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PubMed2003

Population pharmacokinetics of platinum after nedaplatin administration and model validation in adult patients.

AIMS: The pharmacokinetics of unbound platinum after administration of an anticancer drug nedaplatin, cis-diammineglycolateplatinum were examined using population analysis. The relevant covariates and the extent of inter- and intra-individual variability were evaluated. METHODS: In order to clarify the pharmacokinetic profile of nedaplatin, unbound platinum concentrations (789 points) in plasma after intravenous infusion of nedaplatin were obtained from 183 courses for 141 patients. Plasma concentration data were analysed by nonlinear mixed effect modelling using NONMEM to evaluate the population mean parameters and variances for inter- and intra-individual random effects. The final population model was validated by parameter sensitivity analysis using objective function mapping, the bootstrap resampling and a data-splitting technique, i.e. the Jackknife method, and the predictive performance of the final model was evaluated. RESULTS: A two-compartment pharmacokinetic model with zero-order input and first order elimination described the current data well. The significant covariates were creatinine clearance (CLcr) for clearance of platinum (CL) [population mean [95% confidence interval (CI)] CL (l h(-1)) = 4.47 (3.27, 5.67) + 0.0738 (0.0581, 0.0896) x CLcr (CLcr: ml min(-1))] and body weight (BW: kg) for volume of distribution of platinum (Vc) [Vc (l) = 12.0 (7.5, 16.5) + 0.163 (0.081, 0.246) x BW]. Inter-individual variations (CV%, 95% CI) for CL and Vc were 25.5% (20.7, 29.6) and 21.4% (17.0, 24.1), respectively, and intra-individual variation (CV%, 95% CI) was 12.6% (10.5, 14.4). The effects of pretreatment with nedaplatin or other platinum agents on clearance and volume of distribution were also tested, but no significant effect was found. The relationship between the observed and predicted unbound platinum concentration by empirical Bayesian prediction showed good correlation with no bias, suggesting that the final model explains well the observed data in the patients. The mean prediction error and root mean square prediction error (95% CI) were - 0.0164 micro g ml(-1) (- 0.4379, 0.4051) and 0.2155 micro g ml(-1) (not calculable, 0.6523), respectively. The values of mean, standard error and 95% CI for objective function mapping, the bootstrap resampling, the Jackknife estimates and the final model coincided well. CONCLUSIONS: A population pharmacokinetic model was developed for unbound platinum after intravenous infusion of nedaplatin. Only creatinine clearance was found to be a significant covariate of clearance, and BW was found to be a significant covariate of volume of distribution. These population pharmacokinetic estimates are useful for setting initial dosing of nedaplatin using its population mean and can also be used for setting appropriate dosage regimens using empirical Bayesian forecasting.

Adult↗

PubMed1979

Anisotropic flexibility of DNA and the nucleosomal structure.

Potential energy calculations of the DNA duplex dimeric subunit show that the double helix may be bent in the direction of minor and major grooves much more easily than in other directions. It is found that the total winding angle of DNA decreases upon such bending. A new model for DNA folding in the nucleosome is proposed on the basis of these findings according to which the DNA molecule is kinked each fifth base pair to the side of the minor and major grooves alternatively. The model explains the known contradiction between a C-like circular dichroism for the nucleosomal DNA and the nuclease digestion data, which testify to the B-form of DNA.

DNA↗

PubMed2004

Are there reliable predictors of postoperative pain?

BACKGROUND: The purpose of this study was to identify the preoperative determinants of severe postoperative pain. METHODS: Potential predictors were assessed using a questionnaire submitted on the day before surgery. Pain at rest, and pain during coughing/mobilization, were measured using visual analog scales on the day of surgery and on the following 2 days. The type of postoperative pain management was not standardized and was prescribed by the anesthesiologist in charge. Multivariate logistic regression models explaining postoperative pain were developed in Group I, comprising 304 consecutive patients undergoing orthopedic or intraperitoneal surgery, and validated in Group II, comprising 145 independent patients. RESULTS: Of the 62 variables examined by univariate analysis, only five were found to increase the risk of severe postoperative pain in Group I at rest and six factors during cough/mobilization. In the multivariate model for pain at rest, general anesthesia, expectation of postoperative pain, and chronic sleeping difficulties increased the risk of severe postoperative pain. In Group II, only chronic sleeping difficulties remained (OR: 3.97, 95% Cl: 1.69-9.29). In the multivariate model during cough/mobilization, intraperitoneal surgery, fear of postoperative pain, and having a relative with a history of pain increased the risk of severe postoperative pain in Group I. Intraperitoneal surgery OR 2.45 (95% Cl = 1.01-4.50) and having a relative with a history of pain OR 2.06 (95% Cl = 1.005-4.50) remained in Group II. CONCLUSION: Of the many factors that may influence postoperative pain, chronic sleeping difficulties emerge in this population of patients as the strongest determinant of pain at rest. Intraperitoneal surgery and having a relative with a history of pain are the strongest determinants of pain during cough/mobilization. These findings make physiological sense and deserve more attention by anesthesiologists.

Adolescent↗

PubMed1977

Effects of membrane-energy mutations and cations on streptomycin and gentamicin accumulation by bacteria: a model for entry of streptomycin and gentamicin in susceptible and resistant bacteria.

Several mutants of Escherichia coli affecting aerobic energy generation and energization of the bacterial membrane have been examined for their effect on streptomycin and gentamicin accumulation and susceptibility. A heme-deficient mutant (K207) and two mutants (CJ-8 [colicin K insensitive] and NR-70) associated with defective aerobic active transport were associated with decreased transport of streptomycin and gentamicin and increased resistance to those antibiotics. These mutants also exhibited increased resistance to several other aminoglycoside antibiotics, but not the aminocyclitol spectinomycin. The same observations were made with a ubiquinone-deficient mutant, but a strA derivative of this mutant was shown additionally to be saturable for streptomycin accumulation at a concentration four or more times lower than that required for saturation of the parent. A mutant uncoupled for adenosine 5'-triphosphate synthesis from electron transport and membrane Mg-adenosine 5'-triphosphatase deficient was hypersensitive to those aminoglycosides tested and spectinomycin, and showed enhanced transport of streptomycin and gentamicin. A variety of compounds structurally related to streptomycin were examined at high concentrations for inhibition of streptomycin uptake in a strA mutant of E. coli K-12 SA 1306, but no evidence for competition was detected, suggesting the absence of a common transport carrier. Four different divalent cations were shown to inhibit streptomycin and gentamicin accumulation in E. coli K-12 SA 1306. Divalent cations were shown to inhibit uptake of these two drugs in two bacterial species with distinct cell wall structures, Pseudomonas aeruginosa and Staphylococcus aureus, and to inhibit streptomycin uptake in spheroplasts of streptomycin-susceptible and -resistant E. coli. However, calcium had almost no inhibitory effect on streptomycin uptake by the ubiquinone-deficient mutant E. coli AN66. These and previous findings have been used to formulate a model for aminoglycoside entry into bacteria using a low-affinity membranous complex involved in membrane energization that includes respiratory quinones, which probably act to bind and transport aminoglycosides across the cell membrane. This phase of transport is associated with the lowest accumulation rate (termed energy-dependent phase I) that is rate limiting for susceptibility. It is further proposed that subsequent association of the membrane-bound aminoglycoside with higher-affinity binding sites on membrane-associated ribosomes carrying out a normal ribosomal cycle and protein synthesis results in a more rapid transport rate (termed energy-dependent phase II). The increased rate could result from a state of membrane energization analogous to that causing enhanced aminoglycoside transport rates seen in the uncoupled mutant, AN120. How this model explains the mechanism by which enzymatically modified aminoglycosides render cells resistant to unmodified aminoglycosides is also discussed.

Adenosine Triphosphatases↗

PubMedDate not supplied

Potential distribution across a plasma protein-coated poly(L-lactide) microcapsule surface.

A model is presented for the potential distribution across a protein-coated microcapsule membrane. The adsorbed protein layer is assumed to be divided into three sub-layers. The outer sub-layer is rich in positive fixed charges and the medium sub-layer in negative fixed charges, while the inner sub-layer may be either charged or uncharged. Also, the microcapsule membrane is negatively charged. The ionic partition coefficients into the inner sub-layer are less than unity, while those into the other sub-layers are unity. This model explains well the accelerated degradation of poly(L-lactide) microcapsules with an adsorbed protein layer onto their surface (Makino et al., 1987 c).

Blood Proteins↗

PubMed1990

Evidence for cooperative hydrogen ligand binding to sperm whale metmyoglobin.

Potentiometric titrations of sperm whale metmyoglobin from pH 10 to 3 shows the well-known exposure of groups between pH 4.5 and 4. However the reverse titration, at low protein concentration, results in the regeneration of its ionic property in the form of a reversible hysteresis, which was obtained by titrating the same solution twice. The Soret intensity band indicates reversibility for about 94%. Apomyoglobin shows an acid-base reversible titration from pH 9.5 to 3. Since the analysis by electrostatic interaction models do not adequately describe the overall ionic equilibria of metmyoglobin, a cooperative model was introduced. The model exactly reproduces the titration curve, indicating that 6 groups ionize with a cooperative coefficient of 9. The cooperative model explains the anomalous behaviour toward hydrogen ions and the incomplete spectral reversibility of sperm whale metmyoglobin as a molecular mechanism with physiological significance.

Animals↗

PubMed1997

Virulence-associated sequence duplication at the hemagglutinin cleavage site of avian influenza viruses.

Recent highly pathogenic (HP) field isolates of avian influenza (AI) virus from Mexico all possess an insertion of at least two basic amino acids (arg-lys) at the cleavage site of the hemagglutinin (HA) glycoprotein. One HP isolate has additional information which yields a 4 amino acid insert (arg-lys-arg-lys). We present here the nucleotide sequence of the HA gene of this unique isolate and compare it to recent H5N2 and other avian influenza isolates. The complete HA nucleotide sequence of the isolate and phylogenetic relationship suggest that it was derived in direct succession from a non-pathogenic strain isolated about 1 month earlier. The unique insertion sequence is a direct duplication of part of the purine-rich region preceding the arginine codon at the HA cleavage site. This evidence along with other data in this report provide compelling support for a proposed model explaining the mechanism of spontaneous, virulence-related insertions in type A influenza viruses.

Amino Acid Sequence↗

PubMed2004

Formation of deletions during double-strand break repair in Drosophila DmBlm mutants occurs after strand invasion.

Bloom syndrome is a rare disorder associated with cancer predisposition and genomic instability and is caused by loss of the RecQ helicase BLM. The Drosophila ortholog of BLM (DmBlm) is required for accurate repair of DNA double-strand gaps by homologous recombination. Repair products from DmBlm mutants have shorter repair synthesis tract lengths compared to wild type and are frequently associated with deletions flanking the break site. To determine the mechanisms responsible for deletion formation in the absence of DmBlm, we characterized repair after excision of the P[w(a)] element in various genetic backgrounds. Flies lacking DmRad51 do not have an elevated deletion frequency. Moreover, loss of DmRad51 suppresses deletion formation in DmBlm mutants. These data support a model in which DmBlm acts downstream of strand invasion to unwind a D-loop intermediate to free the newly synthesized strand. In the absence of DmBlm, alternative pathways of D-loop disassembly result in short repair synthesis tracts or flanking deletions. This model explains how RecQ helicases can promote homologous recombination while preventing illegitimate recombination.

Animals↗

PubMed1976

Intracellular pH transients in squid giant axons caused by CO2, NH3, and metabolic inhibitors.

The intracellular pH (pHi) of squid giant axons has been measured using glass pH microelectrodes. Resting pHi in artificial seawater (ASW) (pH 7.6-7.8) at 23 degrees C was 7.32 +/- 0.02 (7.28 if corrected for liquid junction potential). Exposure of the axon to 5% CO2 at constant external pH caused a sharp decrease in pHi, while the subsequent removal of the gas caused pHi to overshoot its initial value. If the exposure to CO2 was prolonged, two additional effects were noted: (a) during the exposure, the rapid initial fall in pHi was followed by a slow rise, and (b) after the exposure, the overshoot was greatly exaggerated. Application of external NH4Cl caused pHi to rise sharply; return to normal ASW caused pHi to return to a value below its initial one. If the exposure to NH4Cl was prolonged, two additional effects were noted: (a) during the exposure, the rapid initial rise in pHi was followed by a slow fall, and (b) after the exposure, the undershoot was greatly exaggerated. Exposure to several weak acid metabolic inhibitors caused a fall in pHi whose reversibility depended upon length of exposure. Inverting the electrochemical gradient for H+ with 100 mM K-ASW had no effect on pHi changes resulting from short-term exposure to azide. A mathematical model explains the pHi changes caused by NH4Cl on the basis of passive movements of both NH3 and NH4+. The simultaneous passive movements of CO2 and HCO3-cannot explain the results of the CO2 experiments; these data require the postulation of an active proton extrusion and/or sequestration mechanism.

Ammonium Chloride↗

PubMed1994

A minimal model of the single capacitor biphasic defibrillation waveform.

UNLABELLED: A quantitative model of the single capacitor biphasic defibrillation waveform is proposed. The primary hypothesis of this model is that the first phase leaves a residual charge on the membranes of the unsynchronized cells, which can then reinitiate fibrillation. The second phase diminishes this charge, reducing the potential for refibrillation. To suppress this potential refibrillation, a monophasic shock must be strong enough to synchronize a critical mass of nearly 100% of the myocytes. Since the biphasic waveform performs this protection function by removing the residual charge (with its second phase), its first phase may be of a lower strength than a monophasic shock of equivalent performance. A quantitative model was developed to calculate the residual membrane voltage, Vm, assuming a capacitive membrane being alternately charged and discharged by the first and second phases, respectively. It was further assumed that the amplitude of the first phase would be predicted by a minimum value plus a term proportional to Vm2. The model was evaluated on the pooled data of three relevant published studies comparing biphasic waveforms. The model explained 79% of the variance in the first phase amplitude and predicted optimal durations for various defibrillator capacitances and electrode resistances. Assuming a first phase of optimal duration, the optimal second phase duration appears to be about 2.5 msec for all capacitances and resistances now seen clinically. CONCLUSION: The effectiveness of the single capacitor biphasic waveform may be explained by the second phase "burping" of the deleterious residual charge of the first phase that, in turn, reduces the synchronization requirement and the amplitude requirements of the first phase.

Action Potentials↗

PubMed2006

Dissociative mechanism of F-actin thermal denaturation.

We have applied differential scanning calorimetry to investigate thermal unfolding of F-actin. It has been shown that the thermal stability of F-actin strongly depends on ADP concentration. The transition temperature, T(m), increases with increasing ADP concentration up to 1 mM. The T(m) value also depends on the concentration of F-actin: it increases by almost 3 degrees C as the F-actin concentration is increased from 0.5 to 2.0 mg/ml. Similar dependence of the T(m) value on protein concentration was demonstrated for F-actin stabilized by phalloidin, whereas it was much less pronounced in the presence of AlF4(-). However, T(m) was independent of protein concentration in the case of monomeric G-actin. The results suggest that at least two reversible stages precede irreversible thermal denaturation of F-actin; one of them is dissociation of ADP from actin subunits, and another is dissociation of subunits from the ends of actin filaments. The model explains why unfolding of F-actin depends on both ADP and protein concentration.

Actin Cytoskeleton↗

PubMed2000

Electrogenic ion transport by Na+,K+-ATPase.

Experimental data on the ion electrogenic transport by Na+,K+-ATPase available in the literature are analyzed. Special attention is paid to the measurements of unsteady-state electric currents initiated by alternating voltage or rapid introduction of the substrate. In the final part, a physical model of the Na+,K+-ATPase functioning is discussed. According to this model, active transport is carried out by opening and closing of the access channels used for the sodium and potassium exchange between solutions on either side of the membrane. The model explains most of the experimental data, although some details (the channel size, rates of individual transport steps) need further refinement.

Adenosine Triphosphate↗

PubMed2000

A model for energy flow in the inner ear of the bullfrog (Rana catesbeiana).

We present a quantitative mathematical model that represents the main features of the bullfrog inner ear. Calculated responses based on this model predict the observed frequency separation between the amphibian papilla and basilar papilla responses. The origin of this separation can be traced to the effect of the contact membranes on the impedance of the respective paths. Additionally, we calculated the input impedance of the periotic canal and showed that at low frequencies it acts as a bypass for most of the energy entering the ear, shunting it away from the amphibian-basilar papilla complex. As this shunting decreases with increasing frequency, we propose that the periotic canal functions as a protection mechanism to prevent overload of the amphibian papilla and basilar papilla during ventilation and for quasi-static pressure equalization. Our model explains the main features of the empirical data obtained from direct measurement of the amphibian papilla and basilar papilla contact membranes reported in an accompanying paper (this issue).

Animals↗

PubMedDate not supplied

Factors associated with adherence to antiretroviral therapy.

The purpose of this study was to examine the relationship of sociodemographic characteristics, patient perceptions, and patient characteristics including spirituality, self-reported adherence, and highly active antiretroviral therapy. The convenience sample consisted of 120 English-speaking adults (60% male, 35% female, 5% transgendered) with HIV/AIDS from two HIV service agencies in a large metropolitan city in the southeastern United States. The mean self-reported adherence was 83.1% (SD = 15.7%). Adherence was significantly correlated with perceived support and absence of barriers, strong intentions to adhere, perceived effectiveness of the medications, higher levels of perceived general health, fewer years of HIV disease, and fewer years on antiretroviral medications. Existential well-being (e.g., viewing life as positive and having meaning) was a weak significant correlate. Backward regression analysis was conducted to identify a parsimonious model of predictors of adherence. The final model included presence of support and absence of barriers, fewer years of HIV infection, no current alcohol use, perceived severity of HIV, existential well-being, and male gender. This model explained 19.4% of the variance in adherence (observed F[6, 100] = 5.6, p < .0001).

Adult↗

PubMed1998

Protein farnesyltransferase: structure and implications for substrate binding.

The rat protein farnesyltransferase crystal structure has been solved by multiple isomorphous replacement methods at a resolution of 2.75 A. The three-dimensional structure, together with recent data on the effects of several mutations, led us to propose a model for substrate binding which differs from the model presented by Park et al. based on their independent structure determination [Park, H. -W., Boduluri, S. R., Moomaw, J. F., Casey, P. J., and Beese, L. S. (1997) Science 275, 1800-1804]. Both farnesyl diphosphate and peptide substrates can be accommodated in the hydrophobic active-site barrel, with the sole charged residue inside the barrel, Arg202 of the beta-subunit, forming a salt bridge with the negatively charged carboxy terminus of peptide substrates. Our proposals are based in part on the observation of electron density in the active site which can be modeled as bound farnesyl diphosphate carried through the enzyme purification. In addition, our model explains in structural terms the results of mutational studies which have identified several residues critical for substrate specificity and catalysis.

Alkyl and Aryl Transferases↗

PubMed2005

Interaction between the type-3 copper protein tyrosinase and the substrate analogue p-nitrophenol studied by NMR.

The interaction of the monooxygenating type-3 copper enzyme Tyrosinase (Ty) from Streptomyces antibioticus with its inhibitor p-nitrophenol (pnp) was studied by paramagnetic NMR methods. The pnp binds to oxidized Ty (Ty(met)) and its halide (F(-), Cl(-)) bound derivatives with a dissociation constant in the mM range. The Cu(2) bridging halide ion is not displaced upon the binding of pnp showing that the pnp does not occupy the Cu(2) bridging position. The binding of pnp to Ty(met) or Ty(met)Cl leads to localized changes in the type-3 (Cu-His(3))(2) coordination geometry reflecting a change in the coordination of a single His residue that, still, remains coordinated to Cu. The binding of pnp to Ty(met)Cl causes a decrease in the Cu(2) magnetic exchange parameter -2J from 200 cm(-)(1) in the absence to 150 +/- 10 cm(-)(1) in the presence of pnp. From the (1)H and (2)D NMR relaxation parameters of pnp bound to Ty(met), a structural model of pnp coordination to the Ty type-3 center could be derived. The model explains the absence of hydroxylase activity in the closely related type-3 copper protein catechol oxidase. The relevance of the experimental findings toward the Ty catalytic mechanism is discussed.

Copper↗

PubMed1993

Analysis of the propagation of disinhibition-induced after-discharges along the guinea-pig hippocampal slice in vitro.

1. A model has been proposed of picrotoxin-induced hippocampal in vitro after-discharges; it depends critically upon alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors in the recurrent excitatory connections between pyramidal neurones, and upon the ability of pyramidal neurones to generate bursts at about 10 Hz when their dendrites are sufficiently depolarized. 2. We study here the question of whether this model can account for spatial--as well as temporal--aspects of after-discharges in guinea-pig hippocampal slices. For example, can the model explain the propagation along a transverse slice of the initial burst and the secondary bursts at about the same velocity, approximately 0.10-0.20 m s-1? Under what conditions might the secondary bursts exhibit a different spatial pattern to the initial burst, as we now show can occur in longitudinal slices? To examine these questions, we increased the number of cells in our model from 100 to 8000 (in a 20 x 400 array), arranging the excitatory synaptic connections in a spatially restricted fashion, with an average extent of 1.0 mm (as suggested experimentally). 3. Our model suggests that both AMPA and NMDA receptors contribute to the propagation pattern and velocity of the initial and the secondary bursts in an after-discharge. 4. When unitary AMPA and NMDA conductances are in the range where the primary burst lasts for 100-200 ms, and there are three or four secondary bursts, then both primary and secondary bursts propagate near to the experimentally observed velocity for transverse slices. In the model, however, secondary bursts propagate at somewhat slower velocities than the initial burst. 5. The mechanisms of propagation are different for the initial and for the secondary bursts: propagation of the primary burst depends upon the initiation of electrogenesis in 'resting' dendrites by AMPA and NMDA inputs that are rapidly increasing in time. Propagation of secondary bursts depends upon the timing of calcium spikes in depolarized dendrites with slowly varying NMDA inputs; the timing of calcium spikes can be influenced by a 'wave' of AMPA input, but calcium spikes--we predict--should occur even without the AMPA input, once the after-discharge has been initiated. The blockade of firing in an intermediate region of the disinhibited slice is predicted to have different effects on the primary burst and on secondary bursts distal to the region of blockade.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1997

Dietary and other determinants of vitamin B6 parameters.

OBJECTIVE: To assess the dietary, physical, biochemical and lifestyle determinants of vitamin B6 status parameters among healthy adults. DESIGN AND SUBJECTS: Dietary intake and status variables as well as other relevant characteristics were determined among 444 adults, aged 20-79 y and stratified for sex and 10-years age classes with a randomly selected control group (n = 300) and an over representation of persons with a low habitual vitamin B6 intake (n = 144). RESULTS AND CONCLUSIONS: The direct status parameters (plasma pyridoxal-5'-phosphate (PLP), plasma pyridoxal + PLP (PL + PLP), and 4-pyridoxic acid (4-PA) excretion) were clearly related to dietary variables and plasma concentrations of vitamin C (women only), vitamin B12 and folate. The total percentage of variance in p-PLP explained in multivariate regression analysis was 41 and 30% in men and women, respectively. The most important explaining variables besides vitamin B6 intakes were variables closely related to PLP-metabolism: albumin and alkaline phosphatase. Biochemical function related status parameters showed less statistically significant correlations with dietary variables. Four to 24% of the variance in the stimulation coefficients of erythrocyte aspartate aminotransferase (alpha-EAST) and erythrocyte alanine aminotransferase (alpha-EALT) and change in homocysteine excretion after a methionin load was explained by a combination of dietary, physiological and lifestyle related variables. The low percentages explained for some variables, notably alpha-EAST (women) and the change in homocysteine excretion after a methionin load (men), suggests that these parameters are not sensitive to the level of vitamin B6 intake as found in the present study. Alcohol contributed in many of the explaining models for vitamin B6 status parameters. Therefore, when assessing the vitamin B6 status of a population, it is important to estimate the level of alcohol intake as well. Furthermore, the results illustrate the importance of sex related differences in the metabolism of some parameters, especially homocysteine excretion. The variance in the clinical function related status parameter measured in the present study, handgripstrength, was explained for 50% by a combination of age, body weight and Quetelet Index (QI) with no important contribution of dietary variables.

Adult↗