Patricia M. Plezia

Double-blind crossover study of the antiemetic efficacy of high-dose dexamethasone versus high-dose metoclopramide.

Nausea and vomiting remain common and debilitating side effects of therapy with many anticancer drugs. Recent reports have shown that both metoclopramide and dexamethasone are effective drugs for the treatment of severe nausea and vomiting caused by cis-platinum. A double-blind crossover study comparing the antiemetic properties of high-dose oral and intravenous regimens of metoclopramide and dexamethasone in outpatients was carried out. Standardized patient questionnaires and interviews were used to evaluate response. Dexamethasone and metoclopramide protected against more than five episodes of emesis in 48% and 40% of patients, respectively. Nausea persisted for less than six hours in 45% of patients on dexamethasone and in 37% on metoclopramide. The antiemetic efficacy of both regimens was retained through repeated courses of chemotherapy. Side effects were minimal with dexamethasone; however, 33% of patients experienced unacceptable extrapyramidal side effects to metoclopramide. Patient preference was significantly in favor of dexamethasone: 70% of patients chose to continue dexamethasone compared to 22% who preferred metoclopramide and 8% who chose other antiemetics. Dexamethasone was the preferred antiemetic in this patient population due to minimal side effects.

Transdermal Fentanyl: Pharmacokinetics and Preliminary Clinical Evaluation

A new transdermal drug‐delivery system that administers the synthetic opioid fentanyl through intact skin was evaluated for 24 hours postoperatively in eight patients who had undergone orthopedic surgery. Plasma samples were obtained over a 72‐hour period for pharmacokinetic analysis in five patients. The patients were also evaluated intensively for adequacy of analgesia, frequency of nausea and sedation, and occurrence of ventilatory depression. A median lag time of 2.25 hours after application of the transdermal system was observed before the appearance of fentanyl in the blood. Median peak concentration and time to peak were 1.0 ng/ml and 22 hours, respectively. The apparent elimination of fentanyl after transdermal administration is prolonged relative to previously reported values. Absorption analysis indicates zero‐order fentanyl administration, and in addition, suggests deposition of drug in an epidermal site, with the resultant prolonged absorption process giving the appearance of slow elimination. No significant toxicities were observed. Four patients required no additional analgesia. No consistent correlations among fentanyl concentration and any clinical values were observed. Transdermal administration of fentanyl appears to be a viable alternative to conventional routes of narcotic administration and warrants further study.

Phase I clinical and pharmacokinetic evaluation of high-dose mitoxantrone in combination with cytarabine in patients with acute leukemia.

PURPOSE To determine the maximally tolerated dose of mitoxantrone in combination with cytarabine in patients with acute leukemia and advanced phases of chronic myelogenous leukemia (CML), and to assess the pharmacokinetics of high-dose mitoxantrone in this patient population. PATIENTS AND METHODS In a phase I study, 68 patients with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and accelerated- and blastic-phase CML received induction therapy consisting of cytarabine 3 g/m2 by infusion over 3 hours daily for 5 days, with escalating doses of mitoxantrone 40 to 80 mg/m2 over 1 to 2 days by intravenous infusion over 15 minutes. Mitoxantrone pharmacokinetics were evaluated by high-performance liquid chromatography (HPLC) in 15 patients given a single dose of mitoxantrone ranging from 40 to 80 mg/m2 in combination with cytarabine. RESULTS Severe, but reversible hyperbilirubinemia (> three times normal) was considered the dose-limiting toxicity, and was observed in 25% of all patients and in 35% of those who received 70 to 80 mg/m2 of mitoxantrone. Other extramedullary toxicity, including cardiac dysfunction, was mild. Myelosuppression was universal and the median time to complete remission (CR) was 28 days (range, 19 to 77). The CR rate for previously untreated and relapsed patients with AML was 85% (17 of 20) and 38% (seven of 18), respectively. Eighty-three percent (15 of 18) of patients with ALL achieved a CR, including all patients with previously untreated disease. Eight of 12 patients with advanced-phase CML achieved a CR. No significant changes in mean mitoxantrone plasma elimination rates (ie, terminal plasma half-life and total-body clearance rate) occurred as the mitoxantrone dose doubled, indicating linear pharmacokinetics. CONCLUSIONS The recommended phase II dose of mitoxantrone is 80 mg/m2 administered over 15 minutes as a single intravenous infusion in combination with cytarabine 3 g/m2/d for 5 days. At this dose, high concentrations of mitoxantrone are achievable in vivo to levels that have been shown to be extremely cytotoxic in vitro.

Clinical pharmacology of a novel diarylsulfonylurea anticancer agent.

LY186641 (diarylsulfonylurea, [DSU]) is a novel anticancer agent because of its unique diarylsulfonylurea chemical structure, broad-spectrum antisolid-tumor activity in preclinical models, presumed novel mechanism of action and preclinical toxicities of methemoglobinemia (Met Hgb) and decreased red blood cell (RBC) survival. In this study, the in vitro drug sensitivity of human tumors as well as clinical pharmacology and toxicology of DSU in patients with cancer were examined. DSU was administered orally, daily for 7 days with a 3-week treatment cycle. Dose-limiting toxicities were Met Hgb and RBC hemolysis. The maximum-tolerated dose was found to be 1,200 mg/m2/d for 7 days. In pharmacokinetic studies, DSU was found to have a prolonged serum half-life (approximately 30 hours) and a large area under the plasma disappearance curve (8,883.3 micrograms.hr/mL at 1,200 mg/m2/d). A partial remission was observed in one patient with refractory ovarian cancer. In conclusion, DSU can be safely administered to cancer patients and does display antitumor activity. Potential means of obviating the toxicities of this compound are discussed.

Effects of passive smoking on theophylline clearance

Theophylline disposition was examined in seven passive smokers, defined as nonsmokers with long‐term exposure to cigarette smoke, and seven age‐matched nonsmokers with minimal smoke exposure. Subjects were given an intravenous infusion of aminophylline (6 mg/kg) and blood samples were drawn before and during the 48‐hour postinfusion period. Clearance for passive smokers was 6.01 × 10−2 L/hr · kg and for nonsmokers, clearance was 4.09 × 10−2 L/hr · kg (p < 0.025). Terminal elimination half‐life for passive smokers was 6.93 hours versus 8.69 hours for nonsmokers (p < 0.05). The mean residence time for passive smokers was 9.89 hours. For nonsmokers, the mean residence time was 13.11 hours (p < 0.05). These measurements were statistically different, whereas there was no difference in volume of distribution between the groups, suggesting that passive smokers metabolize theophylline more rapidly than nonsmokers. Plasma and urine cotinine and nicotine concentrations were measured in all subjects. There was a significant difference between the subject groups in plasma (p < 0.004) and urine (p < 0.002) cotinine concentrations. Theophylline clearance correlated with both plasma (r = 0.73, p < 0.01) and urine (r = 0.79, p < 0.01) cotinine concentrations. Additional studies should be conducted to further define the pharmacokinetic characteristics of passive smokers and to assess the effects of passive smoking on drugs metabolized by the mixed function oxidase system.

Antiemetic efficacy of two different single intravenous doses of dolasetron in patients receiving high-dose cisplatin-containing chemotherapy

This randomized, double-blind, parallel-group, multicenter study compared the antiemetic effectiveness, safety, and tolerability of two different intravenous (i.v.) doses of dolasetron mesylate (0.6 and 1.8 mg/kg) in cancer patients receiving their first course of high-dose cisplatin-containing chemotherapy (> or = 75 mg/m2). Efficacy was assessed by recording the timing, number, and severity of emetic episodes in the 24 h following high-dose cisplatin. Safety was evaluated by monitoring adverse events, vital signs, clinical laboratory parameters, and electrocardiograms. Of the 62 patients enrolled in the study, 29 received 0.6 mg/kg of dolasetron mesylate and 33 received 1.8 mg/kg. Patients who received dolasetron mesylate 1.8 mg/kg consistently experienced a greater degree of antiemetic control than those who received 0.6 mg/kg. Complete responses were achieved by 55% of patients who received 1.8 mg/kg compared with 31% for the 0.6-mg/kg group. The 1.8-mg/kg group achieved a significantly (p = 0.039) higher complete/ major response rate than the 0.6-mg/kg group (77% vs 55%, respectively) and a significantly (p = 0.004) longer time to the first emetic episode (> 24 h vs 13.5 h, respectively). More than 80% of patients were either satisfied or very satisfied with dolasetron treatment. The most common adverse events were mild to moderate in intensity, consistent with other studies, and included headache (24.1% of patients) and diarrhea (4.8%). These results demonstrated that a single 1.8-mg/kg i.v. dose of dolasetron mesylate provided effective antiemetic activity in a majority of patients given high-dose cisplatin for the first time and should be evaluated further in clinical trials.

Dose-dependent skin ulcers in mice treated with DNA binding antitumor antibiotics

SummaryThe DNA-binding agents daunomycin (DAUNO), mithramycin (MITH), dactinomycin (ACT-D), amsacrine (mAMSA) and esorubicin (ESO) were tested for local vesicant potential in a quantitative intradermal mouse skin model. Only MITH, which adlineates but doses not intercalate DNA, did not produce dose-dependent skin ulcerations in the mouse. The anthracycline antibiotics DAUNO and ESO produced the largest skin ulcers when administered intradermally at clinically relevant doses (adjusted on the basis of comparable body surface areas). Numerous local pharmacologic adjuvants were tested for activity to decrease skin ulceration patterns in mice given one of the DNA intercalators. Inactive local adjuvants included heat, cold, saline, hyaluronidase, glucorticosteroids and isoproternol. Only one adjuvant, topical dimethylsulfoxide (DMSO), was found to reduce DAUNO skin lesions. A single topical DMSO application significantly decreased ulceration size to almost half of control levels. However, it was ineffective for the other intercalating agents. These results show that the DNA intercalators DAUNO, ESO and ACT-D are potent vesicants in a mammalian skin model. These vesicant agents must be administered cautiously to prevent extravasation. No single local adjuvant treatment can be recommended for extravasation of these drugs in the clinic. One significant exception is DAUNO, where topical DMSO may reduce clinical toxicities.

Influence of Enteral Feedings on Phenytoin Sodium Absorption from Capsules

The influence of enteral feedings (with Ensure) on the absorption of phenytoin sodium from capsules was studied. Six healthy adult volunteers were given a single dose of phenytoin capsules 400 mg po on two occasions. Blood specimens were collected for 48 hours after each dose. In a randomized, crossover fashion, each subject completed the following two phases: (1) phenytoin without enteral feedings, and (2) concomitant enteral feedings before phenytoin and continued at 100 ml/h for ten hours. The areas under the concentration versus time curves from 0-48 hours (AUCo-48) were not significantly different between the two phases (p > 0.5). The percent relative bioavailability of phenytoin with enteral feedings was 101.7 percent. This study suggests that enteral feedings do not affect the serum concentrations of phenytoin after a single dose given in capsule form.

An effective five-drug antiemetic combination for prevention of chemotherapy-related nausea and vomiting - Experience in eighty-four patients

SummaryAntiemetics of known efficacy have been shown to block mainly one of three neurotransmitter receptors in the brain. A combination of antiemetics, designed specifically for outpatient use and consisting of metoclopramide, thiethylperazine, diphenhydramine, dexamethasone, and diazepam, is capable of blocking multiple sites in the emesis pathway. Eighty-four patients receiving highly emetic chemotherapy (85% received cisplatin) completed 200 trials of this five-drug combination using two similar regimens. Complete control (i.e., no nausea or vomiting) was achieved in 45% and two or fewer episodes of vomiting was experienced in 72% of these 200 trials. The mean number of vomiting episodes was 1.65, the median 1.0, and the range 0–15. Sedation was nearly universal, although no serious toxicity was encountered. Thus, this antiemetic combination designed for outpatient use proved highly effective in controlling nausea and vomiting associated with highly emetic anticancer treatment.

The Influence of Enteral Feedings on Sustained‐Release Theophylline Absorption

In a randomized, crossover study the influence of enteral feedings (Ensure) on the absorption of theophylline from a sustained‐release preparation (Theo‐24) was evaluated. Six healthy, male subjects, age 22 to 37 years, participated. In phase 1 the subjects received a single oral dose of Theo‐24 6 mg/kg with 100 ml of water at 8:00 a.m. In phase 2, they received 100 ml boluses of Ensure hourly, beginning 3 hours prior to the oral dose and continuing for a total of 1000 ml. In phase 3, subjects received a single 30‐minute intravenous infusion of an equivalent dose of aminophylline. After each dose, serial blood samples were collected for 72 hours. No statistically significant differences in area under the curve (AUC∞0) (126.0 vs 127.3 μg hr/ml), maximum concentration (3.80 vs 4.08 μg/ml), or time to peak plasma level (13 vs 11 hrs) were found between phases 1 and 2. Mean AUC∞0 for the intravenous phase (161.4 μg hr/ml) was significantly higher than the AUC for either oral study (p < 0.05). The mean bioavailability was 81 % for phase 1 and 80% for phase 2. Percent absorbed versus time plots revealed no difference in rate of absorption between treatments. We conclude that short‐term administration of the enteral feeding Ensure does not influence the absorption of theophylline when administered as the sustained‐release product Theo‐24.