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21.
In a severe case of chloral hydrate intoxication treated with combined hemodialysis and hemoperfusion the pharmacokinetics of the metabolites trichloroethanol (TCE), trichloroethanol glucuronide (TCE-Glu) and trichloroacetic acid (TCA) were studied. Indications of delayed absorption and some slowing of metabolism were found. At a blood flow rate of 200 ml/min clearances by hemodialysis and hemoperfusion, respectively, in ml/min were estimated to be 188 and 156 for TCE, 184 and 181 for TCE-Glu, 142 and 91 for TCA. Clearance by hemoperfusion declined with time. The half-lives of TCE and TCA were 3.2 and 4.3 hours during combined hemodialysis and hemoperfusion. After termination of treatment the half-life of TCE was 12.8 hours, whereas TCA was metabolized so slowly, that no reliable calculation could be performed. We conclude that hemodialysis and hemoperfusion are equally and highly efficient in the treatment of chloral hydrate poisoning, but hemoperfusion may increase the risk of gastric bleeding more than hemodialysis. Hemodialysis may therefore be preferable and should be tried in spite of low blood pressure. 相似文献
22.
The kinetics and mechanism of hydrolysis of various 1-, 3- and 1,3-acyloxymethyl derivatives of 5-fluorouracil were studied to assess their potential as prodrugs with the aim of enhancing the delivery characteristics of the parent drug. All the derivatives hydrolyzed to yield 5-fluorouracil in quantitative amounts, passing through an unstable N-hydroxymethyl-5-fluorouracil intermediate. The pH-rate profiles obtained revealed the occurrence of specific acid and base catalysis as well as of a water-catalyzed reaction. The rates of hydrolysis were accelerated markedly in the presence of human plasma or rat liver homogenate, suggesting the utility of the derivatives as prodrugs. The derivatives were all more lipophilic than 5-fluoro-uracil as determined by partition experiments in octanol-aqueous buffer systems but the aqueous solubility was only slightly reduced or, for some derivatives, even greater than that of 5-fluorouracil. This behaviour was attributed to differences in the crystal lattice energy, and relationships between melting points, partition coefficients and water-solubilities for these and 11 other prodrug derivatives of 5-fluoro-uracil were established. 相似文献
23.
Background and objective: Through interruption of maintenance treatment with 6‐mercaptopurine (6MP), toxicity after high‐dose methotrexate (HDMTX) may compromise the efficiency of the treatment of children with acute lymphocytic leukaemia (ALL). We investigated the influence of polymorphisms in the methylene tetrahydrofolate reductase (MTHFR) gene and coadministration of antimetabolites on post‐HDMTX toxicity. Methods: Toxicity was retrospectively analysed after 656 HDMTX courses administered to 88 paediatric ALL patients at a single treatment centre. Results: High‐dose methotrexate with high‐intensity co‐treatment (6MP 75 mg/m2/d + MTX 20 mg/m2/wk) was found associated with increased odds of haematological toxicity (OR’s: 3.47–7.88; P’s: <0.001), hepatic toxicity (OR = 6.91; P < 0.001), hospitalization with fever (OR = 2.2; P = 0.004) and interruption maintenance treatment (OR = 15.9; P < 0.001) compared to HDMTX with low‐intensity co‐treatment (6MP 25 mg/m2/d). Addition of cytarabine to the low‐intensity co‐treatment increased the odds of neutropenia (OR = 3.51; P = 0.002), thrombocytopenia (OR = 6.56; P < 0.001), hepatic toxicity (OR = 3.84; P = 0.012) and interruption of maintenance treatment (OR = 4.25; P = 0.002). Alterations in 6MP dose were associated with significant changes in toxicity. Dose reduction reduced the odds of haematological toxicity (OR’s: 0.22–0.34; P’s: <0.001–0.020), while dose increase increased the odds of haematological toxicity (OR’s: 2.72–7.42; P’s: 0.006–0.027), fever (OR = 2.65; P = 0.037) and interruption of maintenance treatment (OR = 3.04; P = 0.032). No convincing associations were found between the MTHFR C677T or A1298C polymorphisms and toxicity. Conclusion: Our findings demonstrate that toxicity after HDMTX is influenced by coadministrated antimetabolites, and modifiable by alterations in 6MP dose. Prevention of toxicity related withdrawals through 6MP dose reduction could be a way of increasing total dose intensity. 相似文献
24.
Rasmussen BB Larsen LS Senderovitz T 《BJOG : an international journal of obstetrics and gynaecology》2005,112(11):1492-1499
OBJECTIVES: In two separate trials, we studied the concomitant administration of atosiban with labetalol and betamethasone to determine any possibility of a clinically relevant pharmacokinetic interaction. DESIGN: Study 1 was an open-label, single dose atosiban, multiple dose labetalol, interaction study. Study 2 was an open-label, randomised, three-period crossover pharmacokinetic study. SETTING: The studies were carried out at the Clinical Pharmacology Unit of AAI Deutschland GmbH & Co KG, Neu-Ulm, Germany. POPULATION: The study population consisted of healthy female volunteers. METHODS: In Study 1, 14 healthy female volunteers participated. On study day 1, a 12-hour intravenous infusion of 114.75 mg atosiban was administered; on days 2-4, participants received labetalol orally (100 mg twice daily), and on study day 5 they received the combined treatment. In Study 2, a total of 18 healthy female volunteers received, on three separate occasions, a 12-hour intravenous infusion of 114.75 mg atosiban, a single intramuscular injection of 12 mg betamethasone or the two drugs in combination. MAIN OUTCOME MEASURE: For Study 1, the outcome parameter for atosiban was area under the plasma concentration-time curve (AUC); the study parameters for labetalol were AUC, maximum plasma concentration (C(max)) and time to C(max) (t(max)). In Study 2, AUC, C(max) and time to C(max) (t(max)) were assessed for atosiban and betamethasone. RESULTS: Labetalol had no clinically relevant influence on the bioavailability (AUC) of atosiban. For labetalol, the co-administration with atosiban did not affect the extent of bioavailability, however, C(max) decreased by 36% and t(max) increased by 45 minutes. The C(min) was not affected by atosiban. The betamethasone and atosiban combination led to similar mean plasma concentration-time curves as the administration of each substance alone. Pharmacokinetic parameters (AUC, C(max), t(max)) did not differ markedly between treatments and all 90% CIs for ratios between treatments were fully within limits (80-125%). The co-administration of atosiban with labetalol or betamethasone resulted in similar tolerability to each substance alone. CONCLUSION: The co-administration of atosiban with betamethasone or labetalol had no clinically relevant influence on their bioavailability or tolerability. 相似文献
25.
The potentials for improving decisions about adequacy of dialysis (AD) and daily protein intake (DPI) by urea kinetic modeling (UKM) were examined. Four nephrologists evaluated AD, DPI, and metabolic stability in 62 patients. UKM was done three times; but the results were not revealed. Clinicians' decisions were then compared with UKM measures of effective dialysis (Kt/V) and protein catabolic rate (pcr). Detection of inadequately treated patients by the clinicians was poor (28%, Kt/V less than 1.0; and 40%, Kt/V less than 0.9). Specificities of the clinicians' decisions were 0.96 and 0.92, respectively. Combining pcr and consensus decisions, 59 patients could be assigned a probable DPI. Using this as "gold standard," the average clinician detected 77% of 13 low DPIs. Single or triple pcr determinations alone detected 77% or 62%, respectively. Specificities were 0.91, 0.85, and 1.0. Simulated decision making suggested that combining pcr with clinical evaluation in a logical way would lead to detection of most patients with low DPI. Qualitative data from individual patient cases causing controversies are presented and discussed. It is concluded the UKM should be used routinely to assess the adequacy of dialysis and daily protein intake. 相似文献
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Ohne Zusammenfassung 相似文献
29.
Chien Du-Shieng Sasaki Hitoshi Bundgaard Hans Buur Anders Lee Vincent H. L. 《Pharmaceutical research》1991,8(6):728-733
The main objective of this study was to investigate how enzymatic lability would affect the extent of corneal and conjunctival penetration of a series of alkyl, cycloalkyl, and aryl ester prodrugs of timolol in the pigmented rabbit. Enzymatic lability of the prodrugs was studied in corneal epithelial and conjunctival homogenates, while their corneal and conjunctival penetration was determined using the isolated tissues in the modified Ussing chamber. The straight-chain alkyl and the unsubstituted cycloalkyl esters were hydrolyzed more rapidly than their corresponding branched-chain and substituted analogues as well as the aryl esters. The corneal and conjunctival penetration of all prodrugs, regardless of enzymatic lability, varied parabolically with lipophilicity. Moreover, the enzymatically more labile straight-chain alkyl esters penetrated the cornea and the conjunctiva more readily than the more stable branched-chain esters of comparable lipophilicity. Enzymatic lability is, therefore, an additional factor that should be considered in designing alkyl ester prodrugs with improved ocular drug delivery characteristics. Enzymatic lability does not, however, play as important a role as lipophilicity in the corneal and conjunctival penetration of cycloalkyl and aryl ester prodrugs. 相似文献
30.
Secondary effects of erythropoietin treatment on metabolism and dialysis efficiency in stable hemodialysis patients 总被引:1,自引:0,他引:1
To test the possible effect of erythropoietin (EPO) induced higher hematocrit on dialysis efficacy and metabolism, 14 metabolically stable hemodialysis patients were evaluated with various kinetic methods, including total dialysate collection. Tests were performed twice before EPO treatment and twice when hemoglobin had stabilized in the targeted range. Samples were frozen and batch analyzed for each patient after completion of the study. During this period, dialysis regimens were fixed. EPO treatment caused several significant changes. Hematocrit increased from 21.5% to 34.3%. Pre- and postdialysis serum potassium increased 0.3-0.4 mmol/l, and 56% more potassium binder was given. Serum phosphate concentrations were unchanged, but the aluminum hydroxide dose had been raised 44%. Dialyzer clearance decreased for urea (4.8%), creatinine (14.7%), phosphate (16.5%) and potassium (8.6%). The ratio of postdialysis/predialysis measurements changed for calcium, creatinine and uric acid. Five patients experienced enhanced appetite, but average dry weight did not change, nor could changes be demonstrated for protein catabolism, generation rate of urea and creatinine, or their distribution volumes. Estimated sodium intake remained unchanged. The findings indicate that EPO treatment reduces dialysis efficiency slightly for a number of substances, but in the metabolically stable patient there are no impressive dietary changes. Problems can be overcome by appropriate changes of dialysis regimen and medication. 相似文献