Pharmacological prevention and treatment of opioid-induced constipation in cancer patients: A systematic review and meta-analysis.

BACKGROUND: Cancer-related pain often requires opioid treatment with opioid-induced constipation (OIC) as its most frequent gastrointestinal side-effect. Both for prevention and treatment of OIC osmotic (e.g. polyethylene glycol) and stimulant (e.g. bisacodyl) laxatives are widely used. Newer drugs such as the peripherally acting µ-opioid receptor antagonists (PAMORAs) and naloxone in a fixed combination with oxycodone have become available for the management of OIC. This systematic review and meta-analysis aims to give an overview of the scientific evidence on pharmacological strategies for the prevention and treatment of OIC in cancer patients. METHODS: A systematic search in PubMed, Embase, Web of Science and the Cochrane Library was completed from inception up to 22 October 2022. Randomized and non-randomized studies were systematically selected. Bowel function and adverse drug events were assessed. RESULTS: Twenty trials (prevention: five RCTs and three cohort studies; treatment: ten RCTs and two comparative cohort studies) were included in the review. Regarding the prevention of OIC, three RCTs compared laxatives with other laxatives, finding no clear differences in effectivity of the laxatives used. One cohort study showed a significant benefit of magnesium oxide compared with no laxative. One RCT found a significant benefit for the PAMORA naldemedine compared with magnesium oxide. Preventive use of oxycodone/naloxone did not show a significant difference in two out of three other studies compared to oxycodone or fentanyl. A meta-analysis was not possible. Regarding the treatment of OIC, two RCTs compared laxatives, of which one RCT found that polyethylene glycol was significantly more effective than sennosides. Seven studies compared an opioid antagonist (naloxone, methylnaltrexone or naldemedine) with placebo and three studies compared different dosages of opioid antagonists. These studies with opioid antagonists were used for the meta-analysis. Oxycodone/naloxone showed a significant improvement in Bowel Function Index compared to oxycodone with laxatives (MD -13.68; 95 % CI -18.38 to -8.98; I2 = 58 %). Adverse drug event rates were similar amongst both groups, except for nausea in favour of oxycodone/naloxone (RR 0.51; 95 % CI 0.31-0.83; I2 = 0 %). Naldemedine (NAL) and methylnaltrexone (MNTX) demonstrated significantly higher response rates compared to placebo (NAL: RR 2.07, 95 % CI 1.64-2.61, I2 = 0 %; MNTX: RR 3.83, 95 % CI 2.81-5.22, I2 = 0 %). With regard to adverse events, abdominal pain was more present in treatment with methylnaltrexone and diarrhea was significantly more present in treatment with naldemedine. Different dosages of methylnaltrexone were not significantly different with regard to both efficacy and adverse drug event rates. CONCLUSIONS: Magnesium oxide and naldemedine are most likely effective for prevention of OIC in cancer patients. Naloxone in a fixed combination with oxycodone, naldemedine and methylnaltrexone effectively treat OIC in cancer patients with acceptable adverse events. However, their effect has not been compared to standard (osmotic and stimulant) laxatives. More studies comparing standard laxatives with each other and with opioid antagonists are necessary before recommendations for clinical practice can be made.

Magnesium hydroxide versus macrogol/electrolytes in the prevention of opioid-induced constipation in incurable cancer patients: study protocol for an open-label, randomized controlled trial (the OMAMA study).

BACKGROUND: Opioid-induced constipation (OIC) is a common symptom in cancer patients treated with opioids with a prevalence of up to 59%. International guidelines recommend standard laxatives such as macrogol/electrolytes and magnesium hydroxide to prevent OIC, although evidence from randomized controlled trials is largely lacking. The aim of our study is to compare magnesium hydroxide with macrogol /electrolytes in the prevention of OIC in patients with incurable cancer and to compare side-effects, tolerability and cost-effectiveness. METHODS: Our study is an open-label, randomized, multicenter study to examine if magnesium hydroxide is non-inferior to macrogol/electrolytes in the prevention of OIC. In total, 330 patients with incurable cancer, starting with opioids for pain management, will be randomized to treatment with either macrogol/electrolytes or magnesium hydroxide. The primary outcome measure is the proportion of patients with a score of < 30 on the Bowel Function Index (BFI), measured on day 14. The Rome IV criteria for constipation, side effects of and satisfaction with laxatives, pain scores, quality of life (using the EQ-5D-5L), daily use of laxatives and escape medication, and cost-effectiveness will also be assessed. DISCUSSION: In this study we aim to examine if magnesium hydroxide is non-inferior to macrogol/electrolytes in the prevention of OIC. The outcome of our study will contribute to prevention of OIC and scientific evidence of guidelines on (opioid-induced) constipation. TRIAL REGISTRATION: This trial is registered at clinicaltrials.gov: NCT05216328 and in the Dutch trial register: NTR80508. EudraCT number 2022-000408-36.

Palliative sedation and moral distress: A qualitative study of nurses.

BACKGROUND: Clinical nursing practice may involve moral distress, which has been reported to occur frequently when nurses care for dying patients. Palliative sedation is a practice that is used to alleviate unbearable and refractory suffering in the last phase of life and has been linked to distress in nurses. AIM: The aim of this study was to explore nurses' reports on the practice of palliative sedation focusing on their experiences with pressure, dilemmas and morally distressing situations. METHODS: In-depth interviews with 36 nurses working in hospital, nursing home or primary care. RESULTS: Several nurses described situations in which they felt that administration of palliative sedation was in the patient's best interest, but where they were constrained from taking action. Nurses also reported on situations where they experienced pressure to be actively involved in the provision of palliative sedation, while they felt this was not in the patient's best interest. The latter situation related to (1) starting palliative sedation when the nurse felt not all options to relieve suffering had been explored yet; (2) family requesting an increase of the sedation level where the nurse felt that this may involve unjustified hastening of death; (3) a decision by the physician to start palliative sedation where the patient had previously expressed an explicit wish for euthanasia. CONCLUSIONS: Nurses experienced moral distress in situations where they were not able to act in what they believed is the patient's best interest. Situations involving moral distress require nurses to be well informed and able to adequately communicate with suffering patients, distressed family and physicians.

[Discontinuation of potentially inappropriate medications at the end of life: perspectives from patients, their relatives, and physicians]. / Overbodige medicatie stoppen vlak voor overlijden.

OBJECTIVE: To obtain insight into the perspectives of patients, relatives and physicians towards potentially inappropriate medications (PIMs) at the end of life. DESIGN: Qualitative interview study. METHOD: An analysis of in-depth interviews with 17 patients who were diagnosed as having a life expectancy of less than three months, 12 patient relatives, and 20 medical specialists and 12 general practitioners who cared for them. For analysis we applied the constant comparative method, which forms part of the grounded theory approach. RESULTS: Patients and their relatives are prepared to discontinue PIMs. Still, some patients reported that stopping might give them the feeling that their attending physician has already thrown in the towel. Physicians mentioned several reasons for not ceasing PIMs: cessation not considered, low priority, and unknown consequences of discontinuation. Some physicians were concerned that discussing the discontinuation of PIMs with patients could make patients acutely aware of the approach of death, and give patients the impression that they are receiving inferior medical care. If physicians communicate with patients the possibility of discontinuing medications, they seem to emphasize the clinical futility of continuing PIMs in light of the patient's limited life expectancy. CONCLUSION: Patients with a limited life expectancy and their relatives may be open to discontinue PIMs; however, in reality this happens rarely. When a physician is of the opinion that it would be of benefit to discontinue certain medications, then the advantages of cessation should be highlighted more in discussions with the patient.

To be in pain (or not): a computer enables outpatients to inform their physician.

BACKGROUND: In the outpatient oncology clinic, pain management is often inadequate. Incorporating a systematic pain management program into visits is likely to improve this. We implemented an integrated program, including a structured pain assessment, pain treatment protocol and patient education module. In the present study, we investigated whether this intervention improved pain control. PATIENTS AND METHODS: At seven oncology outpatient clinics, patients were asked to register their pain intensity on a touch screen computer. These scores were made available into their electronic medical records. Additionally, a hospital-wide treatment protocol for cancer-related pain and a patient education module were developed. A data warehouse system enabled us to extract patient data from the electronic medical record anonymously and to use them for analysis. The primary outcome of the study was the percentage of patients with moderate to severe pain [current pain (CPI), NRS > 4] measured during 2 weeks at the start and 6 months after implementation. As secondary outcomes, we studied the percentage of pain registrations in specific patient groups and the percentage of patients treated with a curative and a palliative intention with (moderate-severe) pain. Differences were tested with the χ(2) test. RESULTS: During the first 6 months, 3407 of the 4345 patients (78%) registered their pain intensity on the touch screen computer. The percentage of patients with moderate to severe CPI decreased 32% (P = 0.021): from 12.5% at start to 8.5% after 6 months. More patients in the palliative phase than in the curative phase of their disease registered their pain intensity (82% versus 75%, respectively, P < 0.005), and more patients in the palliative phase experienced moderate to severe pain (23% versus 14%, respectively, P < 0.001). CONCLUSION: Pain registration by patients themselves is feasible, provides insight into patients' pain intensity and may improve pain control in outpatients with cancer-related pain. CLINICAL TRIAL NUMBER: Because this is an innovation project and not a primary research project, it has no clinical trial number. The protocol and all materials involved were approved by the Institutional Review Board of the Erasmus MC (MEC-2009-324).

Pharmacokinetic considerations and recommendations in palliative care, with focus on morphine, midazolam and haloperidol.

INTRODUCTION: A variety of medications are used for symptom control in palliative care, such as morphine, midazolam and haloperidol. The pharmacokinetics of these drugs may be altered in these patients as a result of physiological changes that occur at the end stage of life. AREAS COVERED: This review gives an overview of how the pharmacokinetics in terminally ill patients may differ from the average population and discusses the effect of terminal illness on each of the four pharmacokinetic processes absorption, distribution, metabolism, and elimination. Specific considerations are also given for three commonly prescribed drugs in palliative care: morphine, midazolam and haloperidol). EXPERT OPINION: The pharmacokinetics of drugs in terminally ill patients can be complex and limited evidence exists on guided drug use in this population. To improve the quality of life of these patients, more knowledge and more pharmacokinetic/pharmacodynamics studies in terminally ill patients are needed to develop individualised dosing guidelines. Until then knowledge of pharmacokinetics and the physiological changes that occur in the final days of life can provide a base for dosing adjustments that will improve the quality of life of terminally ill patients. As the interaction of drugs with the physiology of dying is complex, pharmacological treatment is probably best assessed in a multi-disciplinary setting and the advice of a pharmacist, or clinical pharmacologist, is highly recommended.

Variation in medication use in cancer patients at the end of life: a cross-sectional analysis.

PURPOSE: Despite advances in cancer treatment, patients still die with unnecessary suffering. Therefore, high-quality end-of-life care is needed. Variations in medication use at the end of life may suggest areas for improvement. This study aims to describe the use of medications during the last days of life of cancer patients and to explore the possibility of using it as a quality measure. METHODS: We conducted an international survey on experts' opinions regarding potentially inappropriate medications for dying patients. Subsequently, a chart review of deceased cancer patients was conducted, which assessed the current medication use in different settings. RESULTS: The mean number of medications used in the last 3 days of life was 4.8 (SD 2.1). Hospital patients were less likely than hospice patients to receive opioids, midazolam, haloperidol, and drugs for pulmonary secretions or nausea/vomiting. Over 90 % of experts rated 12 medications as unlikely to be appropriate. Hospital patients were more likely than hospice patients to receive these potentially inappropriate medications. Before the implementation of an end-of-life care pathway, hospital patients had a higher probability, than after, to receive potentially inappropriate medication. Moreover, after implementation of such pathway, patients for whom a pathway was not used were more likely to receive potentially inappropriate medications than patients for whom it was used. CONCLUSION: Medication use at the end of life varies widely by setting, both for potentially appropriate and inappropriate medications. Combining experts' opinion and current medication use resulted in the identification of 16 medications that might be used to assess the quality of cancer care at the end of life.

Artificial nutrition and hydration in the last week of life in cancer patients. A systematic literature review of practices and effects.

BACKGROUND: The benefits and burdens of artificial nutrition (AN) and artificial hydration (AH) in end-of-life care are unclear. We carried out a literature review on the use of AN and AH in the last days of life of cancer patients. MATERIALS AND METHODS: We systematically searched for papers in PubMed, CINAHL, PsycInfo and EMBASE. All English papers published between January 1998 and July 2009 that contained data on frequencies or effects of AN or AH in cancer patients in the last days of life were included. RESULTS: Reported percentages of patients receiving AN or AH in the last week of life varied from 3% to 53% and from 12% to 88%, respectively. Five studies reported on the effects of AH: two found positive effects (less chronic nausea, less physical dehydration signs), two found negative effects (more ascites, more intestinal drainage) and four found also no effects on terminal delirium, thirst, chronic nausea and fluid overload. No study reported on the sole effect of AN. CONCLUSIONS: Providing AN or AH to cancer patients who are in the last week of life is a frequent practice. The effects on comfort, symptoms and length of survival seem limited. Further research will contribute to better understanding of this important topic in end-of-life care.

Disposition of docetaxel in the presence of P-glycoprotein inhibition by intravenous administration of R101933.

Recently, a study of docetaxel in combination with the new orally administered P-glycoprotein (P-gp) inhibitor R101933 showed that this combination was feasible. However, due to the low oral bioavailability of R101933 and high interpatient variability, no further attempts to increase the level of P-gp inhibition were made. Here, we assessed the feasibility of combining docetaxel with intravenously (i.v.) administered R101933, and determined the disposition of docetaxel with and without the P-gp inhibitor. Patients received i.v. R101933 alone at a dose escalated from 250 to 500 mg on day 1 (cycle 0), docetaxel 100 mg/m(2) as a 1-h infusion on day 8 (cycle 1) and the combination every 3 weeks thereafter (cycle 2 and further cycles). 12 patients were entered into the study, of whom 9 received the combination treatment. Single treatment with i.v. R101933 was associated with minimal toxicity consisting of temporary drowsiness and somnolence. Dose-limiting toxicity consisting of neutropenic fever was seen in cycles 1 and 2 or in further cycles at both dose levels. The plasma pharmacokinetics of docetaxel were not changed by the R101933 regimen at any dose level tested, as indicated by plasma clearance values of 22.5+/-6.2 l/h/m(2) and 24.2+/-7.4 l/h/m(2) (P=0.38) in cycles 1 and 2, respectively. However, the faecal excretion of unchanged docetaxel decreased significantly after the combination treatment from 2.5+/-2.1% to less than 1% of the administered dose of docetaxel, most likely due to inhibition of the intestinal P-gp by R101933. Plasma concentrations of R101933 were not different in cycles 0 or 2 and the concentrations achieved in the first 12-h period after i.v. infusion were capable of inhibiting P-gp in an ex vivo assay. We conclude that the combination of 100 mg/m(2) i.v. docetaxel and 500 mg i.v. R101933 is feasible, lacks pharmacokinetic interaction in plasma, and shows evidence of P-gp inhibition both in an ex vivo assay and in vivo as indicated by the inhibition of intestinal P-gp.

Role of formulation vehicles in taxane pharmacology.

The non-ionic surfactants Cremophor EL (CrEL) and Tween 80, both used as formulation vehicles of many (anticancer) agents including paclitaxel and docetaxel, are not physiological inert compounds. We describe their biological properties, especially the toxic side effects, and their pharmacological properties, such as modulation of P-glycoprotein activity. In detail, we discuss their influence on the disposition of the solubilized drugs, with focus on CrEL and paclitaxel, and of concomitantly administered drugs. The ability of the surfactants to form micelles in aqueous solution as well as biological fluids (e.g. plasma) appears to be of great importance with respect to the pharmacokinetic behavior of the formulated drugs. Due to drug entrapment in the micelles, plasma concentrations and clearance of free drug change significant leading to alteration in pharmacodynamic characteristics. We conclude with some perspectives related to further investigation and development of alternative methods of administration.

Pharmacokinetic modeling of paclitaxel encapsulation in Cremophor EL micelles.

Nonlinear disposition of paclitaxel (Taxol) in cancer patients has been described in several studies, but the underlying mechanism is still a matter of speculation. Previously, we have shown in vitro that the paclitaxel formulation vehicle, Cremophor EL (CrEL), alters the blood distribution of paclitaxel as a result of entrapment of the compound in circulating CrEL micelles, thereby reducing the free drug fraction available for cellular partitioning. Based on these findings, we prospectively re-evaluated the linearity of paclitaxel disposition in patients using whole blood and plasma analysis, and sought to define a new pharmacokinetic model to describe the data. Seven patients with solid tumors were treated with paclitaxel infused over 3 h, each at consecutive 3-weekly dose levels of 225, 175 and 135 mg/m2 (CrEL dose level, 18.8, 14.6, and 11.3 ml/m2, respectively). Patient samples were collected up to 24 h after the start of infusion, and analyzed by high-performance liquid chromatography. Paclitaxel peak levels and areas under the curve in whole blood increased linearly with dose, whereas plasma levels showed substantial deviation from linearity. This was shown to be caused by a CrEL concentration-dependent decrease in paclitaxel uptake in blood cells, as reflected by the blood:plasma concentration ratios which altered significantly from 0.83 +/- 0.11 (at 135 mg/m2) to 0.68 +/- 0.07 (at 225 mg/m2). It is concluded that the nonlinear disposition of paclitaxel is related to paclitaxel dose-related levels of the formulation vehicle CrEL, leading to a disproportionate drug accumulation in the plasma fraction. The pharmacokinetic model developed accurately described the data, and will help guide future development and refinement of clinical protocols, especially in defining the exposure measure best linked to paclitaxel effects and toxicities.

Development of multidrug-resistance convertors: sense or nonsense?

This review describes the clinical relevance of the two drug transporters P-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP) and the in vitro phenomenon which is referred to as multidrug resistance (MDR). The attempts to try to block these resistance mechanisms are summarized with specific attention for the intentionally designed "second generation" MDR-convertors. Potential explanations of the limited clinical success rate are given and recommendations for the design of future studies provided.

Inter-relationships of paclitaxel disposition, infusion duration and cremophor EL kinetics in cancer patients.

Cremophor EL (CrEL) is a castor oil surfactant used as a vehicle for formulation of a variety of poorly water-soluble agents, including paclitaxel. Recently, we found that CrEL can influence the in vitro blood distribution of paclitaxel by reducing the free drug fraction, thereby altering drug accumulation in erythrocytes. The purpose of this study was to investigate the clinical pharmacokinetics of CrEL, and to examine inter-relationships of paclitaxel disposition, infusion duration and CrEL kinetics. The CrEL plasma clearance, studied in 17 patients for a total of 28 courses, was time dependent and increased significantly with prolongation of the infusion duration from 1 to 3 to 24 h (p<0.03). An indirect response model, applied based on use of a Hill function for CrEL concentration-dependent alteration of in vivo blood distribution of paclitaxel, was used to fit experimental data of the 3 h infusion (r2=0.733; p=0.00001). Simulations for 1 and 24 h infusions using predicted parameters and CrEL kinetic data revealed that both short and prolonged administration schedules induce a low relative net change in paclitaxel blood distribution. Our pharmacokinetic/pharmacodynamic model demonstrates that CrEL causes disproportional accumulation of paclitaxel in plasma in a 3 h schedule, but is unlikely to affect drug pharmacokinetics in this manner with alternative infusion durations.

Role of intestinal P-glycoprotein in the plasma and fecal disposition of docetaxel in humans.

Multidrug resistance (MDR)-1-P-glycoprotein (P-gp) is a drug-transporting protein that is abundantly present in biliary ductal cells and epithelial cells lining the gastrointestinal tract. Here, we have determined the role of P-gp in the metabolic disposition of the antineoplastic agent docetaxel (Taxotere) in humans. Pharmacokinetic profiles were evaluated in five cancer patients receiving treatment cycles with docetaxel alone (100 mg/m2 i.v. over a 1-h period) and in combination with a new potent inhibitor of P-gp activity, R101933 (200-300 mg b.i.d.). The terminal disposition half-life and total plasma clearance of docetaxel were not altered by treatment with oral R101933 (P > or = 0.27). The cumulative fecal excretion of docetaxel, however, was markedly reduced from 8.47 +/- 2.14% (mean +/- SD) of the dose with the single agent to less than 0.5% in the presence of R101933 (P = 0.0016). Levels of the major cytochrome P450 3A4-mediated metabolites of docetaxel in feces were significantly increased after combination treatment with R101933 (P = 0.010), indicating very prominent and efficient detoxification of reabsorbed docetaxel into hydroxylated compounds before reaching the systemic circulation. It is concluded that intestinal P-gp plays a principal role in the fecal elimination of docetaxel by modulating reabsorption of the drug after hepatobiliary secretion. In addition, the results indicate that inhibition of P-gp activity in normal tissues by effective modulators, and the physiological and pharmacological consequences of this treatment, cannot be predicted based on plasma drug monitoring alone.

The orally administered P-glycoprotein inhibitor R101933 does not alter the plasma pharmacokinetics of docetaxel.

This Phase I study was performed to assess the feasibility of combining docetaxel with the new P-glycoprotein inhibitor R101933 and to determine the dose limiting toxicity of this combination. Fifteen patients received oral R101933 alone at a dose escalated from 200 to 300 mg twice daily (b.i.d.; cycle 0), an escalating i.v. dose of docetaxel (60, 75, and 100 mg/m2) as a 1-h infusion (cycle 1), and the combination (cycle 2 and further). Dose limiting toxicity consisting of mucositis and neutropenic fever was reached at the combination of docetaxel, 100 mg/m2, and R101933, 300 mg b.i.d., and the maximum tolerated dose was established at docetaxel, 100 mg/m2, and R101933, 200 mg b.i.d. Plasma concentrations of R101933 achieved in patients were in the same range as required in preclinical rodent models to overcome paclitaxel resistance. The plasma pharmacokinetics of docetaxel were not influenced by the R101933 regimen at any dose level tested, as indicated by plasma clearance values of 26.5 +/- 7.78 liters/h/m2 and 23.4 +/- 4.52 liters/h/m2 (P = 0.15) in cycles 1 and 2, respectively. These findings indicate that the contribution of a P-glycoprotein inhibitor to the activity of anticancer chemotherapy can now be assessed in patients for the first time independent of its effect on drug pharmacokinetics.

Phase I and pharmacologic study of the arotinoid Ro 40-8757 in combination with cisplatin and etoposide in patients with non-small cell lung cancer.

This phase I study was performed to assess the feasibility of combining cisplatin/etoposide (VP-16) with the arotinoid Ro 40-8757 and to determine the dose-limiting toxicity (DLT) of Ro 40-8757 in this combination. Patients with non-small cell lung cancer were eligible. Treatment consisted of Ro 40-8757 p.o. day 1-21, cisplatin 100 mg/m2 i.v. on day 2 and VP-16 100 mg/m2 i.v. on day 2-4, repeated every 3 weeks. Eighteen patients were evaluable for toxicity and response. The doses of Ro 40-8757 ranged from 84 mg/m2 once daily to 42 mg/m2 thrice daily (tid). DLT consisting of delayed nausea/vomiting was reached at 42 mg/m2 tid. Consequently, the maximum tolerated dose was set at one dose level below the DLT, i.e. 28 mg/m2 tid. Skin toxicity occurred but was well manageable. Pharmacological analyses showed a small increase in the volume of distribution of cisplatin and VP-16 between the first and third course. However, no relationship with side effects was found. A response was achieved in 50% of patients. The combination of cisplatin/VP-16 with Ro 40-8757 appears to be feasible at a dose schedule of 28 mg/m2 tid. The response rate was at the upper rate of what can be expected with cisplatin and VP-16.

Cremophor EL-mediated alteration of paclitaxel distribution in human blood: clinical pharmacokinetic implications.

We have determined the in vitro and in vivo cellular distribution of the antineoplastic agent paclitaxel (Taxol) in human blood and the influence of Cremophor EL (CrEL), the vehicle used for i.v. drug administration. In the absence of CrEL, the blood:plasma concentration ratio was 1.07+/-0.004 (mean+/-SD). The addition of CrEL at concentrations corresponding to peak plasma levels achieved after the administration of paclitaxel (175 mg/m2 i.v. over a 3-h period; ie., 0.50%) resulted in a significant decrease in the concentration ratio (0.690+/-0.005; P < 0.05). Kinetic experiments revealed that this effect was caused by reduced erythrocyte uptake of paclitaxel by polyoxyethyleneglycerol triricinoleate, the major compound present in CrEL. Using equilibrium dialysis, it was shown that the affinity of paclitaxel for tested matrices was (in decreasing order) CrEL > plasma > human serum albumin, with CrEL present at or above the critical micellar concentration (approximately 0.01%). Our findings in the present study demonstrate a profound alteration of paclitaxel accumulation in erythrocytes caused by a trapping of the compound in CrEL micelles, thereby reducing the free drug fraction available for cellular partitioning. It is proposed that the nonlinearity of paclitaxel plasma disposition in patients reported previously should be reevaluated prospectively by measuring the free drug fractions and whole blood:plasma concentration ratios.

Determination of 5-fluorouracil in microvolumes of human plasma by solvent extraction and high-performance liquid chromatography.

In the present study, a new reversed-phase HPLC method has been developed and validated for the quantitative determination of 5-fluorouracil (5-FU) in human plasma using only 100-microl samples. The sample extraction and clean-up procedure involved a simple liquid-liquid extraction after addition of 5-chlorouracil (5-CU), used as internal standard, with 5 ml ethyl acetate. Chromatographic separations were performed on an Inertsil ODS-3 column (250x4.6 mm ID; 5 microM particle size), eluted with a mobile phase composed of acidified water (pH 2.0). The column effluent was monitored by UV absorption measurement at a wavelength of 266 nm. The calibration curves were constructed over a range of 0.20-50.0 microM and were fitted by weighted (1/x) linear regression analysis using the ratio of peak heights of 5-FU and 5-CU versus concentrations of the nominal standards. Extraction recoveries over the total range averaged 92 and 93% for 5-FU and 5-CU, respectively. The lower limit of quantitation was established at 0.20 microM (approximately 26 ng/ml), with within-run and between-run precisions of 4.2 and 7.0%, respectively, and an average accuracy of 109.3%. The within-run and between-run precisions at four tested concentrations analyzed in quintuplicate over a time period of four days were < 1.4 and < 4.4%, respectively. The accuracy at the tested concentrations ranged from 98.4 to 102.3%. Compared to previously described validated analytical methods for 5-FU, our present assay provides equivalent to superior sensitivity, using only microvolumes of sample.

Changes of zinc values in children during malignant disease.

In 47 children with malignancy, zinc status, growth, and performance during standard treatment were compared with those in controls. At diagnosis, growth was retarded and hair zinc values were high, 2.4 +/- 0.7 mumol/g, as in chronic deficiency. During induction therapy, serum declined to 10.4 +/- 2.3 mumol/L and urinary excretion increased to 5.3 +/- 2.8 mumol/mol creatinine, as in acute exacerbation of deficiency. Control CSF values in children in remission, 0.04 +/- 0.01 mumol/L, were lower than reference values in adults. No difference in mean CSF zinc was observed during therapy, or in those with acute lymphoblastic leukemia (1) at high risk, (2) with central nervous system involvement, (3) with low performance, or (4) resistant to therapy. In six children unexplained values, up to 0.28 mumol/L during induction, were measured. No correlations between the various zinc parameters were found.