Search PubMed⌕ Search

Biomedical subjects

M Giehl

Publications and source records attributed to M Giehl.

14 recordsLinked to original sources
PubMed2003

Detecting microdamage in bone.

Fatigue-induced microdamage in bone contributes to stress and fragility fractures and acts as a stimulus for bone remodelling. Detecting such microdamage is difficult as pre-existing microdamage sustained in vivo must be differentiated from artefactual damage incurred during specimen preparation. This was addressed by bulk staining specimens in alcohol-soluble basic fuchsin dye, but cutting and grinding them in an aqueous medium. Nonetheless, some artefactual cracks are partially stained and careful observation under transmitted light, or epifluorescence microscopy, is required. Fuchsin lodges in cracks, but is not site-specific. Cracks are discontinuities in the calcium-rich bone matrix and chelating agents, which bind calcium, can selectively label them. Oxytetracycline, alizarin complexone, calcein, calcein blue and xylenol orange all selectively bind microcracks and, as they fluoresce at different wavelengths and colours, can be used in sequence to label microcrack growth. New agents that only fluoresce when involved in a chelate are currently being developed--fluorescent photoinduced electron transfer (PET) sensors. Such agents enable microdamage to be quantified and crack growth to be measured and are useful histological tools in providing data for modelling the material behaviour of bone. However, a non-invasive method is needed to measure microdamage in patients. Micro-CT is being studied and initial work with iodine dyes linked to a chelating group has shown some promise. In the long term, it is hoped that repeated measurements can be made at critical sites and microdamage accumulation monitored. Quantification of microdamage, together with bone mass measurements, will help in predicting and preventing bone fracture failure in patients with osteoporosis.

Animals↗
PubMed2002

PK-PD curve-fitting problems with the Hill equation? Try one of the 1-exp functions derived from Hodgkin, Douglas or Gompertz.

UNLABELLED: Non-linear phenomena are observed with enzyme kinetics, protein binding, pharmacokinetics or pharmacodynamics. The Hill equation, the Michaelis-Menten equation extended by a power coefficient, is traditionally used for sigmoid curve fitting. Sigmoid saturation phenomena can also be described by exponential functions (1-exp), extended by a power coefficient such as those derived by Hodgkin, Douglas or Gompertz. Comparing the 4 equations, the sigmoid 1-exp function in the form of Hodgkin and Huxley comes closest to the principle of simplicity and succinctness with regard to definition, slope and flexibility of the inflection point. To compare the applicability, a standardized sample of 250 curves was generated by each I of the 4 equations and mutually fitted with the remaining 3. The Hill equation gives the closest fit with the data generated by the other functions. The Douglas variant exhibits the highest rate of convergence. The Gompertz function provides the basic feature of a baseline effect. CONCLUSION: The sigmoid functions investigated (Hill, Hodgkin, Douglas, Gompertz) have differing characteristics and can be used interchangeably for solving specific problems in non-linear modeling.

Mathematics↗
PubMed2000

A concept for pharmacokinetic-pharmacodynamic dosage adjustment in renal impairment: the case of aminoglycosides.

BACKGROUND: For patients with impaired renal function, dosage adjustment is necessary for many drugs. Adjustment with respect only to pharmacokinetic parameters may be insufficient. OBJECTIVE: To apply the theory of pharmacokinetics and pharmacodynamics to derive a mathematical model that links the concentration-time course and the clinical response by means of the pharmacokinetic-pharmacodynamic parameter 'area under the effect-time curve' (AUETC), and to use this analysis and clinical data for aminoglycosides to calculate dosage adjustments in renal impairment. METHODS: Model parameters were estimated for the antimicrobial and nephrotoxic effects of aminoglycosides on the basis of data from the literature. Effect parameters were calculated for various degrees of impaired renal function. RESULTS: Use of the model parameters gave a high correlation between the predicted and the observed (literature) values for antimicrobial efficacy and nephrotoxicity. When calculating dosage adjustments in renal impairment, it was possible to hold only one effect (antimicrobial or nephrotoxic) constant by dosage adjustment, whereas the other changed unfavourably. This was explained by differences between the pharmacodynamic parameters for each effect. For high antimicrobial efficacy, a target peak concentration of 9 mg/L (for gentamicin) should be obtained every 48 hours in advanced renal impairment. For low nephrotoxicity, the peak concentration should not exceed 3 mg/L. CONCLUSIONS: The parameter AUETC could be a useful pharmacokinetic-pharmacodynamic surrogate marker for dosage adjustment in renal impairment. Using the AUETC method, the beneficial effect can be balanced against the adverse effect.

Algorithms↗
PubMed1998

Standardized structure and modular design of a pharmacokinetic database.

BACKGROUND: The accumulated knowledge on drugs can be used for an individual drug dosage adjustment if it is placed at our disposal in an informatically structured form. THEORY AND METHODS: We have started building up a pharmacokinetic database aimed at adjusting drug dosages, in exemplary form, to patients with renal impairment. Parameters needed for the three dosage adjustment rules (Dettli, Kunin, Holford) and the most general concept of pharmacokinetics constituted the theoretical basis. TWO PROCESSES PERTAIN TO ALL DRUGS: Distribution and elimination. Total drug clearance and at least two parameters representing distribution and elimination processes are closely interdependent in mathematical terms (clearance = volume of distribution*rate of elimination). This relation yields the unifying concept that serves as a prerequisite for a structured recording of 30 assigned pharmacokinetic and pharmacodynamic parameters within an informatic database. SOLUTIONS AND RESULTS: The information is retrieved and referenced from 2383 original publications by means of a standardized input module. The complete database at present contains 15,397 records for 1573 drugs. A programmed meta-analytic algorithm is used to calculate the statistical measures for the central value and variance--as available--from the pooled values of primary records. The statistically standardized parameters are extracted for 6601 pharmacokinetic parameters, and placed at the users disposal with the output module. PRACTICAL UTILITY: Following meta-analysis, published pharmacokinetics can be used as statistical estimates of population parameters. The statistical estimates with variances permit an individual drug dosage adjustment by applying the Bayesian approach or neural networks.

Algorithms↗
PubMed1998

Intubation complications in the critically ill child.

The acutely ill child requiring intubation is at risk for complications at three crucial points: during the intubation procedure, in the first few hours or days after intubation, and during long-term endotracheal tube (ETT) placement. Consideration must be given to the anatomic and physiologic differences between children and adults that place children at risk for acute respiratory failure and that present difficulties in providing respiratory support. Each potential complication must be understood in terms of cause, assessment, prevention, and intervention. The method of securing the ETT can decrease tube displacement, trauma to the airway, and breakdown of the skin. Intra- and interhospital transport presents more considerations in maintaining ETT placement and physiologic stability of the patient. Prevention of intubation complications in children can reduce length of stay, decrease cost of care, minimize length of time for family separation, decrease potential disabilities and prevent death in the critically ill child who requires intubation.

Adolescent↗
PubMed1998

Relationship between pharmacokinetic half-life and pharmacodynamic half-life in effect-time modeling.

A pharmacodynamic parameter relating time-dependent changes of the effect with time-dependent changes of concentrations has yet to be developed. In pharmacokinetics, half-lives (T1/2kin) are used to describe the relation between concentration (C) and time (t). In pharmacodynamics, often the sigmoid Emax model and the Hill equation are used (E = Emax CH/(EC50H + CH)) to describe the relation between effect (E) and concentration (C). To describe the correlation between effect (E) and time (t), a pharmacodynamic half-life (T1/2dyn) could be estimated if the use of the term half-life is not restricted only to log-linear first order processes. To bisect the drug effect a variable time (t1-2 = t2-t1) will be required for this nonlinear process. The bisection of the effect (E2 = 1/2 E1) is associated with a decrease in concentrations (C2 = C1 exp(-0.693 t1-2/T1/2kin)). A mathematical relationship can be derived between pharmacodynamic half-life (T1/2dyn = t1-2) and pharmacokinetic half-life (T1/2dyn = T1/2kin (ln (1 + ln(a)/ln(2))/H ) with (a = (EC50H + C1H)/(EC50H + C2H)). For concentrations in the range of the EC50 value with the Hill coefficient (H = 1), the pharmacodynamic half-life will be 1.6-2.0 times the kinetic half-life (T1/2dyn < or = 2.0 T1/2kin). For high concentrations (C1 > EC50), the dynamic half-life will grow much longer than the kinetic half-life, consequently the effect of a drug will not increase but it will last longer. The pharmacodynamic half-life turns out to be a specific estimate for the effect time relation, being a concentration-dependent function of the kinetic half-life.

Dose-Response Relationship, Drug↗
PubMed1996

Structured data entry for reliable acquisition of pharmacokinetic data.

A pharmacokinetic database was constructed that is as free of errors as possible. Pharmacokinetic parameters were derived from the literature using a text-processing system and a database system. A random data sample from each system was compared with the original literature. The estimated error frequencies using statistical methods differed significantly between the two systems. The estimated error frequency in the text-processing system was 7.2%, that in the database system 2.7%. Compared with the original values in the literature, the estimated probability of error for identical pharmacokinetic parameters recorded in both systems is 2.4% and is not significantly different from the error frequency in the database. Parallel data entry with a text-processing system and a database system is, therefore, not significantly better than structured data entry for reducing the error frequency.

Data Collection↗
PubMed1995

Aminoglycoside pharmacokinetics and -dynamics: a nonlinear approach.

A model which correctly describes the pharmacokinetic-pharmacodynamic relationship is necessary to perform a rational pharmacotherapy. This model could predict the effects under variable conditions. The prediction will provide a basis for adapting therapy to individuals. A nonlinear model should be most appropriate for describing drug effects. A new model, containing nonlinear pharmacokinetics and pharmacodynamics, is presented to describe effects of aminoglycosides on bacterial growth and accumulation in kidney tissue.

Amikacin↗
PubMed1994

Vancomycin dosing in haemodialysis patients and Bayesian estimate of individual pharmacokinetic parameters.

A dose reduction of vancomycin to 1000 mg once a week usually is recommended for haemodialysis patients. Our modified dosing schedule consists of a loading dose of 1000 mg and a maintenance dose of 500 mg administered 3 times a week after haemodialysis. Different vancomycin regimens were retrospectively evaluated by therapeutic drug monitoring and bayesian parameter estimates in 39 dialysis patients. The mean (+/- SD) trough level in 7 patients receiving only the conventional dosage regimen was significantly lower than in 17 patients strictly treated by the modified schedule (7 +/- 4 versus 17 +/- 8 mg/L; p = 0.001). The corresponding peaks were low in both groups and no different (23 +/- 10 versus 27 +/- 12 mg/L). The one week average vancomycin clearance was significantly lower in the conventional dosage group compared to the modified dosage group (6 +/- 3 versus 10 +/- 3 ml/min; p = 0.001). High-flux dialysers were not used in the conventional dosage group but for 30 percent of the procedures in the modified dosage group, where the vancomycin one week average elimination half-life was 66 hours (+/- 18) and the volume of distribution 50 litres (+/- 5). As compared to the bayesian programme, NONMEM calculated comparable pharmacokinetic parameters but could be applied only in 5 cases with a sufficient number of concentration measurements. Ototoxicity occurred in 1 patient, whereas vancomycin treatment was judged as ineffective against infection in 5 of the 39 patients. Their troughs were below 15 mg/L.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗
PubMed1993

Nonlinear kinetics and the 1-exp function in nephropharmacology.

The basic law in nephropharmacology states that pharmacokinetic parameters depend linearly on renal function. Few exceptions to linear dependence have been reported, e.g. substances with saturable tubular reabsorption or secretion. A further example is cyclosporin, which was found to be eliminated according to log-concave nonlinear kinetics in 3 patients with hepatotoxicity after kidney transplantation. The nonlinear cyclosporin kinetics were computer-fitted to the integrated forms of the 1-exp function and the Michaelis-Menten equation by nonlinear regression analysis. The same maximal velocity (Vmax = 23 ng ml-1 h-1) and Michaelis constant (Km = 686 ng ml-1) were calculated for cyclosporin when applying either the 1-exp function or the Michaelis-Menten equation. The nonlinear elimination of cyclosporin, however, was described even more closely by the 1-exp function than by the Michaelis-Menten equation.

Humans↗
PubMed1993

Nonparametric meta-analysis of published data on kidney-function dependence of pharmacokinetic parameters for the aminoglycoside netilmicin.

The distribution and elimination of various drugs depend on kidney function. This dependence is published either as a linear regression equation or as the discrete extreme values for normal kidney function and anuria. A meta-analysis of the published pharmacokinetic data is required to build up a knowledge-based computer system for dosage adjustment in renal failure. A sample comparison of 4 statistical methods for meta-analysis was performed by applying them to 13 publications about the aminoglycoside netilmicin. Parametric meta-analytical methods I and II are based on regression equations alone (Z-transformation, maximum likelihood) and yield unreliable data, especially with regard to extreme values for anuria. The parametric meta-analytical method III is based on means of extreme values (standard 2-stage approach) and does not permit a decision as to whether linear interpolation of a parameter (e.g. volume of distribution) can be used for all degrees of renal insufficiency. In contrast, the nonparametric median (meta-analytical method IV) is based on the extreme values calculated from regression equations and empirical extreme values combined into 1 group of data on normal kidney function and another on anuria. For netilmicin, the meta-analytical median with the 95% confidence interval (95% CI) yields a significant increase in the dominant elimination half-life from 2h (95% CI 1.9h, 2.6h) in patients with normal kidney function to 45h (95% CI 41h, 301h) in those with anuria (p = 0.001). For a normal bodyweight of 65kg, the volume of distribution also increases significantly from 13L (95% CI 9L, 15L) to 20L (95% CI 14L, 21L) in patients with anuria (p = 0.04). Thus, drug dosage adjustment according to therapeutic peak and trough concentrations requires knowledge of the distribution and elimination parameters, since they can both be independently altered in renal failure. We conclude that the most robust meta-analysis of these alterations is achieved with the nonparametric median of extreme values.

Creatinine↗