摘要:

Diltiazem is widely prescribed in Australasia as a cyclosporine-sparing agent. On seven separate occasions at 2-week intervals, the authors studied eight patients who had undergone renal transplantation, were treated with cyclosporin A, and were in stable condition. The patients were administered escalating doses of conventional-release diltiazem, and (in an extension study) controlled diffusion diltiazem, to consider the disposition and metabolism of diltiazem. Blood samples were drawn during a 24-hour period, and the AUC024of diltiazem and three major metabolites was determined. Results demonstrated that seven patients had comparable diltiazem metabolite AUC024profiles, despite considerable variability in parent diltiazem areas under the curve (AUCs), with DM-DTZ > DA-DTZ > DMDA-DTZ. The eighth patient displayed a different metabolite profile. The controlled-diffusion formulation reduced the interpatient variability in diltiazem AUC024from 46-fold to <3-fold, but it did not appear to have release characteristics consistent with the manufacturer's specifications. The apparent bioavailability of the conventional-release diltiazem formulation appeared to be highly variable, and this has implications for its use in recipients of organ transplants. The dosage escalating demonstrated a linear relationship between dose and AUC for diltiazem and for each of the metabolites. There may be a subset of patients who display a different diltiazem metabolite profile.

ISSN:0163-4356    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The effect of active and passive cigarette smoking on CYP1A2-mediated phenacetin disposition was evaluated in a controlled study of 36 healthy Chinese subjects. Each subject was administered a single oral dose of phenacetin (900 mg), and frequent blood samples were taken for up to 12 hours for simultaneous high-pressure liquid chromatography determinations of plasma concentrations of phenacetin and metabolically derived paracetamol. Compared with values observed in controls not exposed to cigarette smoking, subjects who smoked 7 to 40 (median, 20) cigarettes per day exhibited a 2.5-fold higher phenacetin apparent oral clearance (7.2, 4.3-12.0 L.h-1.kg-1vs 2.9, 1.8-4.6 L.h-1.kg-1[geometric means, 95% confidence intervals];n= 12,p< 0.05). In subjects exposed to passive smoking, phenacetin's apparent oral clearance (3.6, 2.0-6.6 L.h-1.kg-1,n= 12) was intermediate between the values observed in the two other groups. Plasma paracetamol levels were moderately lower in active smokers than in passive smokers and controls. These results demonstrated that, in contrast to results found in previous studies, Chinese subjects were fully susceptible to the inducing effect of cigarette smoke on CYP1A2 activity.

ISSN:0163-4356    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The introduction of tacrolimus as rescue therapy represents a significant advance in the prevention of late graft failure and second liver transplantation. The authors report the blood level monitoring of tacrolimus as a rescue therapy in 21 children who underwent liver transplantation, and they report the dose-concentration relationship in the presence or absence of hepatitis C virus (HCV) in these patients. This was a retrospective study conducted from May 1993 to January 1997. Indication for the conversion from cyclosporine (CsA) to tacrolimus were acute rejection (62%), chronic rejection (33%), and CsA toxicity (5%). Mean daily dose in the first month was 0.32 mg/kg, whereas at the end of the follow-up period it was 0.14 mg/kg. Tacrolimus mean whole blood concentration levels were between 7.1 ng/ml and 9.4 ng/ml, without significant differences over time. Mean daily doses in HCV+ and HCV- patients were 0.08 and 0.24 mg/kg, respectively (p< 0.01), and mean concentrations were 8.3 and 8.4 ng/ml (NS). HCV+ children required a mean dose three times lower than the dose used in HCV- children to obtain the same tacrolimus trough blood level. Therefore, doses in HCV+ children must be decreased to achieve levels within the therapeutic range.

ISSN:0163-4356    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Steady state serum concentrations of risperidone and 9-hydroxyrisperidone(9-OH-risperidone), the active moiety, were measured in 42 patients. The concentration-to-dose ratios (C/D) varied by a factor of 20, from 1.8 to 36.8(nmol/1)/(mg/24 hours), and 90% of the active moiety was constituted of 9-OH-risperidone. No correlation between the serum concentration of the active moiety and the side effects evaluated by the UKU Side Effect Scale was found. The absence of CYP2D6 (poor metabolizers) or the coadministration of drugs other than benzodiazepines increased the ratio between parent compound and metabolite but did not significantly influence the C/D of the total active moiety. A therapeutic range for serum risperidone has not been established, but 6 mg/day is considered the optimum dose for most patients. The authors found that in 90% of 22 patients administered 6 mg/day risperidone, the serum levels were within 50 to 150 nmol/l.

ISSN:0163-4356    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The authors report toxicity caused by valacyclovir in a patient on hemodialysis. After initial recuperation resulting from treatment with hemodialysis, the patient experienced a relapse of neurologic symptoms, again necessitating hemodialysis. Although acyclovir and its analogues are generally safe drugs, they should be used with caution in patients with end-stage renal disease. Therapeutic drug monitoring may be indicated.

ISSN:0163-4356    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The authors report the induction of Cushing syndrome by daily betamethasone enema in a patient with ulcerative colitis, and they determine for the first time the pharmacokinetic profile of betamethasone after rectal dosing. The authors found high plasma concentrations of betamethasone, which could have been enough to cause Cushing syndrome. Suppression of the hypothalamus-pituitary-adrenal axis disappeared after the dose schedule was changed from every day to three times a week. These findings suggest that a considerable amount of betamethasone is absorbed after rectal dosing.

ISSN:0163-4356    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Drugs known to inhibit the metabolism of cyclosporine are administered concomitantly to those who undergo cardiothoracic transplantation. The aim of this study was to examine in quantitative terms the relationship between cyclosporine oral dose rate and the trough concentration (Csstrough) at steady state in patients who undergo cardiothoracic transplantation and are administered cyclosporine alone or in combination with drugs known to inhibit its metabolism. Dose and whole blood cyclosporine Csstroughobservations measured using the enzyme-multiplied immunoassay technique(EMIT) (396 observations) or the TDx assay (435 observations) were collected as part of routine blood concentration monitoring from 182 patients who underwent cardiothoracic transplantation. Data were analyzed using a linear mixed-effects modeling approach to examine the effect of metabolic inhibitors on dose-rate-Csstroughratio. The mean (and 95% confidence interval) dose-rate-Csstroughratio for cyclosporine generated from concentrations measured using EMIT was 94 (82.5-105.5) Lh-1for patients administered cyclosporine alone, 66.7 (58.1-75.3) Lh-1for patients administered concomitant diltiazem, 47.9 (15.4 -80.4) Lh-1for patients administered concomitant itraconazole, 21.7 (14.8-28.5) Lh-1for patients administered concomitant ketoconazole, and 14.9(11.8-18.1) Lh-1for patients concomitantly administered diltiazem and ketoconazole. For patients administered concomitant cyclosporine, ketoconazole, and diltiazem, the dosage of cyclosporine, if it is administered alone, should be 20% to achieve the same blood concentrations. This will allow safer drug concentration targeting of cyclosporine after cardiothoracic transplantation.

ISSN:0163-4356    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Serum concentrations of valproic acid (VPA) were reduced to 0% to 40% of the original levels by concomitant use with panipenem-betamipron (PAM-BP) in three patients. The serum VPA level began to decrease 2 days after the administration of PAPM-BP, and it began to increase within 24 hours of the last dose. The rapid change in the serum VPA level suggests the existence of unique and as yet unknown mechanisms of interaction between VPA and PAPM-BP. Epileptic seizures developed in two of the three patients during PAPM-BP use, which signaled the dangers of PAPM-BP administration to patients concomitantly administered VPA. PAPM-BP should not be used in patients administered VPA.

ISSN:0163-4356    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Neoral, the microemulsion formulation of cyclosporine (CsA), demonstrates more consistent bioavailability than the corn oil formulation Sandimmune. Because of Neoral's rapid peak and metabolism, 8-hour dosing has to be used in many pediatric and some adult patients to maintain adequate CsA peak-to-trough ratios. Although the area under the curve (AUC) is considered the best estimate of total drug exposure, it requires repeated blood sampling. Abbreviated AUC profiles yielding excellent estimates of Neoral AUC with twice daily dosing have been described, but no such abbreviated strategy exists for 8-hour dosing. One hundred fifty-two pharmacokinetic profiles in 23 patients were used to derive and prospectively test a limited two-sample strategy to predict Neoral AUCs in pediatric and adult patients on 8-hour dosing regimens of Neoral. The formula was derived from 69 full 8-hour CsA pharmacokinetic profiles in nine children who underwent renal transplantation. Stepwise forward linear and multiple-curve regression techniques assessed the relative importance of single and combination concentration time points to predict AUC. The abbreviated profiles were validated by comparing the mean prediction error for each regression equation. The abbreviated profile calculated by second (C2)- and fourth (C4)-hour levels (AUC = 129 + 1.84× C2 + 4.39 × C4) correlated well with the full AUC(r2= 0.96;p< 0001). Mean prediction error was-0.4% ± 5.48%, and no values fell outside the clinically acceptable 15% prediction error limit. Prospectively applying the formula to 83 AUCs of 14 adults who underwent renal transplantation and were taking Neoral three times a day demonstrated an excellent fit (r2= 0.93;p< 0.001), with 94% of predicted values falling inside the ±15% limit. The authors describe the development of a clinically acceptable, limited sampling strategy to predict 8-hour Neoral AUCs in children and adults who underwent renal transplantation.

ISSN:0163-4356    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

This observational study explored the effects of demographics, sickness, and polypharmacy on the non-steady state population pharmacokinetics of intravenous phenytoin. One hundred fifteen patients were studied. Models were developed using the NONMEM program with hybrid first-order conditional estimation. A Michaelis-Menten model with delayed induction was preferred over a Michaelis-Menten model without induction, a Michaelis-Menten model with immediate induction, or a linear model with delayed induction. When the data were fit to a Michaelis-Menten Model with delayed induction, the volume of distribution (Vd) was found to depend on weight and serum albumin. TheVdwas estimated to be 0.95 l/kg, assuming an albumin level of 3 g/dl. The Michaelis-Menten constant(km) was estimated to be 7.9 mg/l. The baseline maximum metabolic rate was 580 mg/day for a 70-kg patient. The average time to onset of induction was 59.5 hours. If a fever developed after induction began, it increased the extent of induction. This model was evaluated retrospectively in 26 additional patients, yielding a mean prediction error of -0.4 mg/l(-3.0-2.2 mg/l) and a mean absolute prediction error of 4.7 mg/l (3.2-6.2 mg/l) based on two-level feed-back. Given the large interindividual variances in maximum metabolic rate, phenytoin levels should be measured frequently.

ISSN:0163-4356    

出版商:OVID    

年代:1998

数据来源: OVID