerase genes.

DNA Replication↗
PubMed2006

Compartmentalization of cAMP-dependent signaling by phosphodiesterase-4D is involved in the regulation of vasopressin-mediated water reabsorption in renal principal cells.

The cAMP/protein kinase A (PKA)-dependent insertion of water channel aquaporin-2 (AQP2)-bearing vesicles into the plasma membrane in renal collecting duct principal cells (AQP2 shuttle) constitutes the molecular basis of arginine vasopressin (AVP)-regulated water reabsorption. cAMP/PKA signaling systems are compartmentalized by A kinase anchoring proteins (AKAP) that tether PKA to subcellular sites and by phosphodiesterases (PDE) that terminate PKA signaling through hydrolysis of localized cAMP. In primary cultured principal cells, AVP causes focal activation of PKA. PKA and cAMP-specific phosphodiesterase-4D (PDE4D) are located on AQP2-bearing vesicles. The selective PDE4 inhibitor rolipram increases AKAP-tethered PKA activity on AQP2-bearing vesicles and enhances the AQP2 shuttle and thereby the osmotic water permeability. AKAP18delta, which is located on AQP2-bearing vesicles, directly interacts with PDE4D and PKA. In response to AVP, PDE4D and AQP2 translocate to the plasma membrane. Here PDE4D is activated through PKA phosphorylation and reduces the osmotic water permeability. Taken together, a novel, compartmentalized, and physiologically relevant cAMP-dependent signal transduction module on AQP2-bearing vesicles, comprising anchored PDE4D, AKAP18delta, and PKA, has been identified.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1986

Equilibration and passage of water in the gastrointestinal tract of cattle in relation to estimating body water by compartmental kinetic models.

The volume of water in the rumen of four steers was increased (P less than .01) 47% when the level of ground cobs in the diet fed to the steers was changed from 10% to 50%. The difference in gut water content due to diet was not accurately (P greater than .10) estimated by deuterium oxide dilution using either one-, two- or three-compartmental models. Gut water was overestimated and empty body water underestimated when calculated by two-compartment models. The proportions of total body water within each compartment of a three-compartment model were quite variable among steers. When the two-compartment model was solved on the basis of measurements taken from either compartment, different compartment volumes were obtained. This indicated that the two-compartment model did not accurately describe the water equilibration process. Water in the contents of the proximal duodenum and terminal ileum equilibrated with blood in 30 min (range, 10 to 75 min), fecal water equilibrated in 4.3 h (range, 1.7 to 6.7 h) and water in rumen contents equilibrated in 8.3 h (range, 3.8 to 12.5 h). Diet did not affect (P greater than .10) equilibration time or the mean retention time of water in the gastrointestinal tract. Mean retention time was much longer than equilibration time; thus, the equilibration of water in the gastrointestinal tract contents was primarily dependent upon movement of water across the gut mucosa and not upon the flow of water through the gut. One-third of the water in the contents of the gastrointestinal tract was located outside the rumen. Compartmental modeling based only upon D2O disappearance from blood did not enable either gut water or rumen water to be accurately estimated.

Animals↗
PubMed1984

Estimation of guinea pig tracheobronchial transport rates using a compartmental model.

Mucociliary clearance in the tracheobronchial tree of guinea pigs was examined using monodisperse 7.9 micrometers MMAD polystyrene particles. Animals were exposed for approximately 1 h by inhalation via an intratracheal tube to aerosols tagged with gold-198 and fluorescent dyes. Following exposure, animals were radioactively monitored and sacrificed at predetermined times. The lungs were removed, freeze-dried, sectioned completely, and examined with a fluorescent microscope. Measurements were made of airway diameters where particles were found. An anatomic model for guinea pig lung morphology was used to assign ranges of airway diameters to five zones, which were incorporated into a compartmental model for lung clearance. Kinetic analysis of particle distributions in the zones led to development of first-order equations describing the compartmental clearance. Rate constants obtained from the kinetic analysis were used to estimate mucociliary transport rates in specific bronchial generations, which ranged from approximately 0.001 mm/min in the distal bronchioles to approximately 8 mm/min in the trachea, and resulted in a calculated 24-h clearance time for tracheobronchial clearance in the guinea pig. No evidence for either bronchial penetration by particles or relatively prolonged bronchial retention of particles was found in this study.

Aerosols↗
PubMed1982

Use of a guide instrument for compartmental knee arthroplasty.

To improve the positioning of the tibial component in compartmental knee arthroplasty a guide instrument was introduced. With the guide instrument the position in the frontal plane significantly improved from a mean medial slope of 10 degrees to 2 degrees. In the sagittal plane the change from a mean posterior slope of 5 degrees to 3 degrees was insignificant. The mean value for the Hip-Knee-Ankle angle (HKA) (ideal 180 degrees) was 186 degrees after "free-hand" operation and 183 degrees with the modified operative technique. Thus, it is possible with the aid of a guide instrument to improve the precision in compartmental knee arthroplasty.

Aged↗
PubMed1993

True anatomical compartmentalization of the cavernous sinus in a patient with bilateral cavernous dural arteriovenous fistulae. Case report.

An unusual case of complete anatomical compartmentalization of the cavernous sinus in a patient with bilateral Type D cavernous dural arteriovenous fistulae is described. This anatomical anomaly isolated the anterior cavernous sinus and orbital venous system, which was primarily responsible for the patient's clinical presentation. The compartmentalization of the cavernous sinus also limited options for definitive endovascular therapy to a transvenous approach via the superior ophthalmic vein.

Adult↗
PubMed2000

Compartmental differences in NK cell responsiveness to IL-12 during lymphocytic choriomeningitis virus infection.

Some, but not all, viral infections induce endogenous IL-12 to drive NK cell IFN-gamma production and downstream antiviral defenses during innate immune responses. Even though lymphocytic choriomeningitis virus (LCMV) can be sensitive to IFN-gamma-mediated antiviral effects, infections with this agent do not elicit IL-12 or early IFN-gamma in immunocompetent hosts. Studies presented here demonstrate that LCMV infections of mice not only fail to induce IL-12, but also modify responsiveness to exogenous IL-12 for IFN-gamma production. IFN-gamma responses induced by IL-12 administration were greatly diminished in splenic populations, but significantly increased in serum and hepatic leukocytes, during the early course of LCMV infections. The IFN-gamma production was NK cell dependent, and the compartmental dichotomy between spleen and liver was also demonstrated in response to in vitro IL-12 stimulation. Although infections did increase proportions and numbers of liver NK cells, changes in responsiveness for IFN-gamma expression could not be explained by cell redistribution. Corroborating changes in proportions of NK cells induced to express intracellular IFN-gamma protein within the compartments were observed. The reduction in ability of splenic populations to produce IL-12-induced IFN-gamma after infection by LCMV was associated with decreased efficacy of administered IL-12 for promoting IFN-gamma-dependent antiviral effects in the spleen. Concomitantly, the maintenance of hepatic population IFN-gamma production was associated with preserved efficacy of administered IL-12 to elicit IFN-gamma-dependent antiviral effects in the liver. Taken together, these results demonstrate modifications of compartmental responses to IL-12 by viral infections and the consequences of these changes for efficacy of cytokine therapy.

Animals↗
PubMedDate not supplied

[Compartmentalized organization of human corpus striatum].

INTRODUCTION: The compartmentalization of the human striatum was first established thanks to the pioneer work of Graybiel and Ragsdale in 1978. These authors described in the human striatum, as well as in the cats and primates, zones poorly stained for the enzyme acetylcholinesterase, which they termed striosomes, that lie in more intensely stained matrix. The striosome/matrix subdivision of the striatum is supported by the distribution of a wide variety of transmitter-related substances and by the organization of striatal afferent and efferent connections. DEVELOPMENT: The results of many studies performed in different species in the last twenty years have indicated that the chemical heterogeneity of striatum is more complex than the simple subdivision into striosomes and matrix compartments. Thus, a further subdivisions of the dual striosome/matrix system has been proposed on the basis of the results of a huge amount of works combining tract tracing methods with histochemical techniques. The matrix has been demonstrated to be heterogeneous by containing numerous functional modules that were termed matrisomes. Furthermore, the most recent study of the distribution of a wide variety of neurochemical markers in the striosomal compartment of the human striatum, has revealed that the striosomes are themselves heterogeneous, being composed of a central core and a peripheral region. CONCLUSIONS: Since it is now twenty years from the first description of the striosome/matrix organization of the striatum, in this review we intend to summarize the major finding regarding the compartmental organization of this subcortical structure that have been obtained during this period of time.

Animals↗
PubMed2000

[Report of a case of compartmental syndrome secondary to prolonged lithotomy position].

The lithotomy position is widely used in urological surgery to obtain adequate exposure of the perineal plane. It is used, for instance, for stenosis of the posterior urethra. Fortunately, it rarely gives rise to complications although if the operation takes a long time the patient may suffer various adverse reactions; these range from simple peroneal nerve distress to thromboembolism [1, 2] and the much more serious "compartmental syndrome" [2, 3, 4]. There is still debate about the best therapeutic approach to a lesion caused by prolonged muscle compression. Some suggest immediate fasciotomy, whether others hold out for conservative treatment. We report here a case of compartmental syndrome arising in a patient who had to remain the the lithotomy position for a long time, which responded well to conservative treatment.

Adult↗
PubMed2000

Non-invasive quantification of liver perfusion with dynamic computed tomography and a dual-input one-compartmental model.

Various liver diseases lead to significant alterations of the hepatic microcirculation. Therefore, quantification of hepatic perfusion has the potential to improve the assessment and management of liver diseases. Most methods used to quantify liver perfusion are invasive or controversial. This paper describes and validates a non-invasive method for the quantification of liver perfusion using computed tomography (CT). Dynamic single-section CT of the liver was performed after intravenous bolus administration of a low-molecular-mass iodinated contrast agent. Hepatic, aortic and portal-venous time-density curves were fitted with a dual-input one-compartmental model to calculate liver perfusion. Validation studies consisted of simultaneous measurements of hepatic perfusion with CT and with radiolabelled microspheres in rabbits at rest and after adenosine infusion. The feasibility and reproducibility of the CT method in humans was assessed by three observers in 10 patients without liver disease. In rabbits, significant correlations were observed between perfusion measurements obtained with CT and with microspheres (r=0.92 for total liver perfusion, r=0.81 for arterial perfusion and r=0.85 for portal perfusion). In patients, total liver plasma perfusion measured with CT was 112+/-28 ml.min(-1).100 ml(-1), arterial plasma perfusion was 18+/-12 ml.min(-1).100 ml(-1) and portal plasma perfusion was 93+/-31 ml.min(-1).100 ml(-1). The measurements obtained by the three observers were not significantly different from each other (P>0.1). Our results indicate that dynamic CT combined with a dual-input one-compartmental model provides a valid and reliable method for the non-invasive quantification of perfusion in the normal liver.

Adult↗
PubMed1975

Structural analysis of compartmental models for the hepatic kinetics of drugs.

The structure of some compartmental models for the analysis of the hepatobiliary kinetics of bromosulphalein (BSP) was studied in order to evaluate their adequacy in the estimation of the processes involved in the hepatic metabolism of drugs, namely uptake, conugation, and biliary excretion. Biological measurements were obtained from 4 cholecystectomized patients with a biliary T-tube. Blood and bile specimens were taken at various intervals after the administration of a single intravenous dose of BSP and analyzed for both direct BSP quantitation and chromatographic separation and estimation of BSP metabolic fractions. The structural analysis was carried out by using a mathematical model that described the kinetics of BSP. By means of computer simulations different measurement situations were analyzed, showing for each experimental condition the available information and the degree of accuracy of each estimated parameter. The obtained results show that the use of compartmental models can provide a useful theoretical framework by which the experimental data can be interpreted for the evaluation of the hepatobiliary metabolism and for a discriminant analysis between different physiopathological conditions.

Bile↗
PubMed2001

The entire trajectories of single olivocerebellar axons in the cerebellar cortex and their contribution to Cerebellar compartmentalization.

The functional partitioning of the cerebellar cortex depends on the projection patterns of its afferent and efferent neurons. However, the entire morphology of individual projection neurons has been demonstrated in only a few classes of neurons in the vertebrate CNS. To investigate the contribution of the projection pattern of individual olivocerebellar axons to the cerebellar functional compartmentalization, we labeled individual olivocerebellar axons, which terminate in the cerebellar cortex as climbing fibers, with biotinylated dextran amine injected into the inferior olive in the rat, and completely reconstructed the entire trajectories of 34 olivocerebellar axons from serial sections of the cerebellum and medulla. Single axons had seven climbing fibers on average, which terminated at similar distances from the midline in a single or in multiple lobules. Cortical projection areas of adjacent olivary neurons were clustered as narrow but separate longitudinal segments and often innervated by collaterals of single neurons. Comparison of the cerebellar distribution of olivocerebellar axons arising from different sites within a single olivary subnucleus indicated that slightly distant neurons projected to complementary sets of such segments in a single longitudinal band. Several of these longitudinal bands formed a so-called parasagittal zone innervated by a subnucleus of the inferior olive. Single olivocerebellar axons projected rostrocaudally to segments within a single band but did not project mediolaterally to multiple bands. These results suggest fine substructural organization in the cerebellar compartmentalization that may represent functional units.

Animals↗
PubMed1977

Compartmentalization of adenosine 3':5'-monophosphate and adenosine 3':5'-monophosphate-dependent protein kinase in heart tissue.

In rabbit heart homogenates about 50% of the cAMP-dependent protein kinase activity was associated with the low speed particulate fraction. In homogenates of rat or beef heart this fraction represented approximately 30% of the activity. The percentage of the enzyme in the particulate fraction was not appreciably affected either by preparing more dilute homogenates or by aging homogenates for up to 2 h before centrifugation. The particulate enzyme was not solubilized at physiological ionic strength or by the presence of exogenous proteins during homogenization. However, the holoenzyme or regulatory subunit could be solubilized either by Triton X-100, high pH, or trypsin treatment. In hearts of all species studied, the particulate-bound protein kinase was mainly or entirely the type II isozyme, suggesting isozyme compartmentalization. In rabbit hearts perfused in the absence of hormones and homogenized in the presence of 0.25 M NaCl, at least 50% of the cAMP in homogenates was associated with the particulate fraction. Omitting NaCl reduced the amount of particulate-bound cAMP. Most of the particulate-bound cAMP was probably associated with the regulatory subunit in this fraction since approximately 70% of the bound nucleotide was solubilized by addition of homogeneous catalytic subunit to the particulate fraction. The amount of cAMP in the particulate fraction (0.16 nmol/g of tissue) was approximately one-half the amount of the regulatory subunit monomer (0.31 nmol/g of tissue) in this fraction. The calculated amount of catalytic subunit in the particulate fraction was 0.18 nmol/g of tissue. Either epinephrine alone or epinephrine plus 1-methyl-3-isobutylxanthine increased the cAMP content of the particulate and supernatant fractions. The cAMP level was increased more in the supernatant fraction, possibly because the cAMP level became saturating for the regulatory subunit in the particulate fraction. The increase in cAMP was associated with translocation of a large percentage of the catalytic subunit activity from the particulate to the supernatant fraction. The distribution of the regulatory subunit of the enzyme was not significantly affected by this treatment. The catalytic subunit translocation could be mimicked by addition of cAMP to homogenates before centrifugation. The data suggest that the regulatory subunit of the protein kinase, at least that of isozyme II, is bound to particulate material, and theactive catalytic subunit is released by formation of the regulatory subunit-cAMP complex when the tissue cAMP concentration is elevated. A model for compartmentalized hormonal control is presented.

Animals↗
PubMed1991

[Does covered tibial intramedullary nailing promote formation of a compartment syndrome? Perioperative and intraoperative continuous monitoring of compartmental pressure in covered tibial intramedullary nailing].

Between October 1988 and October 1989 we performed a continuously pressure monitoring with the infusion technique in the tibialis anterior and deep posterior compartment of the lower leg during the nailing of the tibia in complete fractures of the lower leg in 16 patients. We set up 2 groups of patients because of different pathophysiological conditions: patients, who were operated on a few days after trauma (Group A) and patients operated on months after the trauma (Group B) because of non-union of the tibia. The effects of the preoperative, intraoperative, and postoperative manipulations were recorded. In no case we saw a beginning compartmental syndrome, although very high pressures of 100 mmHg in Group A and 55 mmHg in Group B in the deep posterior compartment during reduction of the fracture were registrated. The registrated pressures correlated very well with the manipulations during the operation and were absolutely reversible after the ending of these manipulations. In our observation the closed tibia nailing does not favorize the development of a compartmental syndrome, if not done during the vulnerable phase after the first days after trauma, in blunt multiple trauma patients and during bleeding complications.

Adult↗
PubMed1991

Compartmental analysis of steady-state taurocholate transport kinetics by isolated rat hepatocytes.

We used compartmental modeling to describe taurocholate transport by isolated rat liver cells in suspension. Cells are preincubated in the presence of unlabeled taurocholate. When a steady-state for taurocholate is reached, radiolabeled taurocholate is added to the medium and its exchange kinetics between the medium and the cells are followed over time. Because the studies are performed under steady-state conditions, the kinetics can be described by linear compartmental models. We found a closed two-compartment model sufficient to describe the steady-state transport data. Simulations reveal that if the pools of free and bound intracellular taurocholate exchange rapidly, the cells will behave as a single, kinetically homogeneous compartment and intracellular events will not influence the exchange kinetics of taurocholate between the medium and the cells. The two-compartment model was used to study the concentration dependence of taurocholate transport by isolated cells. Steady-state transport rates and taurocholate concentrations in the medium and the cells were calculated using the model equations. Taurocholate influx, accumulation and efflux processes were studied simultaneously by examining the relationship between appropriate combinations of these variables. Application of this approach to study the inhibition of taurocholate transport by taurochenodeoxycholate is illustrated. In conclusion, this method provides a complementary approach to initial rate studies, which are generally used to investigate bile acid transport by isolated cells.

Animals↗