Morphine bioavailability from a topical gel formulation in volunteers.

Although available therapies provide relief to many patients with cancer-related pain, swallowing difficulties or intestinal obstruction may preclude oral analgesic delivery in some. Topical morphine might provide an alternate delivery form but morphine bioavailability from a topical gel formulation has not been reported in humans. We conducted a randomized, placebo-controlled, double-blind, crossover study of five volunteers after they provided institutionally-approved, written, informed consent. They were admitted to the Northwestern University General Clinical Research Center twice, being randomly assigned to receive either 1mL of morphine compounded at 10mg/mL in pluronic lecithin organogel (PLO) base applied to the wrist and 1mL of normal saline administered subcutaneously, or 1mL of topical drug-free PLO base and 1mL of subcutaneous morphine, 3mg/mL, the first time and the opposite combination the second. Seventeen blood samples were collected from 5minutes to 10hours after dose administration for morphine concentration determination. Plasma samples were prepared by solid-phase extraction and morphine concentrations measured by a mass spectrometric technique with a linear range of 0.5-500ng/mL. Bioavailability of the topical formulation relative to the subcutaneous dose was to be estimated from doses and the plasma morphine concentration versus time relationships. Because morphine was seldom detected in plasma samples after topical administration and was unquantifiable when it was, the low bioavailability of topical morphine was unquantifiable. These results suggest that topical administration of morphine compounded in a PLO base for transdermal drug delivery is unlikely to provide relief of cancer-related pain.

Synthesis and anticancer activities of 6-amino amonafide derivatives.

Amonafide is a DNA intercalator and topoisomerase II inhibitor in clinical development for the treatment of neoplastic diseases. Amonafide contains a free arylamine, which causes it to be metabolized in humans by N-acetyl transferase-2 (NAT2) into a toxic form. To eliminate the NAT2 acetylation of amonafide while retaining the anticancer properties, we have synthesized nine derivatives that are structurally similar to amonafide that should not be acetylated. Eight derivatives have arylamines at the 6-position (vs. 5-position of amonafide) and one derivative completely lacks the arylamine. The derivative with a free amine in the 6-position and one with a substituted amine in the 6-position are not acetylated, whereas amonafide is extensively acetylated as determined by an NAT2 assay. The biological activities of these compounds were evaluated to determine whether they behaved similarly to amonafide in purified systems and in vitro. We found that three compounds had similar cancer cell-selective growth inhibition to amonafide, while retaining similar subcellular localization, DNA intercalation and topoisomerase II inhibition activities. In addition, these compounds were able to eliminate a marker of metastatic potential, the perinucleolar compartment. These three compounds (named numonafides) might thus allow for better patient management than those treated with amonafide; hence, they should be developed further as potential clinical replacements for amonafide or as novel anticancer drugs.

Pharmacokinetics of midazolam, propofol, and fentanyl transfer to human breast milk.

BACKGROUND AND OBJECTIVES: Lactating women undergoing operations requiring general anesthesia are advised to pump and discard their milk for 24 hours after the procedure. Data on anesthetic drug transfer into breast milk are limited. This study determined the pharmacokinetics of midazolam, propofol, and fentanyl transfer into milk to provide caregivers with data regarding the safety of breast milk after administration of these drugs. METHODS: Five lactating women participated in this study after providing institutionally approved written informed consent. Patients underwent premedication with midazolam before induction of anesthesia with propofol and fentanyl. Anesthesia was maintained with a potent volatile anesthetic. Milk and blood were collected before drug administration. Milk was collected 5, 7, 9, 11, and 24 hours after drug administration. Venous blood was collected at intervals up to 7 hours. Plasma and milk midazolam, propofol, and fentanyl concentrations were measured by HPLC with tandem mass spectrometric or fluorescence detection. The pharmacokinetics of drug transfer into milk was modeled with plasma pharmacokinetics. RESULTS: Plasma midazolam, propofol, and fentanyl pharmacokinetics were consistent with reports of others. In 24 hours of milk collection, averages of 0.005% (range, 0.002%-0.013%) of the maternal midazolam dose, 0.027% (0.004%-0.082%) of the propofol dose, and 0.033% (0.006%-0.073%) of the fentanyl dose were collected in milk, representing averages of 0.009%, 0.025%, and 0.039% of the respective elimination clearances. CONCLUSION: The amount of midazolam, propofol, and fentanyl excreted into milk within 24 hours of induction of anesthesia provides insufficient justification for interrupting breast-feeding.

Phase I and pharmacokinetic study of docetaxel, irinotecan, and celecoxib in patients with advanced non-small cell lung cancer.

PURPOSE: We studied the toxicities, potential pharmacokinetic interactions, and preliminary antitumor activity of the combination of docetaxel and irinotecan with celecoxib, a selective cyclooxygenase-2 inhibitor. PATIENTS AND METHODS: Eligible patients had advanced non-small lung cancer (NSCLC) with measurable disease, good performance status, and adequate end organ function. Docetaxel and irinotecan were administered intravenously on days 1 and 8, every 21 days, and their doses were escalated on successive patient cohorts at three dose levels: 30/50, 30/60, and 35/60 (doses in mg/m2). Celecoxib was administered at a starting dose of 400 mg orally twice daily without interruption, beginning on day 2 of cycle 1. Pharmacokinetic studies were performed on day 1 of cycle 1 and day 1 of cycle 2. RESULTS: Seventeen patients with advanced NSCLC were enrolled and collectively received 78 cycles of therapy. Diarrhea was the most common toxicity; it was noted in 13 patients (76%). Dose-limiting toxicities occurred at dose level 1 (myocardial infarction in a patient with multiple coronary artery disease risk factors) and dose level 3 (grade 4 neutropenia with fatal urosepsis). Other major toxicities were: grade 3 neutropenia (2 patients); grade 3/4 diarrhea (3/1); grade 3 nausea (2); grade 2 rash (1); and grade 3 pneumonitis (1). The maximum tolerated dose was at dose level 3, i.e., docetaxel 35 mg/m2 and irinotecan 60 mg/m2 on days 1 and 8, plus celecoxib 400 mg twice daily, repeated every 21 days. Five of 15 evaluable patients achieved an objective response. The pharmacokinetics of docetaxel were not altered by celecoxib. However, we observed an 18% increase in the average elimination clearance of irinotecan coincident with the addition of celecoxib. CONCLUSIONS: The addition of celecoxib to docetaxel and irinotecan was generally well tolerated but unpredictable fatal toxicity occurred. Diarrhea was the most common toxicity. Antitumor activity was promising. The alteration of irinotecan pharmacokinetic parameters observed may not be clinically relevant.