Clonidine pharmacokinetics in pregnancy.

The objective of this study was to determine the pharmacokinetic parameters of clonidine during pregnancy compared with previously published data in nonpregnant subjects. Serial blood and urine samples were collected in 17 women during mid to late pregnancy over one steady-state dosing interval to determine clonidine noncompartmental pharmacokinetic parameters (n = 17) and creatinine clearance. In six of these pregnant subjects, maternal and umbilical cord (venous and arterial) plasma samples were collected at the time of delivery for measurement of clonidine concentrations. Clonidine apparent oral clearance was found to be 440 +/- 168 ml/min during pregnancy compared with 245 +/- 72 ml/min as previously reported in nonpregnant subjects (p < 0.0001) (Cunningham et al., 1994). There was a strong correlation (r = 0.82, p < 0.001) between clonidine renal clearance, adjusted for variation in glomerular filtration rate, and urine pH. Umbilical cord to maternal plasma clonidine concentration ratios were 1.0 +/- 0.1 (arterial) and 1.0 +/- 0.1 (venous). In conclusion, clonidine is cleared more rapidly in pregnant women than in nonpregnant subjects. At the time of delivery, the fetus is exposed to similar plasma clonidine concentrations as the mother.

Busulfan concentration and graft rejection in pediatric patients undergoing hematopoietic stem cell transplantation.

We retrospectively analyzed the relationship between busulfan average steady-state plasma concentration (C(SS)) and graft rejection in 53 children receiving busulfan/cyclophosphamide (BU/CY) preparative regimens prior to hematopoietic stem cell transplantation (HSCT). Patients received a total oral busulfan dose of 11 to 28 mg/kg followed by a total cyclophosphamide dose of 120 to 335 mg/kg in preparation for allogeneic grafts (HLA-matched or HLA partially matched sibling, parent or unrelated donor). Graft rejection occurred in eight (15%) patients. Busulfan C(SS) (P = 0.0024) was the only statistically significant predictor of rejection on univariate logistic regression analysis, with the risk of rejection decreasing with an increase in busulfan C(SS). Severe (grade 3 or 4) regimen-related toxicity (RRT) occurred in four patients. Ten patients (19%) had a busulfan C(SS) higher than 900 ng/ml, one of whom had severe RRT. Higher and variable doses of cyclophosphamide may explain the lack of a relationship between busulfan C(SS) and RRT in children. It may be possible to improve the outcome of HSCT in pediatric patients receiving the BU/CY regimen through optimization of busulfan C(SS) and better definition of the contribution of activated cyclophosphamide metabolites to toxicity.

Target dose adjustment of busulfan in pediatric patients undergoing bone marrow transplantation.

Published data suggest that the average concentration of busulfan at steady state (Bu Css) is critical for successful engraftment in children receiving busulfan as a conditioning agent for bone marrow transplantation (BMT). We previously found in children that a Bu Css <600 ng/ml correlated with autologous recovery/mixed chimerism; there was no correlation between Bu Css and regimen-related toxicity (RRT). In a cohort continuous with the previous trial, we prospectively evaluated targeted busulfan concentrations in 32 pediatric patients (age 0.6-18.5 years) with AML (n = 6), CML (n = 6) and non-malignant disorders (n = 20) receiving HLA-closely matched donor grafts. In this trial, individual busulfan pharmacokinetics were performed prior to admission. Busulfan doses were then adjusted to achieve a Bu Css target range of 600-900 ng/ml +/- 10% depending on donor source and disease. A repeat study was done following dose 1 of the conditioning regimen. Thirty of thirty-two (94%) patients achieved target concentrations. Total busulfan doses ranged from 10.9 to 29 mg/kg. Thirty of thirty-two patients (94%) have durably engrafted. Grade 3/4 RRT occurred in seven patients (21%). Targeting Bu Css ranges of 600-900 ng/ml significantly improved our rate of successful engraftment from 74% to 94% (P = 0.043). These results indicate that targeted busulfan dosing optimizes allogeneic engraftment in children.

Morphine-fluoxetine interactions in healthy volunteers: analgesia and side effects.

The authors evaluated the ability of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), to enhance the analgesic potency of morphine. Fifteen volunteers participated in this double-blind crossover study. All received combinations of morphine or saline with either fluoxetine 30 mg or placebo. The authors used individual morphine pharmacokinetics to program an infusion pump to achieve plasma morphine levels of 15, 30, and 60 ng/ml. Analgesia during morphine infusion was assessed using a model of electrical tooth stimulation. Subjective side effects, measurements of end-tidal CO2, O2 saturation, pupil size, and testing of psychomotor performance were obtained. Plasma morphine concentrations were not affected by fluoxetine. In comparison to placebo, oral fluoxetine resulted in less sedation during morphine infusion and less nausea during morphine washout. Morphine-induced pruritus, psychomotor function, and respiratory depression were unaffected by fluoxetine. Acute administration of 30 mg oral fluoxetine augmented analgesia by approximately 3% to 8% and reduced morphine-associated nausea, mood reduction, and drowsiness.

An evaluation of engraftment, toxicity and busulfan concentration in children receiving bone marrow transplantation for leukemia or genetic disease.

Autologous recovery is a major problem with busulfan as a marrow ablative agent in conditioning children for allogeneic BMT. Data suggest the average concentration of busulfan at steady state (Bu Css) is critical for successful engraftment. We prospectively evaluated busulfan pharmacokinetics in 31 children (age 0.6-18 years) with AML (n = 9), and non-malignant diseases (n = 22) receiving HLA-closely matched (sibling, parent, unrelated) donor grafts. Blood samples were obtained following dose 1 and 13 of a standard 16 dose, 4-day regimen. The busulfan dose varied from 14 to 20 mg/kg. Patients received cyclophosphamide 200-240 mg/kg; 22/31 received 80-90 mg/kg of ATG. Eight patients failed to engraft (26%). ATG did not appear to influence engraftment (P = 0.38). Bu Css levels <600 ng/ml correlated with autologous recovery/mixed chimerism (P = 0.018). There were no graft failures in patients with a Bu Css >600 ng/ml. A correlation between Bu Css levels and regimen-related toxicity (RRT) was not identified for grade 2 or higher toxicities, only 1/31 had a Bu Css >900 ng/ml. Our data support the use of pharmacokinetic monitoring of busulfan.

Equivalent analgesia and side effects during epidural and pharmacokinetically tailored intravenous infusion with matching plasma alfentanil concentration.

BACKGROUND: Recently, several clinical studies comparing intravenous and epidural infusions of fentanyl and its derivatives suggested that epidural infusions act primarily by systemic absorption to produce supraspinal analgesia. To evaluate this hypothesis, the authors used pharmacokinetically tailored intravenous infusions to produce matching plasma alfentanil concentrations during epidural and intravenous administration. The analgesia and side effects achieved with each mode of administration were compared. METHODS: Twelve volunteers participated in this placebo-controlled crossover study. The pain model was cutaneous electric stimulation of the finger and toe. The test battery included subjective rating of pain intensity; end-tidal carbon dioxide level; pupil size; ratings of alertness, nausea, and pruritus; and a plasma alfentanil assay. On one test day, the participants received epidural alfentanil (400 microg bolus + a 400-microg/h infusion for 2 h) and an intravenous saline infusion. The test battery was administered at regular intervals. On another test day, the participants received epidural saline and a computer-controlled intravenous infusion of alfentanil. The testing protocol was repeated as on the first test day. On the day the placebo was administered, the participants received epidural and intravenous saline infusions. The order of the placebo day was randomized. RESULTS: Plasma alfentanil concentration-time profiles were identical during epidural and intravenous infusions. A nearly equivalent analgesic response was observed with epidural and intravenous alfentanil at the upper and lower extremities. There were no differences in side effects for epidural and intravenous administration. CONCLUSIONS: The systemic redistribution of alfentanil accounts for most of the analgesia and effects produced by epidural infusion.

Therapeutic monitoring of busulfan in hematopoietic stem cell transplantation.

Busulfan is an alkylating agent commonly used to ablate marrow before hematopoietic stem cell transplantation. High levels have been shown to increase the chance for severe hepatic veno-occlusive disease, for which there is no treatment and which can be fatal. Low levels are associated with recurrence of chronic myeloid leukemia, whereas even lower levels are associated with graft rejection. The therapeutic window for busulfan is narrow and disease and graft-source dependent. Busulfan concentration in plasma is readily assayed by gas chromatography. In the authors' center, busulfan levels determined from the first dose of the drug are used to adjust the dose to that selected to achieve the desired therapeutic outcome by the third dose of the 16-dose regimen. Thus, turnaround time is less than 6 hours. Analytical and pharmacokinetic aspects of busulfan therapeutic monitoring are described. The cost of pharmacokinetically targeting busulfan concentration is < or = 1% of the cost of hematopoietic stem cell transplantation.

Age-dependent tetrahydrothiophenium ion formation in young children and adults receiving high-dose busulfan.

Busulfan, a bifunctional alkylating agent, is a mainstay of myeloablative preparative regimens before hematopoietic stem cell transplantation. The apparent oral clearance of busulfan expressed relative to body surface area is 2-3-fold higher in children 1-4 years old than it is in adults. The first step in busulfan elimination is the formation of a tetrahydrothiophenium ion (THT+) in a glutathione S-transferase-catalyzed reaction. We present computer simulations that demonstrate that the ratio of the AUC of THT+ to that of busulfan over 6 h [(AUC(THT+)/AUC(BU))(0-->6)] is highly correlated (r2 = 0.805) with the determinants of THT+ formation and is virtually independent of the determinants of its elimination (r2 = 0.0201). We compared (AUC(THT+)/AUC(BU))(0-->6) determined in 14 children (0.5-4 years) to that of 11 adults (12-54 years) and found a 1.5-fold elevation in the area ratio (P = 0.0098) and a similarly significant increase in busulfan apparent oral clearance expressed relative to body surface area (P = 0.042). The only common explanation for the elevated busulfan apparent oral clearance and (AUC(THT+)/AUC(BU))(0-->6) is an enhanced ability of children to metabolize busulfan through glutathione conjugation.

Excreted steroids in primate feces over the menstrual cycle and pregnancy.

Techniques were established for the extraction and measurement of 17 beta-estradiol (E2) and progestins (P4) from feces of Old World primates. Studies were conducted to show the sensitivity of these measures, means of preserving fecal samples in the field, effects of urinary contamination, and means to eliminate these effects. Our results show that excreted steroid measures can be used to distinguish between mid-follicular and luteal phases in the menstrual cycle, and to identify pregnancy by Day 20 of gestation; the steroid measures can also be used to identify ovulatory levels of E2 and to establish the length of the menstrual cycle. Urine was shown to contaminate the fecal sample and to confound the estimate of steroid levels in feces; prolonged storage (less than 6 h) was shown to change the steroid estimate. Both urinary contamination and storage-dependent changes were eliminated by the addition of ethanol to the sample. Preliminary results also suggest that effects of dietary fiber on steroid hormone levels are minimal when controlled quantitatively by adjusting for water content of the fecal sample. We conclude that these measurements of excreted steroids provide a valid, noninvasive measure of physiological state of the hypothalamic-pituitary-ovarian axis among free-ranging animals in the field.