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Biomedical subjects

R H Earhart

Publications and source records attributed to R H Earhart.

11 recordsLinked to original sources
PubMed1992

Phase 1 trial of oral bropirimine in superficial bladder cancer.

A total of 34 patients with measurable superficial transitional cell cancer of the bladder entered into a phase 1, nonrandomized, noncomparative trial to assess the toxicity of the oral interferon inducer bropirimine. Of the patients 26 were also evaluable for response. The toxicity of bropirimine was minimal. At the 3-month evaluation 6 patients had experienced complete regression of tumor and had negative cytology studies, and 2 had partial responses. The majority of complete responses were in patients with carcinoma in situ only, with most responses seen at higher dose levels. One patient with papillary tumor and carcinoma in situ had a complete response. Some early responses appear to be durable. Most importantly, a high rate of complete response was noted at higher dose levels among patients who had failed prior therapy with bacillus Calmette-Guerin. Further clinical trials of bropirimine in bladder cancer appear warranted.

Administration, Oral↗
PubMed1990

Prevention of central nervous system toxicity of the antitumor antibiotic acivicin by concomitant infusion of an amino acid mixture.

Acivicin is an investigational amino acid antitumor antibiotic currently being evaluated in Phase II clinical trials. In humans acivicin causes reversible, dose-limiting central nervous system (CNS) effects including somnolence, ataxia, personality changes, and hallucinations. We have observed and reported previously that acivicin-treated cats exhibit symptoms (ataxia, sedation, somnolence) resembling CNS toxicity reported in humans. We hypothesized that if acivicin uptake into brain were mediated by a saturable transport system common to endogenous amino acids, drug uptake and CNS toxicity might be blocked by elevation of normal amino acid concentrations in circulating plasma. To test this hypothesis, cats received constant-rate i.v. infusions of either saline or Aminosyn, 10% (a commercially available mixture of 16 amino acids not containing glutamine, glutamate, aspartate, or cysteine) for 4 h prior to and 18 h subsequent to administration of acivicin at a dose producing marked behavioral changes in control cats. Presence or absence of ataxia and sedation were noted at intervals after acivicin treatment. Results showed that Aminosyn infusion prevented CNS symptoms in six of eight cats. Subsequent experiments showed that acivicin levels in brain tissue of Aminosyn-treated cats were 13% of the drug levels in saline-infused cats. Acivicin levels in most peripheral tissues were also decreased significantly by Aminosyn infusion but not to the extent observed in brain. Decreased brain uptake was shown to be due to a combination of amino acid blockade of drug transport into that organ and of increased total body clearance of drug. Concomitant Aminosyn treatment did not alter the efficacy of acivicin in mice bearing L1210 leukemia or MX-1 human mammary carcinoma. Further studies demonstrated that a solution containing only four large neutral amino acids (leucine, isoleucine, phenylalanine, and valine) could also protect cats from acivicin-induced CNS toxicity, apparently without increasing acivicin total body clearance. However, a mixture of several other amino acids contained in Aminosyn (alanine, arginine, tyrosine, histidine, proline, serine, and glycine) failed to prevent CNS toxicity. We conclude that cotreatment with Aminosyn or a mixture of large neutral amino acids could protect cancer patients from acivicin-induced CNS toxicity without ablating antitumor efficacy.

Amino Acids↗
PubMed1990

A phase II study of menogaril (NSC-269148) in colorectal carcinoma. A Southwest Oncology Group study.

In this phase II trial, menogaril was administered to patients with metastatic colon cancer at a dose of 200 mg/m2 IV over one hour with cycles repeated every 28 days provided the absolute granulocyte count was greater than or equal to 2000 cells/microliters. Dose adjustments up or down were made depending upon nadir counts. Twenty-four patients were entered on this study with 21 eligible and evaluable for response. There was 1 CR lasting four and one-half months and 1 PR lasting three months for an overall CR + PR rate of 10% with a 95% confidence interval of 1% to 30%. Six patients (29%) had stable disease and 13 (62%) progressed. Median survival is 13.1 months. Toxicity was primarily hematologic with two cases of life-threatening leukopenia (less than 1000 cells/microliters) and one case of life-threatening granulocytopenia (less than 250 cells/microliters) among the 21 eligible patients, and one case of life-threatening leukopenia and granulocytopenia in one ineligible patient. There were no deaths due to treatment.

Adult↗
PubMed1990

Phase I study of oral menogaril administered on a once weekly schedule.

Forty-seven patients with solid tumors were treated on a phase I study of menogaril administered by mouth once per week. Nausea and vomiting were excessive at weekly doses of 350 and 450 mg/m2/week but were tolerable and controlled reasonably well by antiemetics at lower doses. There appeared to be a relatively shallow dose-vs-granulocytopenia curve above a menogaril dose of 180 mg/m2/week. No patient receiving chronic dexamethasone for cerebral edema developed granulocytopenia, even at menogaril doses of 350-450 mg/m2/week. Two patients developed neutropenic infection. No patient developed thrombocytopenia. Mild arrhythmias were seen in 3 patients. Two patients suffered possible myocardial infarcts that may not have been related to treatment. Asymptomatic blood pressure fluctuations were common and were probably not related to treatment. Diarrhea was dose-related but was generally not severe. Alopecia and stomatitis occurred occasionally. Minor responses were seen in two patients with gliomas, and three of five evaluable prostate cancer patients experienced marked pain relief. The dose recommended for phase II studies is 250-300 mg/m2/week with antiemetic pretreatment. This schedule appears to allow an oral menogaril dose-intensity that is approximately double that attainable with other oral schedules that have been studied.

Administration, Oral↗
PubMed1990

Phase II trial of 6-diazo-5-oxo-L-norleucine versus aclacinomycin-A in advanced sarcomas and mesotheliomas.

Ninety-eight patients with previously-treated advanced soft tissue sarcoma, bone sarcoma, or mesothelioma were randomly assigned to one of two intravenous single-agent treatment regimens, either 6-diazo-5-oxo-l-norleucine (DON; brief infusions of 50 mg/m2/day for 5 consecutive days every 4 weeks) or aclacinomycin-A (ACM-A, as 30-min infusions of 100 mg/m2 or 85 mg/m2, administered every 3 weeks). Of 43 patients who were evaluable for response, survival and toxicity, there were two responses (5%) produced by ACM-A; one in a male with mesothelioma, and one in a female with malignant fibrous histiocytoma. None of the 36 evaluable patients treated with DON developed an objective tumor response. Median survival was 4.8 months in the DON treatment arm, and 6.8 months in the ACM-A treatment arm. No patients on the DON arm experienced lethal or life-threatening toxicities, and severe toxicities resulting from this treatment included nausea and emesis (10%), stomatitis (2%), gastrointestinal toxicity (2%), and anemia (2%). Moderate toxicities included vomiting (24%), hematologic toxicity (24%), neurologic toxicity (7%), diarrhea (7%), mucositis (5%), fever (5%), palpitations (2%), hepatotoxicity (2%), bleeding (2%) and edema (2%). Fifteen percent experienced at least one severe reaction, and 63% experienced at least one moderate or greater toxicity. ACM-A was associated with four cases of life-threatening myelosuppression (7%); severe toxicities included myelosuppression (11%), neurologic toxicity (4%), diarrhea (2%), respiratory toxicity (2%), pain and muscle spasms (2%), edema (2%), and ulceration following extravasation (2%).(ABSTRACT TRUNCATED AT 250 WORDS)

Aclarubicin↗
PubMed1989

Phase II trial of continuous drug infusions in advanced ovarian carcinoma: acivicin versus vinblastine.

Sixty-six women with advanced ovarian carcinoma of coelomic epithelial origin were randomly assigned to one of two intravenous single-agent infusion treatment regimens, either acivicin (60 mg/m2/course, administered as a 72-hr infusion) or vinblastine (7.5 mg/m2/course, administered as a 120-hr infusion) every three weeks. All had progressive disease after one to three prior chemotherapeutic regimens. Of 62 patients who were evaluable for response, survival and toxicity, there was one partial response (2%) produced by vinblastine. Median survival was 13 weeks on either treatment arm. Three patients (10%) on the acivicin arm experienced life-threatening myelosuppression. Severe toxicities resulting from this treatment included myelosuppression (26%), neurotoxicity (16%), mucositis (3%) and vomiting (6%). Vinblastine was associated with one lethal pneumonia and five cases of life-threatening myelosuppression (16%); severe toxicities included myelosuppression (58%), genitourinary toxicity (6%), infection (3%), and edema (3%). Neither regimen produces useful clinical results in patients who have relapsed after prior chemotherapy for ovarian carcinoma.

Adenocarcinoma↗
PubMed1989

Phase I study of weekly intravenous administration of menogaril to adults with solid tumors.

Thirty-nine adults with solid tumors were treated on a Phase I study of menogaril administered i.v. once each week. Granulocytopenia was dose-limiting at a menogaril dose of 115 mg/m2/wk. Ten patients required delays in treatment of 1-4 weeks (median, 1 week) at some point during their treatment until they recovered from granulocytopenia. The average dose intensity possible on this schedule was at least 80% higher than that possible using a single-day or a five-times-daily schedule every 4 weeks. One patient developed infection while neutropenic, and only one patient developed thrombocytopenia. Dexamethasone appeared to reduce the degree of myelosuppression. Gastrointestinal toxicity was quite mild, and alopecia was uncommon. Arm vein phlebitis frequently followed menogaril administration, requiring the use of Hickman catheters (or equivalents). Two patients had myocardial infarcts while on treatment. It was unclear if the menogaril was in any way responsible. Reversible dyspnea and cough (with no evidence of congestive heart failure) were seen in some patients. Responses were seen in patients with gliomas, renal-cell carcinoma, and bladder carcinoma, and marked subjective improvement occurred in a single patient with prostate cancer. We plan to conduct a Phase II study in astrocytoma patients using a menogaril dose of 115 mg/m2/wk i.v.

Adult↗
PubMed1979

Dibromodulcitol.

Explore the source record for details and available documents.

Animals↗
PubMed1976

Blood ethanol concentrations during and following constant-rate intravenous infusion of alcohol.

Blood ethanol concentrations were determined in 7 subjects during and subsequent to a 2-hr constant-rate intravenous infusion of ethyl alcohol (8% v/v). Eight to 10 capillary blood samples were collected during the infusion and 10 to 21 samples were obtained after the infusion ceased. Thus, the total time course of blood ethanol concentrations in man was defined, both during and postinfusion. Blood ethanol concentration data from each of 6 subjects were fitted simultaneously to the two equations for the one-compartment open model with zero order input and Michaelis-Menten elimination kinetics. The average Vm[0.232 mg/(ml x hr)] and Km[0.0821 mg/ml] obtained fron these fittings correspond very closely with corresponding values estimated by the fitting of all the mean concentration-time data obtained following oral administration of 4 different doses of ethanol to 8 other fasting subjects in another study. A disproportionate increase in area under the concentration-time curve with increase in dose (gm/kg) was observed in a single subject who was infused with equal volumes of a 4% and an 8% (v/v) ethanol solution at the same constant rate.

Adult↗