Superheated water as eluent in high-temperature high-performance liquid chromatographic separations of steroids on a polymer-coated zirconia column.

High-temperature liquid chromatography (HTLC), with a superheated water mobile phase, has been shown to be a feasible replacement for medium-polarity acetonitrile-water mixtures as an eluent in reversed-phase HPLC. Instrumental parameters of flow-rate, injection volume and mobile phase preheating were shown to have significant effects on the quality of the chromatographic peaks. The selectivity and retention patterns of testosterone and several related compounds were investigated on a porous zirconia, polybutadiene-coated column at temperatures up to 200 degrees C and compared with that of a porous silica, octadecylsilane-coated column and the zirconia column under traditional reversed-phase conditions of an acetonitrile-water mobile phase at 40 degrees C. The selectivity differences observed for testosterone and related compounds show that the separation mechanisms are complementary and unique selectivity is obtained with the zirconia column under HTLC conditions.

Prehospital stability of diazepam and lorazepam.

Injectable benzodiazepines are commonly stocked on ambulances for use by paramedics. We evaluated the stability of lorazepam and diazepam as a function of storage temperature. Diazepam (5 mg/mL) and lorazepam (2 mg/mL) injectable solutions were stored for up to 210 days in clear glass syringes at three conditions: 4 degrees C to 10 degrees C (refrigerated); 15 degrees C to 30 degrees C (on-ambulance ambient temperature); and 37 degrees C (oven-heated). High-performance liquid chromatography (HPLC) analyses of syringe contents were performed at 30-day intervals. After 210 days, the reduction in diazepam concentration was 7% refrigerated, 15% at ambient temperature, and 25% at 37 degrees C. The reduction in lorazepam concentration was 0% refrigerated, 10% at ambient temperature, and 75% at 37 degrees C. Whereas diazepam retained 90% of its original concentration for 30 days of on-ambulance storage, lorazepam retained 90% of its original concentration for 150 days. The decrease in lorazepam concentration correlated with an increase in the maximum ambient temperature in San Francisco. These results suggest that diazepam and lorazepam can be stored on ambulances. When ambient storage temperatures are 30 degrees C or less, ambulances carrying lorazepam and diazepam should be restocked every 30 to 60 days. When drug storage temperatures exceed 30 degrees C, more frequent stocking or refrigeration is required.

A phase I and pharmacokinetic trial of terephthalamidine (NSC 57155) as a 120-hour continuous infusion.

In this phase I study, terephthalamidine was administered as a 120-hour continuous infusion repeated every 21 days. Thirteen patients received 27 courses of terephthalamidine at four dose levels ( 14, 28, 46, and 70 mg/m2/day). Dose-limiting toxicity consisted of profound and intractable anorexia, weight loss and prostration in all patients. Toxicity was delayed and accompanied by hyponatremia and hypokalemia. No hematologic or other toxicity was documented. One patient with adenocarcinoma of the lung had a 40% decrease in mediastinal lymph nodes and resolution of a pleural effusion lasting 2 months. Pharmacokinetic analysis by HPLC was performed in all patients during their first course. The harmonic mean terminal half-life for terephthalamidine was 23 hours with a plasma clearance of 1.7 1/hr/m2. Both plasma concentrations achieved during infusion (r2 = 0.9) and area under the curve (AUC) (r2 = 0.8) were proportional to increase in dose (p < 0.002). Renal excretion accounted for 64% of the total cumulative dose, with an average renal clearance of 1.16 1/hr/m2. Due to the unacceptable toxicity seen at all doses with this schedule, no further studies are recommended unless the mechanism of toxicity is better understood and can be prevented.

Phase I study with the DNA sequence-specific agent adozelesin.

Adozelesin, a synthetic analog of the antitumor antibiotic CC-1065, is a novel cytotoxic agent which inhibits DNA synthesis by binding to the minor groove of the DNA helix. Preclinical studies have shown a broad spectrum of activity against a variety of murine and human tumor xenograft models. We conducted a phase I study of adozelesin to (i) determine a recommended dose for phase II testing using a 10 min i.v. infusion, (ii) characterize the toxic effects of the drug using this schedule and (iii) document any antitumor activity observed. Adozelesin was administered as an i.v. infusion every 6 weeks. CBC and biological parameters were performed weekly. The starting dose of 10 microg/m2, corresponding to 1/30 the mouse equivalent lethal dose, was escalated, according to a modified Fibonacci scheme, until dose-limiting toxicity was encountered. Forty-seven adult patients with solid malignancies were entered in the study. Successive dose levels used were 10, 20, 33, 50, 70, 105, 120, 150 and 180 microg/m2. The main toxic effect was myelosuppression, which was dose limiting. The maximally tolerated dose was defined as 180 microg/m2. A minor response with a 4 month duration was reported in one previously treated patient with melanoma. We conclude that the recommended phase II dose of adozelesin given as a 10 min infusion is 150 microg/m2, repeated every 4 weeks.

Silica xerogel as a continuous column support for high-performance liquid chromatography.

A preliminary study of the chromatographic performance and permeability of a continuous silica xerogel column under reversed-phase HPLC conditions was performed. A porous chromatographic support was synthesized inside a 0.32 mm i.d. × 13 cm fused silica tube from potassium silicate solution and derivatized with dimethyloctadecylchlorosilane. The plate height at 0.01 cm/s (0.5 µL/min), near the apparent optimum linear velocity, was about 65 µm. The column efficiencies in terms of numbers of plates per meter were 5000 and 13 000 for ethyl benzoate (k = 0.8) and naphthalene (k = 2.0), respectively, at 0.5 µL/min. The major parameter affecting column efficiency was the heterogeneous morphology of the xerogel, modifications to which are expected to improve chromatographic performance. The column provided efficiencies comparable to those reported for continuous polymeric columns but less than that previously reported for a continuous silica column. Gradient elution mode was demonstrated with a mixture of polycyclic aromatic hydrocarbons. The column was highly permeable, exhibiting a linear dependence of pressure to flow rate and a back pressure of only 632 psi at 10 µL/min when a 95% aqueous mobile phase was used.

Initial phase I evaluation of the novel thymidylate synthase inhibitor, LY231514, using the modified continual reassessment method for dose escalation.

PURPOSE: To determine the toxicities, maximal-tolerated dose (MTD), pharmacokinetic profile, and potential antitumor activity of LY231514, a novel thymidylate synthase (TS) inhibitor. PATIENTS AND METHODS: Patients with advanced solid tumors were administered LY231514 intravenously over 10 minutes, weekly for 4 weeks, every 42 days. Dose escalation was based on the modified continual reassessment method (MCRM), with one patient treated at each minimally toxic dose level. Pharmacokinetic studies were performed in all patients. RESULTS: Twenty-five patients were administered 58 courses of LY231514 at doses that ranged from 10 to 40 mg/m2/wk. Reversible neutropenia was the dose-limiting toxicity. Inability to maintain the weekly treatment schedule due to neutropenia limited dose escalation on this schedule. Nonhematologic toxicities observed included mild fatigue, anorexia, and nausea. At the 40-mg/m2/wk dose level, the mean harmonic half-life, maximum plasma concentration, clearance, and apparent volume of distribution at steady-state were 2.02 hours, 11.20 micrograms/mL, 52.3 mL/min/m2, and 6.64 L/m2, respectively. No major antitumor responses were observed; however, minor responses were achieved in two patients with advanced colorectal cancer. CONCLUSION: The dose-limiting toxicity, MTD, and recommended phase II dose of LY231514 when administered weekly for 4 weeks every 42 days are neutropenia, 40 mg/m2, and 30 mg/m2, respectively.

A phase II trial of DaunoXome, liposome-encapsulated daunorubicin, in patients with metastatic adenocarcinoma of the colon.

CONTEXT: Liposomal encapsulation of drugs can potentially ameliorate toxicities and improve acute and chronic tolerance. The increased uptake of liposomes by colon adenocarcinoma cell lines may enable DaunoXome to circumvent the p-glycoprotein-mediated anthracycline resistance of colon cancer cells. PURPOSE: To determine if DaunoXome, liposome-encapsulated daunorubicin, has clinical activity in patients with adenocarcinoma of the colon who failed treatment with a 5-fluorouracil containing regimen. METHOD: In a Phase II trial, patients with metastatic adenocarcinoma of the colon, whose disease has progressed after receiving one 5-fluorouracil-containing regimen, were treated with DaunoXome 100 mg/m2 repeated every 3 weeks. RESULTS: In this trial 16 patients received 45 courses of therapy. No objective tumor responses were seen. Hematologic toxicities consisted of neutropenia (grade 3 and 4), grade 2 anemia, and grade 2 thrombocytopenia. Nonhematologic toxicities were mild and manageable. Of the 16 patients, 5 experienced flushing, shortness of breath, chest tightness, and back pain during DaunoXome infusion, which resolved with infusion interruption, diphenhydramine, and meperidine. CONCLUSIONS: DaunoXome is generally well tolerated at a dose of 100 mg/m2 every 3 weeks. Toxicities are mild and reversible. On this schedule DaunoXome does not have significant clinical activity in patients with metastatic adenocarcinoma of the colon who have progressed after one 5-fluorouracil-containing regimen.

Topoisomerase I inhibitors. An overview of the camptothecin analogs.

The topoisomerase I inhibitors are an exciting new class of antineoplastic agents currently under clinical development. Analogues of camptothecin with improved toxicity profiles and antitumor activity included CPT-11 and topotecan. CPT-11 has demonstrated activity against a variety of tumor types, particularly colon and lung cancer. Early results with topotecan against ovarian and lung cancer are also encouraging. Combination trials with other antineoplastic agents including cisplatin and etoposide, and early clinical trials with new topoisomerase I inhibitors, such as 9-aminocamptothecin, are underway.

Preclinical and phase I trials of topoisomerase I inhibitors.

A total of three topoisomerase I inhibitors, including topotecan, CPT-11 (irinotecan), and intoplicine, have been studied in both preclinical and clinical/clinical pharmacology studies. In in vitro testing against human tumor colony-forming units, all three compounds were significantly more effective when tested as a continuous exposure as compared with a 1-h exposure. The dose-limiting toxicities were different for all three of the agents, with neutropenia and thrombocytopenia being dose-limiting for topotecan; diarrhea, for CPT-11; and hepatotoxicity, for intoplicine. In these phase I studies a number of marginal responses were noted with topotecan; partial and marginal responses, with CPT-11 (particularly in patients with colon cancer); and no response, with intoplicine. The detailed pharmacology of all three agents documented a very short half-life for topotecan, an intermediate half-life for CPT-11, and a prolonged half-life for intoplicine. Based on our experience to date, these compounds (particularly CPT-11) have promise as useful additions to our tremendous therapeutic armamentarium.

A randomized phase I trial of chronic oral etoposide with or without granulocyte-macrophage colony-stimulating factor in patients with advanced malignancies.

Data from an in vitro human tumor-cloning assay suggested synergistic cytotoxicity when etoposide (VP16) and granulocyte-macrophage colony-stimulating factor (GM-CSF) were combined. To explore this potential, we undertook a prospectively randomized three-arm trial in a phase I setting with various schedules of VP16 and GM-CSF. Thirty-one patients were enrolled in the three-arm trial. Arm A consisted of oral VP16 daily for up to 21 days with cycles repeated every 35 days. Arm B included oral VP16 daily for up to 21 days plus concomitant GM-CSF at 5 micrograms/kg/day s.c. days 1-10. Arm C included oral VP16 daily for up to 21 days plus pretreatment with GM-CSF at the same dose for 5 days (days -6 to -2). VP16 was begun at 25 mg/m2/day on level 1 and increased to 50 mg/m2/day on level 2. Twenty-seven patients were evaluable for toxicity, nine on each arm (six patients on each arm on level 1, three patients on each arm on level 2). Neutropenia on arm B (concomitant VP16 and GM-CSF) was earlier and more profound than on arm A or C. The median absolute neutrophil count and day of nadir for arms A, B, and C were 3295, 988, and 1600/mm3 and days 23, 15, and 26, respectively. Thrombocytopenia was generally uncommon except on arm C level 2, where the median platelet count was 26,000/mm3. One partial response (arm B) in a patient with non-small cell lung cancer was seen. Dose intensity favored arm A. Neither concomitant therapy with VP16 and GM-CSF (arm B) nor pretreatment with GM-CSF (arm C) improved dose intensity over VP16 alone (arm A), and arms B and C were complicated by increased neutropenia and thrombocytopenia.

Idarubicin: a second-generation anthracycline.

Because of its in vitro activity in leukemic cell lines and Phase I studies of acute leukemia, Phase II and III clinical trials with idarubicin hydrochloride were conducted in patients with acute lymphocytic leukemia or acute nonlymphocytic leukemia. In the Phase III comparative trials between the combinations of idarubicin and cytarabine and daunorubicin hydrochloride and cytarabine, the idarubicin/cytarabine combination resulted in significantly greater complete remission rates and longer overall survival in two of three studies conducted in the US. As a result, the Food and Drug Administration approved intravenous idarubicin with a Class 1A rating in September 1990 for use in combination with other antileukemic drugs (e.g., cytarabine) for the treatment of acute myelogenous leukemia in adults. The recommended dose of idarubicin is 12 mg/m2 daily for three days by slow intravenous injection in combination with cytarabine. Although idarubicin causes myelosuppression similar to that described with daunorubicin, the incidence of cardiotoxicity in animal models is lower. Idarubicin also has the advantage of oral administration, but the oral formulation of the drug remains investigational. The use of idarubicin in pediatric patients also remains to be established.

Capillary isotachophoresis with UV and tandem mass spectrometric detection for peptides and proteins.

The application of capillary isotachophoresis (CITP) and combined CITP-mass spectrometry (MS) for peptides and proteins is demonstrated. Separation of simple peptide mixtures, as well as enzymatic digets of proteins, is also reported using CITP with UV detection. The potential utility of CITP for proteins is demonstrated. Initial studies of combined CITP-MS of enzymatic digests is also demonstrated, showing the potential for rapid sequence determination.

Narcotic analgesics. Clinical pharmacology and therapeutics.

Nurses often are responsible for administering narcotic analgesics to patients with pain due to cancer or the treatment of cancer. Because of frequent use of these agents, and their various and dramatic effects throughout the body, it is important to understand their pharmacological properties and appropriate therapeutic use. This article reviews the actions and side effects, appropriate selection and use of narcotic analgesics and provides guidelines for administration.

Incidence and duration of chemotherapy-induced nausea and vomiting in the outpatient oncology population.

Nausea and vomiting are commonly recognized side effects of chemotherapy. However, the incidence and duration of these effects have not been systematically studied in a large outpatient oncology population. This survey was conducted over two consecutive 6-week periods in the adult oncology clinics of two university teaching hospitals. The objectives were: (1) to document the incidence and duration of chemotherapy-induced nausea and vomiting; (2) to identify variables that influence nausea and vomiting; and (3) to describe patterns of antiemetic prescribing and compliance. One hundred thirty-eight completed patient-maintained diaries were returned (70% response rate). Anticipatory nausea and vomiting were reported by 9.4% and 6.5% of patients, respectively. Fifty percent and 27% of patients reported nausea and vomiting, respectively, on the day chemotherapy was administered (day 1: acute nausea and vomiting phase). Percentages fell to 22% and 11% by day three and 14% and 2.5% on day 5. Of patients who reported nausea and vomiting during the five-day period, 52% and 33% experienced nausea and vomiting, respectively, during the delayed period only (days 2 through 5: delayed emesis phase). Emetogenicity of chemotherapy significantly influenced incidence and duration of those symptoms. Sixty-seven percent of patients reported taking antiemetics on one or more days during the survey period. Of patients who reported antiemetic use, 92% reported antiemetics on day 1, 51% on day 3, and 31% on day 5. At-home antiemetic use was related to the emetogenicity of chemotherapy received. Patients who receive moderate to strong emetogens as defined in this report should receive antiemetic therapy for a minimum of three days. Increasing the dose of antiemetic prescribed both in the clinic and at home may be of benefit.

Thrombotic microangiopathy associated with chemotherapy: case report and review of the literature.

Thrombotic microangiopathy (TMA) is a serious toxicity associated with a small number of antineoplastic agents. A case report of a patient with probable cisplatin and bleomycin-induced TMA is presented. The basic triad of symptoms that occurs in the TMA syndrome include microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Cardiovascular, pulmonary, and neurologic complications also occur frequently. The pathogenesis of chemotherapy-associated thrombotic microangiopathy (C-TMA) has not been established. Proposed mechanisms include von Willebrand Factor abnormalities, decreased prostacyclin production, and immune complex formation. Treatment modalities have been unsuccessful and the majority of patients reported have died. Immunoperfusion with staphylococcal protein A is the most effective treatment available and this new technique appears promising. This article reviews the results of all cases of C-TMA reported to date in the English literature and discusses the theories of pathogenesis, clinical features, treatment, and treatment-related complications of the syndrome.