Drug interaction and pharmacological considerations during anti-infective therapy in cancer patients.
Explore the source record for details and available documents.
Alkalies↗
Biomedical subjects
M Tod
Publications and source records attributed to M Tod.
Daily validation procedure of chromatographic assay using gaussoexponential modelling.
High performance liquid chromatography is one of the most successful analytical methods used for the quantitative determination of drugs in biological samples. However, this method is marked by a lack of performance reproducibility: chromatographic peaks become wider and even asymmetrical as the column ages. These progressive changes in the chromatographic parameters have to be taken into account when evaluating the validation criteria for the method. These criteria change with the ageing process of the column leading to the need for new estimations to assure the quality of the results. Procedures are proposed for the daily determination of some validation criteria using the exponentially modified Gaussian (EMG) model of the chromatographic peak. This modelling has been studied on simulated chromatographic peaks in order to obtain the relationships between chromatographic measurements and EMG parameters.
Chromatography, High Pressure Liquid↗
Influence of methodological aspects on tissue drug concentration estimation.
Fundamental studies in tissue drug extraction have been made using rokitamycin as a test probe. Radiolabelled rokitamycin was administered intravenously to 12 rats. Lungs and femurs were excised a few minutes later. Rokitamycin was extracted from lungs using six procedures (based either on ion-pairing, dissolution or deproteinization) whose performances (mean recovery and reproducibility) were compared. Three grinding procedures were also compared for the extraction of rokitamycin from bone: pulverization by a magnetic stirring bar in a liquid nitrogen bath, slicing into small pieces and crushing with pestle and mortar. The effect of binding proteins (albumin or alpha 1-acid glycoprotein) in the extraction mixture was also evaluated. Magnetic stirring bar grinding was the most efficient. Deproteinization was necessary to obtain the highest recovery, but the agent had to be chosen carefully. Binding proteins either had no effect or decreased the recovery of rokitamycin. Recovery from bone was lower than that from lung. Binding to cellular components in the post-extraction pellet was only 3% (lung) and 9% (bone). It is concluded that a careful optimization of the extraction procedure of a drug from a tissue allows quantitative and reproducible measurement of its concentration.
Animals↗
Aminoglycosides.
Despite their nephrotoxic and ototoxic side effects, AG remain useful antibiotics because of their major, rapid, and dose-dependent bactericidal effects. Combination therapy with an AG appears particularly important in neutropenic and other high-risk patients to provide broad-spectrum bactericidal activity, synergism, and reduction of emergence of resistant pathogens. OD AG therapy is associated with high peak levels in serum that maintain efficacy and low-to-undetectable trough levels in serum that attenuate the risk of toxicity. Administration of short-term OD AG therapy to patients not at risk without renal impairment may not absolutely require dosing monitoring. This therapeutic strategy has been proved useful in clinical trials, now including febrile episodes in neutropenic patients, but it should be avoided during infections in which antimicrobial synergism is required, such as enterococcal endocarditis.
Aminoglycosides↗
Fluconazole penetration in cerebral parenchyma in humans at steady state.
We studied fluconazole penetration in the brain in five patients who had a deep cerebral tumor whose removal required the excision of healthy brain tissue. Plasma and brain samples were simultaneously obtained after oral ingestion of 400 mg of fluconazole daily for 4 days (90% of steady state). Fluconazole penetration in healthy cerebral parenchyma was determined. Plasma and brain samples were assayed by high-pressure liquid chromatography. Concentrations in plasma and brain tissue were 13.5 +/- 5.5 micrograms/ml and 17.6 +/- 6.6 micrograms/g, respectively. The average ratio of concentrations in the brain and plasma (four patients) was 1.33 (range, 0.70 to 2.39). Despite the lack of data concerning the penetration of fluconazole in brain abscesses, these results should permit the use of a daily dose of 400 mg of fluconazole in prospective clinical studies that evaluate the effectiveness of this drug in the treatment of brain abscesses due to susceptible species of fungi.
Adult↗
Time- and dose-dependent kinetics of all-trans-retinoic acid in rats after oral or intravenous administration(s).
The kinetics of all-trans-retinoic (RA) acid are known to be nonlinear. To clarify the mechanisms involved, RA kinetics were determined in four groups of rats: group 1 received a single 2-mg RA dose intravenously (N = 5); group 2 received the same treatment as group 1 after 12 days of oral RA (2 mg/day) (N = 6); group 3 received a single, oral 2-mg (N = 6) or 5-mg RA dose (N = 6); and group 4 (N = 5 + 3) received the same treatment as group 3 after 12 days of oral RA (2 mg/day). Blood samples, 10-12/animal, were taken during the 7 hr following the final dosage. Plasma RA concentrations were determined by liquid chromatography. Noncompartmental analysis showed that RA disposition after intravenous bolus dosing obeyed Michaelis-Menten (MM) kinetics in group 1 (no pretreatment) and linear kinetics in group 2 (pretreated), with a lower area under the concentration vs. time curve, which suggested time-dependent kinetics with autoinduction. The same autoinduction phenomenon was observed after oral dosing in groups 3 and 4. Moreover, the mean area under the concentration vs. time curve was not higher after 5 mg dosing than after 2 mg dosing, which indicated a saturable mechanism of absorption. Fitting the data to a three-compartment model with saturable absorption and elimination kinetics confirmed the autoinduction of RA elimination (maximal velocity of elimination = 3330 vs. 541 micrograms/hr, p = 0.006, MM constant KMe = 7.53 vs. 1.10 micrograms/ml, p = 0.006) after 12 days RA administration, and an MM absorption mechanism resulting in a saturable absorption (bioavailability F = 0.58 at 2 mg vs. 0.25 at 5 mg, group 3) that decreased after 12 days of RA treatment: the maximal velocity of absorption decreased from 1632 (group 3) to 631 micrograms/hr (group 4) (p = 0.02). The volume of distribution also decreased after pretreatment, which indicated a modification in tissular distribution (565 vs. 358 ml, p < 0.001, group 3 vs. 4).
Absorption↗
The penetration of amphotericin B from an Intralipid formulation into fibrin loci in a rabbit model of candidiasis.
The kinetics of amphotericin B (AMB) concentrations in plasma and interstitial fluid were studied in an experimental model of Candida albicans infection in rabbits. Rabbits were infected by subcutaneously implanted fibrin clots containing the yeast. Three groups of five rabbits received a 4 mg kg-1 AMB infusion. AMB (Fungizone) was dissolved in 5% glucose (group I) or in 20% Intralipid at a final concentration of 1.5 (group II) or 3 mg mL-1 (group III). AMB was measured by liquid chromatography in plasma and in trypsin-dissolved fibrin clots up to 72 h after the infusion. No significant differences in AMB plasma and interstitial-fluid concentration kinetics between the three modes of administration were found. AMB penetration into fibrin clots was slow, with no significant differences between treatments. Thus, formulation of AMB in Intralipid does not modify either the drug's interstitial or plasma kinetics at equivalent doses.
Amphotericin B↗
Application of optimal sampling theory to the determination of metacycline pharmacokinetic parameters: effect of model misspecification.
Use of optimal sampling theory (OST) in pharmacokinetic studies allows the number of sampling times to be greatly reduced without loss in parameter estimation precision. OST has been applied to the determination of the bioavailability parameters (area under the curve (AUC), maximal concentration (Cmax), time to reach maximal concentration (Tmax), elimination half-life (T1/2), of metacycline in 16 healthy volunteers. Five different models were used to fit the data and to define the optimal sampling times: one-compartment first-order, two-compartment first-order, two-compartment zero-order, two-compartment with Michaelis-Menten absorption kinetics, and a stochastic model. The adequacy of these models was first evaluated in a 6-subject pilot study. Only the stochastic model with zero-order absorption kinetics was adequate. Then, bioavailability parameters were estimated in a group of 16 subjects by means of noncompartmental analysis (with 19 samples per subject) using each optimal sampling schedule based procedure (with 6 to 9 samples depending on the model). Bias (PE) and precision (RMSE) of each bioavailability parameter estimation were calculated by reference to noncompartmental analysis, and were satisfactory for the 3 adequate models. The most relevant criteria for discrimination of the best model were the coefficient of determination, the standard deviation, and the mean residual error vs. time plot. Additional criteria were the number of required sampling times and the coefficient of variation of the estimates. In this context, the stochastic model was superior and yielded very good estimates of the bioavailability parameters with only 8 samples per subject.
Adult↗
Extracorporeal photochemotherapy: evaluation of two techniques and use in connective tissue disorders.
Extracorporeal photochemotherapy (ECP) consists of collection of mononuclear cells, their irradiation with UV-A light in the presence of a photoactivable molecule--8-methoxy-psoralen (8-MOP) being the most widely used--and their reinjection into a patient. Two technical approaches have been developed. The photopheresis procedure involves four steps: (i) 8-MOP is given to the patient orally, 2 h before collection of white blood cells; (ii) a discontinuous flow cell separator (UVAR, Therakos, West Chester, PA, U.S.A.) is used for cell collection. The final product (740 mL) has a hematocrit of 4.5 +/- 1.7%); (iii) irradiation, performed with the same UVAR apparatus, begins before all the cells are collected, and lasts for 180 min after collection; and (iv) after irradiation, the buffy-coat is reinjected into the patient. We developed a technique summarized as follows: (i) mononuclear cell collection is performed using the Spectra (Cobe, Denver, CO, U.S.A.) cell separator, which provides a highly enriched mononuclear cell concentrate (always > 90% purity), in a small volume < 150 mL, subsequently adjusted to 300 mL for irradiation. Hematocrit of the final product is always < 2%. (ii) Soluble 8-MOP is added to the mononuclear cell concentrate at a final concentration of 200 ng/mL. (iii) Mononuclear cell concentrate is transferred in an EVA plastic bag (Macopharma, Tourcoing, France) to ensure an efficient irradiation with a UV irradiator (Vilber Lourmat, Marne-la-Vallée, France). (iv) After irradiation at 2 J/cm2 (time < 20 min), the cells are reinfused into the patient. Experimental and clinical data suggest that ECP has potential applications in the treatment of connective tissue disorders, such as systemic sclerosis and rheumatoid arthritis. Although encouraging data have been obtained, further clinical trials are warranted to establish the role of this therapy in these indications.
Animals↗
Fever and associated changes in glomerular filtration rate erase anticipated diurnal variations in aminoglycoside pharmacokinetics.
Netilmicin (4.5 mg/kg of lean body weight) was administered intravenously once every 24 h at 10 a.m. to 23 patients (group I) and at 10 p.m. to 20 patients (group II) with severe infection. No significant differences (P > 0.05) in peak and trough concentrations in serum were found between groups I and II (peak, 12.9 +/- 3.7 versus 12.8 +/- 4.4 mg/liter, respectively; trough, 0.7 +/- 0.6 versus 0.8 +/- 0.6 mg/liter, respectively [mean +/- standard deviation]). Pharmacokinetic parameters (half-life [5.0 +/- 2.2 versus 4.9 +/- 1.8 h], volume of distribution [0.32 +/- 0.04 versus 0.35 +/- 0.06 liter/kg], and total clearance [0.920 +/- 0.417 versus 1.015 +/- 0.546 ml/min/kg]) were similar in the two groups and not influenced by the time of administration. These data suggest that, in the once-daily schedule, 10 a.m. or 10 p.m. administration had no influence on netilmicin levels in serum and pharmacokinetic parameters in these ill febrile patients.
Adult↗
Pharmacokinetics of ceftriaxone during plasma exchange in polyarteritis nodosa patients.
Plasma exchange (PE) is currently being used to treat a variety of disorders involving immune complexes, such as polyarteritis nodosa. This procedure removes endogenous toxic components that accumulate in patients with this disease, but it also removes drugs. Plasma-protein binding and the volume of distribution (V) are two kinetic parameters which strongly affect the efficiency of drug removal by PE. Drugs that are highly bound to plasma proteins and have a low V may show a marked decrease in plasma levels as a result of PE. Because ceftriaxone exhibits saturable plasma-protein binding, which influences its pharmacokinetic parameters, particularly its V, we evaluated its removal during PE therapy in this nonrandomized crossover study. Twelve polyarteritis nodosa patients undergoing PE were studied. Each patient was given ceftriaxone intravenously in doses of 1 and 3 g on days 4 and 11, respectively, immediately before (n = six patients; group I) and 6 h before (n = six patients; group II) PE. Plasma was assayed for ceftriaxone by high-pressure liquid chromatography. The mean amounts eliminated +/- standard deviations were 230.8 +/- 38.5 mg (1 g) and 750.0 +/- 168.5 mg (3 g) for group I and 161.0 +/- 66.0 mg (1 g) and 347.0 +/- 121.0 mg (3 g) for group II. The drug fractions eliminated by PE were 23.0% +/- 3.9% (1-g dose) and 24.9% +/- 5.6% (3-g dose) for group I (P > 0.05), and 16.6% +/- 5.9% (1-g dose) and 11.5% +/- 4.0% (3-g dose) for group II (P < 0.05). These results showed that the drug fraction eliminated decreased when V increased only when the distribution phase of ceftriaxone had been completed (group II). These findings suggest that PE may influence ceftriaxone disposition and that it would be better to administer the drug after PE to assure its therapeutic efficacy.
Adult↗
[Luminescence and detection in liquid chromatography: III. Chemiluminescence].
Chemiluminescence avoiding the fluctuations of the light of excitation, Rayleigh and Raman scattering, allows to get detection threshold 100 to 1,000 times lower than fluorimetry. Processes using the luminol, lucigenin, aryloxalic esters and ozone are employed in liquid chromatographic detection. Some pharmaceutical, biological and toxicological examples illustrate their applications.
Acridines↗
Pharmacokinetics of diacerein in patients with liver cirrhosis.
The pharmacokinetics of diacerein following a single oral dose of 50 mg was studied in 12 healthy volunteers, 10 patients with a mild liver cirrhosis (Child Pugh's grade A), and 6 patients with a more severe liver cirrhosis (Child Pugh's grade B to C). Statistical analysis using a Kruskal-Wallis test showed no significant differences between the three groups for the following parameters: median Cmax was 3.9 mg l-1 for the cirrhotic patients group I (CPI) and 3.2 mg l-1 for the cirrhotic patients group II (CPII) versus 3.2 mg l-1 for the healthy volunteers (HV); median t1/2 was 4.9 h for CPI and 4.3 h for CPII versus 4.3 h for HV; median Cl/F was 2.1 l h-1 for CPI and 2.5 l h-1 for CPII versus 1.6 l h-1 for HV; median Vdss/F was 12.6 l for CPI and 14.0 l for CPII versus 13.21 for HV. The urinary parameters were comparable. It was concluded that, from a pharmacokinetic point of view, no reduction in the initial dosage of diacerein need be proposed in liver cirrhosis.
Adult↗
Cefotiam concentrations in the sinus fluid of patients with chronic sinusitis after administration of cefotiam hexetil.
Cefotiam hexetil is a prodrug of cefotiam. The concentrations of cefotiam in plasma and sinus secretions were determined in 18 patients (10 males, 8 females, aged 39.3 +/- 13.0 years) with chronic sinusitis. All patients received two 200 mg oral doses of cefotiam hexetil 12 h apart and were divided into four groups according to the time which elapsed between the last dose and collection of secretion samples. The last dose was given 2 h (group I), 3 h (group II), 4 h (group III) or 6 h (group IV) before sinus puncture. Cefotiam concentrations were measured by high-pressure liquid chromatography and microbiological assay, results being very similar with both methods. Mean concentrations of cefotiam with the standard deviation in sinus exudates were 1.04 +/- 0.60 mg/l at 2 h (n = 6), 1.04 +/- 0.33 mg/l at 3 h (n = 4), 0.75 +/- 0.74 mg/l at 4 h (n = 4) and < 0.10 mg/l at 6 h (n = 4). Mean sinus fluid concentrations were higher than mean plasma concentrations in all groups. These results suggest that cefotiam concentrations higher than the MICs for common pathogens are found in sinus secretions up to 4 h after oral administration of cefotiam hexetil.
Adult↗
Influence of renal function on the pharmacokinetics of diacerein after a single oral dose.
The pharmacokinetics of diacerein (a new anti-inflammatory analgesic antipyretic drug) following a single oral dose of 50 mg was studied in 12 healthy volunteers and two groups of eight patients with mild or severe renal insufficiency. Statistical analysis using a Kruskal-Wallis rank sum test showed a significant difference between the three groups for the following parameters. In severely uraemic patients, median AUC0-infinity was multiplied by a factor of ca 2: 40.5 mg h/l versus 21.3 in healthy subjects, P = 0.04; and t1/2 was prolonged by the same factor: 9.6 h versus 4.3 in the control group, P = 0.003. Apparent drug availability and renal clearance assessed through urinary data decreased with renal failure, respectively: 14.5% and 0.045 l/h versus 35.4% (P = 0.01) and 0.13 l/h (P = 0.008) in healthy subjects. Amounts of glucuro and sulfo conjugates in urine were lower in severely uraemic patients. Intermediate values were observed for mildly uraemic patients. Other parameters: lag-time, Cmax, tmax, Vss/F, urinary glucuro- to sulphoconjugate ratios did not change significantly. Apparent total clearance of rhein was poorly correlated with creatinine clearance and this was related to a decrease of non-renal clearance of rhein in renal insufficiency. It was concluded that, from a pharmacokinetic point of view, a reduction (50%) in the maintenance dosage of diacerein should be considered in severe renal failure.
Administration, Oral↗
Influence of local radiotherapy on penetration of fluconazole into human saliva.
The pharmacokinetics of fluconazole (50 mg, single oral dose) in saliva and plasma were determined for five healthy subjects and five patients who underwent radiotherapy (dose, > 45 Gy over a 6-week period) in the salivary gland area and suffered from oropharyngeal candidiasis. Saliva was collected after electrical stimulation. Fluconazole was measured by liquid chromatography. From healthy volunteers and patients, saliva and plasma were sampled from 0 to 24 h. Although fluconazole penetration kinetics were significantly slowed down in irradiated patients, saliva concentrations of fluconazole were higher than those in the plasma, except at 1 h. In the postdistribution phase, the saliva/plasma concentration ratio was in the range of 1.2 to 1.4, and there was no significant difference between healthy subjects and patients. The saliva concentration of fluconazole was over 1 mg/liter throughout the entire interval 2 to 24 h after drug intake. From these results, the clinical efficacy of fluconazole for oropharyngeal candidiasis is not expected to be less than that in subjects with normal salivary glands, provided that salivary secretion remains.
Administration, Oral↗
Pharmacokinetics and bactericidal activities of one 800-milligram dose versus two 400-milligram doses of intravenously administered pefloxacin in healthy volunteers.
Pefloxacin pharmacokinetics and serum bactericidal activities (SBA) against Escherichia coli and Staphylococcus aureus were compared after intravenous infusion of either a single 800-mg dose or twice-daily 400-mg doses into 16 healthy volunteers. Plasma pefloxacin concentrations were measured for up to 60 h, and SBAs were determined 1, 12, and 24 h after the start of the infusion. The mean areas under the concentration-versus-time curve for plasma were not different (138 versus 136 h.mg/liter). The mean clearances, volumes of distribution, and half-lives were also comparable. The mean (+/- standard deviation) maximal concentration after the 800-mg infusion was 12.11 +/- 1.35 versus 6.51 +/- 0.73 mg/liter after the first 400-mg infusion and 7.42 +/- 0.76 mg/liter after the second 400-mg infusion. Mean trough concentrations at 24 h were significantly different: 2.77 +/- 0.63 (800 mg) versus 1.93 +/- 0.49 (400 mg twice) mg/liter (P = 0.0007). Mean SBAs against E. coli after 800 mg of pefloxacin were higher than 1/128 (1 h), 1/32 (12 h), and 1/16 (24 h). Mean SBAs against S. aureus under the same conditions were higher than 1/64 (1 h), 1/16 (12 h), and 1/8 (24 h). Mean SBAs at 1 and 12 h were significantly higher after the 800-mg infusion than after the 400-mg infusion but were similar at 24 h for both regimens. Comparison of SBAs according to National Committee for Clinical Laboratory Standards criteria showed a similar adequacy at 24 h for both regimens against both strains. Administration of 800 mg of pefloxacin once a day is bioequivalent to 400 mg twice a day, and bactericidal activity of the 800-mg infusion is not less than that of two 400-mg infusions.
Adult↗
[Luminescence and detection in liquid chromatography. II--Energy transfer from a stimulated molecule: indirect potentialization or sensitized luminescence].
Under the words of sensitized luminescence, the processes who include the transfers of energy from a donor to an acceptor are described. They are to the origin of new possibilities of detection in liquid chromatography by emission or inhibition of phosphorescence and fluorescence. These news technologies are illustrated by examples in pharmaceutic, biologic or food applications.
Chromatography, Liquid↗