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Biomedical subjects

L H Baker

Publications and source records attributed to L H Baker.

At least 55 records · Page 3Linked to original sources
PubMed1990

Phase II trial of intravenous melphalan for metastatic colorectal carcinoma. A Southwest Oncology Group study.

Based on the high response rates seen among patients with colon cancer receiving high dose Melphalan with autologous marrow infusion, the Southwest Oncology Group conducted a Phase II trial of the compound at a conventional dose. The initial starting dose of 40 mg/m2 was reduced to 30 mg/m2 after severe myelotoxicity was encountered in the first five patients. Toxicity was primarily myeloid and was moderate to severe in most patients with one treatment related death. There were two complete and one partial response among 43 patients. Melphalan at 30 mg/m2 has little activity among patients with metastatic colorectal carcinoma.

Adult↗
PubMed1990

Alteration of dacarbazine pharmacokinetics after interleukin-2 administration in melanoma patients.

In an effort to improve the treatment of metastatic malignant melanoma, we evaluated the sequential administration of the chemotherapeutic agent dacarbazine (DTIC) and the biological response modifier interleukin-2 (rIL-2) in a phase I-II study. Since the combination of biological response modifiers and chemotherapeutic agents could alter drug disposition, we evaluated the pharmacokinetics of DTIC and its major metabolite, 5-amino-imidazole 4-carboxamide (AIC), before and after rIL-2 administration. DTIC (1 g/m2, 24-h i.v. infusion) was given on day 1 and rIL-2 (2-4 million Cetus units/m2, 30-min i.v. injection), on days 15-19 and 22-26 of each course of therapy. The second DTIC dose was given on day 29, i.e., 3 days after the last rIL-2 administration. DTIC and AIC were assayed by reversed-phase HPLC. DTIC plasma levels showed a significant decrease after rIL-2 administration as compared with DTIC values obtained in the same patients before rIL-2 administration. DTIC area under the curve (AUC) values obtained after rIL-2 were lower than those obtained on day 1 before rIL-2 administration (P = 0.02). After rIL-2, the total body clearance (ClT) was increased (P = 0.04), as was the volume of distribution at steady state (Vss; P = 0.02). The decrease in AUC after rIL-2 administration became more pronounced as the rIL-2 dose was increased (P = 0.03). No significant difference was detected in the elimination phase of DTIC when half-lives obtained before and after rIL-2 administration were compared; the mean half-lives were 0.7 and 2.8 h for the alpha- and beta-phases, respectively. The model-independent mean residence time was 3.4 h. The plasma AUC for the metabolite AIC did not charge after rIL-2 administration. AIC biphasic plasma elimination was also similar after rIL-2 administration, with alpha- and beta-half-lives of 0.7 and 11.4 h, respectively. Urinary excretion of DTIC and AIC did not differ after rIL-2 administration; the overall DTIC excretion was 39% of the dose over 48 h, and AIC urinary excretion was 25% of the DTIC dose. The observed decrease in the DTIC plasma AUC after rIL-2 administration appears to be due to an increase in the volume of distribution, since other factors such as half-lives, urinary excretion, and metabolism were not significantly altered. The clinical consequences of the rIL-2-DTIC interaction remain difficult to assess based on presently available data, but this drug interaction should be taken into consideration in the development of future chemo-immunotherapy regimens that include high-dose rIL-2.

Chromatography, High Pressure Liquid↗
PubMed1990

Concurrent chemotherapy/radiotherapy for limited small-cell lung carcinoma: a Southwest Oncology Group Study.

The Southwest Oncology Group (SWOG) has conducted a phase II study to explore the efficacy and toxicity of initial, concurrent use of radiation therapy with cisplatin, etoposide (VP-16), and vincristine in limited-stage small-cell carcinoma of the lung. Two courses of cisplatin, VP-16, and vincristine chemotherapy were given with concurrent radiotherapy (XRT) to the primary tumor to a total dose of 4,500 cGy. Elective brain XRT was given to all patients concurrent with a third course of cisplatin/VP-16 therapy. Consolidation chemotherapy consisting of vincristine, methotrexate, and VP-16 alternating with Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) and cyclophosphamide, was given for 12 weeks following the initial induction chemotherapy/XRT program. Patients with a complete response had all therapy discontinued. Among 154 eligible patients treated, the complete response rate was 56%, with a partial response rate of 27%. The median survival is 17.5 months with an estimated 30% survival rate at 4 years from initiation of treatment. Combined modality toxicities were acceptable with the predominant toxicity being moderate to severe leukopenia and mild radiation esophagitis. The results of this treatment program appear superior to any previously reported by our group and compare favorably to those in the literature at large.

Adult↗
PubMed1989

Pharmacokinetics and toxicity of continuous infusion amphotericin B in cancer patients.

To evaluate the role of amphotericin B (AmB) in the biochemical modulation of antineoplastic agents, AmB was administered as a continuous infusion over a period of 52 to 120 h to 14 patients (26 courses) with advanced carcinomas. Continuous infusion amphotericin B (CI-AmB) was delivered at a rate of 0.5 to 0.8 mg/kg/d (19-31 mg/m2/d). The AmB plateau levels assayed by HPLC ranged from 0.7 to 1.9 micrograms/mL and were directly related to the infusion rate. The AmB plasma disposition was biphasic, with mean half-lives of 17 h for the first phase and 11 d for the terminal phase, and a mean residence time of 12 d. Biochemical modulation of antineoplastic agents (lomustine, doxorubicin, cyclophosphamide) by CI-AmB was not demonstrated clinically. Acute toxicities of fever and chills were noted in only 3 of the 26 courses. Reversible renal toxicity was observed in 23 courses. Therapeutic antifungal plasma levels were rapidly reached and maintained for the duration of infusion, with a reduction of acute toxicities associated with shorter infusions. These observations provide impetus for further clinical investigation of CI-AmB.

Adolescent↗
PubMed1989

Pharmacodynamics and causes of dose-dependent pharmacokinetics of flavone-8-acetic acid (LM-975; NSC-347512) in mice.

Flavone acetic acid (FAA) is a novel antitumor agent with broad solid-tumor activity. However, this drug has shown a steep dose-response curve in preclinical trials, with a narrow sublethal window of efficacy. To investigate this threshold behavior, we studied various aspects of FAA pharmacology in mice after i.v. administration. Mice bearing advanced-stage s.c. colon 38 adenocarcinoma were treated at four dose levels (39, 65, 108 and 180 mg/kg), and only the highest dose produced significant antitumor activity, showing a steep dose-response curve. Using an HPLC assay, FAA pharmacokinetics in both plasma and tumors were found to be dose-dependent. As the dose increased, there was a decrease in both total body clearance and volume of distribution at steady state. The increase in tumor area under the curve (AUC) was more pronounced than the corresponding increase in plasma AUC, showing a better tumor exposure to FAA at high doses. The distribution of FAA in normal tissues showed a short-term retention in the liver and kidneys; low concentrations were observed in the heart, spleen, and brain, with some retention in the latter. The highest FAA concentrations were found in the gastrointestinal (GI) tract, mainly in the duodenum, suggesting an important biliary excretion of the drug. Various possible causes of FAA nonlinear pharmacokinetics were investigated. Serum protein binding was high (79%) and remained constant up to 100 micrograms/ml, but decreased thereafter at higher FAA concentrations, e.g., 76% at 500 micrograms/ml and 64% at 1,000 micrograms/ml. Urinary and biliary clearances were dose-dependent and decreased 5- and 9-fold, from the 39- to the 180-mg/kg dose levels, respectively. A direct assessment of FAA enterohepatic circulation using intercannulated mice showed that 27% of the plasma AUC was accounted for by enterohepatic circulation. FAA acyl glucuronide was identified as the major metabolite in mice and was found to contribute to the nonlinear pharmacokinetics due to its facile hydrolysis under physiological conditions, regenerating FAA. In conclusion, the steep FAA dose-response curve was found to be caused by dose-dependent pharmacokinetics in mice. The nonlinear pharmacokinetics of this drug was attributed to a dose-dependent decrease in both urinary and biliary clearances, concentration-dependent serum protein binding, enterohepatic circulation, and the instability of FAA acyl glucuronide under physiological conditions forming a futile cycle.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗
PubMed1989

Randomized phase III trial of chemoimmunotherapy in patients with previously untreated stages III and IV suboptimal disease ovarian cancer: a Southwest Oncology Group Study.

Between 1979 and 1984, 185 fully evaluable patients with stage III or IV epithelial type ovarian cancer and suboptimal surgical resections were randomly assigned to treatment with doxorubicin + cyclophosphamide + BCG (DC + BCG) vs doxorubicin + cyclophosphamide + cisplatin (DCP) vs. doxorubicin + cyclophosphamide + cisplatin + BCG (DCP + BCG). Patients with measurable disease (119) were analyzed separately from those with nonmeasurable disease (66). In measurable disease patients the overall clinical complete plus partial response rates for DC + BCG, DCP, and DCP + BCG-treated patients were 36, 57, and 59%, respectively. Although there were no significant patient characteristic differences between the DCP and DCP + BCG treatment groups, the addition of cisplatin to the DC + BCG regimen resulted in significantly prolonged response (P less than 0.03) and survival (P less than 0.002) durations. To the contrary, the addition of BCG to the DCP regimen did not improve objective response rates or response or survival durations. For patients with nonmeasurable, suboptimal disease there were no significant differences between the three treatments with respect to response or survival parameters; however, patients in this disease category fared generally better than those with clinically measurable disease. We conclude that cisplatin adds significantly to the efficacy of DC + BCG, but BCG does not add to the efficacy of DCP in patients with measurable, stage III or IV disease.

Aged↗
PubMed1989

Randomized phase III trial of chemoimmunotherapy in patients with previously untreated stage III, optimal disease ovarian cancer: a Southwest Oncology Group Study.

Between 1979 and 1984, 98 patients considered to have stage III epithelial type ovarian cancer and optimal surgical resections (i.e., less than 2 cm residual tumor masses) were randomly assigned to treatment with 2 cm residual tumor masses) were randomly assigned to treatment with doxorubicin + cyclophosphamide + BCG (DC + BCG) vs doxorubicin + cyclophosphamide + cisplatin (DCP) vs. doxorubicin + cyclophosphamide + cisplatin + BCG (DCP + BCG). Seventeen (17%) were considered ineligible on the basis of formal histopathologic review. The pathologically proven complete response rates for DC + BCG, DCP, and DCP + BCG-treated patients were 20, 23, and 41%, respectively, and the median survival durations were 36.8, 48.2, and 57.4 months, respectively. Because of the relatively small sample size, definite conclusions concerning the response or survival impact of adding cisplatin to DC + BCG or BCG to DCP can not be drawn; nevertheless, all three groups of patients experienced prolonged survival durations with approximately 40% of all eligible patients alive at 5 years.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Acodazole hydrochloride: phase I trial, pharmacokinetics, and evaluation of cardiotoxicity in dogs.

Acodazole (NSC 305884) was examined in a Phase I trial evaluating a 1-h infusion repeated every 21 days in 37 patients with advanced carcinomas. Cardiac toxicity was dose-limiting at 1370 mg/m2, manifested as multiple premature ventricular contractions, QTc interval prolongation, and decreasing heart rate. Other toxicities included mild to moderate nausea and vomiting and local reaction near the i.v. injection site requiring the use of central venous catheters. Antineoplastic activity was not observed. Acodazole levels assayed by high-performance liquid chromatography disclosed a peak plasma level of 19 +/- 4 (SEM) micrograms/ml for 1370 mg/m2. Acodazole plasma levels decreased in a triphasic manner over a 100-fold range. The volume of distribution at steady state was 238 +/- 18 liter/m2 suggesting extensive tissue binding. The total body clearance was 13.6 +/- 0.9 liter/h/m2; the percentage of urinary excretion was 29 +/- 2% for 48 h. To evaluate cardiac toxicity, acodazole was administered to five dogs at 2262 mg/m2 (1-h infusion) which provided plasma concentrations similar to those achieved at 1370 mg/m2 in humans. Consistent findings in dogs were drug-related prolongation of QTc intervals, and reduction in heart rate, left ventricular dP/dt, and mean blood pressures. Clinical development of acodazole requires studies to further elucidate and alleviate this cardiac toxicity.

Aminoquinolines↗
PubMed1988

Ifosfamide.

The alkylating agent ifosfamide, an analog of cyclophosphamide, has demonstrated significant activity in soft tissue sarcoma and testicular carcinoma. Understanding and control of the urinary toxicity of ifosfamide therapy has allowed greater use and inclusion of ifosfamide in combinations in the treatment of malignant diseases. While preliminary results with ifosfamide in a number of diseases are encouraging, final determination of its efficacy awaits further study. A comprehensive review of preclinical data and clinical trials with ifosfamide is presented.

Breast Neoplasms↗
PubMed1988

PCNU: phase II evaluation in advanced colorectal carcinoma.

PCNU, a N-(2-chloroethyl)-N-nitrosourea, was administered to 37 previously treated patients with metastatic adenocarcinoma of the colon and rectum. The drug dose was 100 mg/m2, intravenously, over one hour for good risk patients and 75 mg/m2 for poor risk patients. Poor risk patients were defined as patients over 65 years of age or having liver enzymes greater than twice normal. The infusion was repeated at 6 week intervals. Seventeen patients (median performance status 80%) received PCNU at the 100 mg/m2 dose; 20 patients (median performance status 70%) received PCNU at the 75 mg/m2 dose. Complete responses were not observed. One patient treated with 100 mg/m2 achieved a partial response. Toxicity was primarily hematological with life-threatening leukopenia and thrombocytopenia observed in six patients. PCNU administered in the described dose schedule demonstrated little therapeutic efficacy in this patient population.

Adenocarcinoma↗
PubMed1987

Phase I trial of spiromustine (NSC 172112) and evaluation of toxicity and schedule in a murine model.

Phase I evaluation of spiromustine was performed using an every-3-week schedule and a weekly X 3 schedule. Neurotoxicity was the dose-limiting toxicity presenting as alterations in cortical integrative functions (orientation, language, coordination), leading to a decrease in the level of consciousness. Traditional criteria for grading neurotoxicity poorly characterized these toxicities. The maximum tolerated dose was 6 mg/m2 every 3 weeks and 3 mg/m2 weekly X 3. Concurrent murine studies confirmed spiromustine as a schedule independent drug with toxicity correlating with peak plasma levels. Physostigmine had little effect on decreasing neurotoxicity in the murine model. The solvating agent used was not responsible for the neurotoxicity. Injection of spiromustine on a split-dose schedule decreased the acute neurological toxicity in mice and allowed a larger total dosage to be delivered (compared to single bolus dosage). Based on these results a split-dose schedule is suggested for future clinical trials.

Animals↗
PubMed1987

Phase I study and pharmacokinetics of caracemide (NSC-253272) administered as a short infusion.

A Phase I study of caracemide evaluating a short intravenous infusion repeated every 21 days is presented. Patients were entered at 85 mg/m2 with subsequent escalation levels of 170, 425, 595, and 795 mg/m2. Mild to moderate nausea and vomiting occurred at all dose levels. An apparent allergic reaction was observed at the 425 mg/m2 level. A "burning pain" originating in the mucosal areas of the head and neck, progressing to the chest and abdomen, was noted at the 425 mg/m2 level. Because of this observation, the infusion time was extended to 4 h. At the 795 mg/m2, this toxicity precluded completion of the 4 h infusion. Pharmacokinetic evaluation disclosed blood levels of 0.74-2.31 microgram/ml at the 425 mg/m2 during the 0.5 h infusion. At the same dose for a 4 h infusion time, blood levels were 0.15-0.18 microgram/ml. At 595 mg/m2 administered as a 4 h infusion, blood levels increased to 0.33 +/- 0.14 microgram/ml. The drug was cleared rapidly from the blood compartment with a half-life of 2.5 min and a total body clearance of 11.51/min/m2. No partial or complete response was observed. However, an advanced colon carcinoma patient experienced subjective pain relief with a decrease in carcinoembryonic antigen. The dose-limiting toxicity of caracemide using the 4 h infusion was an intolerable "burning pain" with a maximum tolerated dose of 795 mg/m2. Further characterization of this dose-limiting toxicity is required prior to further clinical evaluation of caracemide.

Antineoplastic Agents↗
PubMed1987

Aclacinomycin A. Phase II evaluation in bronchogenic squamous-cell carcinoma.

Aclacinomycin A (ACLA-A) was administered to 22 patients with metastatic measurable bronchogenic squamous-cell carcinoma in a Phase II trial of the drug. Sixteen patients were fully assessable for response and toxicity. The initial dose of ACLA-A was 85 mg/m2 weekly for 4 consecutive weeks; however, due to severe myelosuppression, the weekly dose was reduced to 65 mg/m2. Fifteen patients were previously untreated. Toxicity was primarily hematological. Complete or partial responses were not observed on this treatment schedule. ACLA-A administered on this schedule lacks therapeutic efficacy in the treatment of patients with advanced bronchogenic squamous-cell carcinoma.

Aclarubicin↗
PubMed1987

Aclacinomycin A. Phase II evaluation in advanced soft tissue sarcoma.

Aclacinomycin A (ACLA-A), an anthracycline antibiotic, was administered in a Phase II study to 20 patients with advanced, measurable soft tissue sarcomas. The dose schedule consisted of 85 mg/m2 intravenous ACLA-A given weekly for 4 weeks followed by a 2-week rest. Because of severe myelosuppression in the initial patients, the weekly dose was reduced to 65 mg/m2. Seventeen patients were fully evaluable for toxicity and response to the drug. Complete or partial responses were not identified. Toxicity was primarily hematological. ACLA-A administered in the above schedule demonstrated no therapeutic efficacy in patients with advanced soft tissue sarcomas.

Aclarubicin↗
PubMed1987

Fludarabine phosphate. Phase II evaluation in advanced soft-tissue sarcomas.

Fludarabine phosphate (NSC-312878) was administered to 23 patients with advanced soft-tissue sarcomas. Patients entered on the study had a median performance status of 80 and had prior chemotherapy restricted to one previous regimen. Dose schedule was 100 mg/m2 in poor-risk patients (creatinine clearance less than 70 cc/min) and 125 mg/m2 in good-risk patients every 3 weeks. No complete or partial responses were noted in the 20 evaluable patients. Median survival was 12 weeks. Leukopenia was the most common toxicity. Fludarabine phosphate in the above schedule failed to demonstrate therapeutic efficacy in this patient population.

Antimetabolites, Antineoplastic↗