Recall, recognition, and rate: memory and the heart.
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Adolescent↗
Biomedical subjects
S W Hall
Publications and source records attributed to S W Hall.
Phase II study of 4'-(9-acridinylamino) methanesulfon-m- anisidide (AMSA) in metastatic melanoma.
A phase II study of AMSA in previously treated patients with metastatic malignant melanoma was conducted. The dose schedule of AMSA was 40 mg/m2/day for 3 days repeated at 3-week intervals. Among the 30 evaluable patients, one achieved a complete response, one a partial response, and four had minor responses. Side effects included mild nausea and vomiting and moderate degree of myelosuppression. AMSA has poor activity against previously treated metastatic melanoma.
Adult↗
Actinomycin-D, levamisole chemoimmunotherapy of refractory malignant melanoma.
Sixty adult patients with disseminated melanoma refractory to DTIC or Dacarbazine were given chemoimmunotherapy with intermittent high single dose Actinomycin-D and Levamisole. Actinomycin-D was given at a dose of 1.5-2.0 mg/m2 intravenously every 3 to 4 weeks. Levamisole was given in a dose of 150 mg/day for two consecutive days each week (50 patients) and in a dose of 200 mg every other day (10 patients). Antitumor responses consisted of 2% complete remissions (CR), 2% partial remissions (PR), and 33% disease improvement less than PR or stabilization (S). Comparison of these patients who received Actinomycin-D + Levamisole with those on an immediately preceding study in a similar population where Actinomycin-D was given as a single agent revealed no difference in response rates. Patients who responded to Actinomycin-D + Levamisole (CR + PR + S) survived significantly longer (35 weeks) than nonresponders (12 weeks, p less than 0.01). Survival was not longer (p less than .05) in responding patients (CR + PR + S) receiving Actinomycin-D + Levamisole (35 weeks) compared to those responding to Actinomycin-D alone (18 weeks, p = 0.09). Hematologic toxicity was tolerable with median lowest granulocyte counts of 1.6 x 10(3)/microliter and platelet counts of 134,000/microliter. Other toxic effects were predominantly nausea, vomiting, and mucositis. In those patients who received alternate day Levamisole there was greater gastrointestinal upset as well as fever, rash and central nervous system toxicity which was unacceptable.
Adult↗
Adriamycin, BCNU, ftorafur chemotherapy of pancreatic and biliary tract cancer.
Twenty-six evaluable patients with disseminated or locally unresectable pancreatic or biliary tract carcinoma received Ftorafur (4 g/m2 iv day 1 and 22 and 2 g/m2 iv day 4 and 26), Adriamycin (60 mg/m1 IV day 1 and 45 mg/m2 iv day 22) and BCNU (150 MG/M2 IV DAY 1) combination chemotherapy (FAB) repeated at 6--8 week intervals. Two (29%) complete and one (14%) partial remissions were observed in 7 patients with biliary carcinoma while 5 of 19 (26%) patients with pancreatic carcinoma achieved partial remissions. Median survival for responding patients was approximately 11 months (range 7--16+) with median survivals of about 6 months (p less than 0.05 and about 3 months (p less than 0.05) for patients with stable and progressive disease. Major drug toxicity was myelosuppression with median lowest granulocyte counts of 1,000/microliters and platelet counts of 88,000/microliters. Approximately 25% of patients required antibiotic therapy for fever of unknown origin or documented infections. Other tolerable drug toxicities included nausea, vomiting and mucositis. The FAB regimen appears quite promising in biliary tract cancer and has efficacy in pancreatic carcinoma that warrants further clinical trials. Because of myelotoxicity observed with this regimen we now recommend a BCNU starting dose of 100 mg/m2 instead of 150 mg/m2.
Adult↗
Kinetics of gallium nitrate, a new anticancer agent.
Pharmacokinetic studies were conducted in 8 patients with disseminated neoplasms refractory to conventional chemotherapy, who received gallium nitrate at doses of 300 to 600 mg/m2 intravenously in a phase I clinical trial. Gallium concentrations in biological fluids were determined colorimetrically. In patients with normal renal function, gallium showed a biphasic plasma disappearance with an initial half-life (t1/2) of 0.5 to 1.8 hr (mean 1.0) and a terminal t1/2 of 10.5 to 50.4 hr (mean 25.1). Gallium was distributed in total body water and often localized in some body compartment as evidenced by a volume of distribution ranging from 0.25 to 2.53 L/kg (mean 1.19). The total drug clearance from the plasma was 0.13 to 1.00 ml/kg/min (mean 0.65) in patients with normal renal function. Cumulative urinary excretion of gallium was 15% to 72% (mean 35%) of the administered dose in 24 hr (it fell to 23% in 8 days in a patient with acute oliguric renal failure). Gallium kinetics are altered in patients with acute renal dysfunction and in patients who have received multiple doses of gallium or other metal chemotherapy.
Adult↗
Enzymatic assay for the antitumor agent-N-(phosphonacetyl)-L-aspartic acid (PALA).
A method is described for the assay of N-(phosphonacetyl)-L-aspartic acid in plasma or urine, based on inhibition of partially purified aspartate carbamoyltransferase from rat liver. Concentrations of N-(phosphonacetyl)-L-aspartic acid as low as 0.1 microgram/ml can be detected. Plasma disappearance and urinary excretion curves from one patient are shown as examples of the application of the method.
Animals↗
Regression of regionally confined melanoma with intra-arterial cis-dichlorodiammineplatinum(II).
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Aged↗
Penetration of 3-deazauridine into human brain, intracerebral tumor, and cerebrospinal fluid.
The antitumor agent 3-deazauridine (DAU) was administered rapidly to four patients before surgical removal of intracerebral tumor. Tumor, adjacent brain tissue, and temporalis muscle were assayed for DAU by high-pressure liquid chromatography. DAU penetrated comparably into tumor, brain, and muscle; in one patient, tissue concentrations were higher than concurrent plasma concentrations. The active metabolite 3-deazauridine 5'-triphosphate was quantitated in one tumor sample and greatly exceeded its Ki for cytidine 5'-triphosphate synthetase. DAU was also present in autopsy brain specimens from two patients treated shortly antemortem. Cerebrospinal fluid concentrations were 22.1 and 59.0%, respectively, of concurrent plasma concentrations during continuous infusion of DAU in two patients. Cerebrospinal fluid concentration was 3.1 microgram/ml 2 hr after a 30-min infusion of 1.5 g of drug per sq m and fell to 1.9 microgram/ml at 16 hr. Thus, DAU is capable of penetrating into intracerebral tumor, brain, and cerebrospinal fluid and is worthy of investigation in the treatment of intracerebral and meningeal neoplasms.
3-Deazauridine↗
Pharmacokinetics and disposition of 3-deazauridine in humans.
3-Deazauridine (3-DAU) pharmacology was studied in 20 patients who received the drug by rapid or continuous infusion. In 8 studies, the plasma clearance of 3-DAU after rapid administration was biphasic, with an average terminal t1/2 of 4.4 hr and an extrapolated volume of distribution of 0.57 liter/kg. After 5-day continuous infusion of 3-DAU, the plasma clearance was also biphasic, with an average terminal t1/2 of 21.3 hr and an extrapolated volume of distribution of 18.8 liter/kg. 2,4-Dihydroxypyridine, the aglycone of 3-DAU, was observed in plasma but not in urine of patients receiving the drug by rapid infusion. The urinary excretion of 3-DAU was low, only 7.8% 24 hr after rapid infusion and 7.2% up to 4 days after continuous infusion. Tissue distribution of 3-DAU was determined from autopsy samples of 2 patients. Not only were high levels of 3-DAU detected in the tissues studied, but 3-DAU triphosphate, the active metabolite of 3-DAU, was present in brain, lung, and liver.
3-Deazauridine↗
The pharmacokinetics of bleomycin in man.
A series of studies were carried out to investigate the pharmacokinetics of the antineoplastic antibiotic bleomycin in patients with neoplastic disorders. Drug was administered by long (four to five days) and short (10 minutes) zero-order infusions, and serial plasma and urine samples were collected. Serum and urine bleomycin concentrations were determined by radioimmunoassay. The disposition of bleomycin after the 10-minute infusion was described by a two-compartment open model. However, following multiple-day infusion estimates were obtained that were inconsistent with those from the short infusion. Parameters from the long infusions agreed with those from the short infusion when terminal plasma bleomycin levels less than 10 microunits/ml were excluded. The time to reach steady state following the long infusion (ca. 12 hours) was consistent with the half-life (3 hours) predicted by the short infusion and the long infusion excluding levels less than 10 microunits/ml. Possible explanations include assay interference by an unknown metabolite or strong binding of drug to tissues with release at a rate much less than the apparent rate of elimination of drug from the body.
Adult↗
Calcinosis in nonparathyroid malignant disease: an unusual case report and clinicopathologic review of 17 cases.
An unusual finding of systemic calcinosis in a patient with a nonparathyroid malignant neoplasm stimulated us to do a sclinicopathologic review of similar cases at our institution in the past seven years. Of 3,268 autopsies performed from 1968 to 1975, a total of 17 cases of calcinosis were found, 11 with solid tumors and 6 with hematopoietic neoplasms. Calcinosis was most prominent in the lung, kidney, heart, and stomach and was rarely discovered prior to death. Eighty-two percent of the patients had hypercalcemia and 53% had associated bony metastatic disease. Corticosteroid or phosphate treatment for the hypercalcemia may have contributed to the tissue deposition of calcium. Significant hepatic, renal, metabolic, and pulmonary dysfunctions were also associated with this disorder. Thirty-six percent of the patients had hypercalcemia without skeletal involvement; tumor-produced parathormone-like substances may be responsible for these calcium abnormalities. Calcinosis was a significant complication of neoplastic disease in these patients and contributed to morbidity and mortality.
Adolescent↗
Clinical, toxicological, and pharmacological studies of combination chemotherapy of adenocarcinoma with adriamycin and Baker's antifolate.
Ten patients with disseminated adenocarcinoma were treated with combination chemotherapy employing Adriamycin and Baker's Antifolate (BAF). There were seven patients with lung adenocarcinoma, two of whom achieved partial remission while the remaining five had their disease stabilized. Drug toxicity to the bone marrow, gastrointestinal mucosa, and skin was dose-limiting and was greater than the known toxicities of the individual drugs. Pharmacological studies of both drugs were performed on five patients to determine whether abnormal pharmacokinetics could explain this collateral toxicity. Adriamycin plasma concentrations and disappearance seemed to be unaffected by BAF. However, BAF levels were prolonged, apparently due to an Adriamycin effect on the plasma elimination of BAF, resulting in a prolonged exposure of sensitive tissues and organs to BAF. Consequently, when BAF and Adriamycin are used in combination, appropriate dose and schedule changes must be made to avoid any potentially serious side effects.
Adenocarcinoma↗
Clinical pharmacology of systemic chemotherapeutic agents in skin neoplasms.
Considerable progress recently has been made in the systemic chemotherapy of disseminated skin neoplasms. Several agents are particularly useful in this regard: the nitrosoureas, methotrexate, actinomycin D, and dacarbazine. This paper reviews their pharmacologic disposition in man. The nitrosoureas have short plasma half-lives; however, they are extensively degraded to metabolites that persist in the body, and are only slowly excreted. Highly soluble in lipids, the nitrosoureas penetrate significantly into the central nervous system. Actinomycin D is only minimally metabolized in vivo; its elimination from the plasma shows a prolonged slow phase with a half-life of 36 hours; but its excretion is even slower than expected about 30% in a week. A potent inhibitor of dihydrofolate reductase, methotrexate exhibits a multiphasic plasma disappearance, and accumulates in tissues with high dihydrofolate reductase activities. At the normal therapeutic dosages, methotrexate is eliminated by the kidneys as the unchanged drug; appropriate dosage modifications are mandatory if renal function is compromised. Dacarbazine has a relatively short plasma half-life, and is rapidly excreted partly as the unchanged drug; it undergoes extensive biotransformation in the body. Like other antitumor agents, these drugs may cause gastrointestinal toxicities and myelosuppression; in addition each drug can have its own individual organ toxicity.
Antineoplastic Agents↗
Metabolism and disposition of Baker's antifolate (NSC-139105), ftorafur (NSC-148958), and dichloroallyl lawsone (NSC-126771) in man.
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Antineoplastic Agents↗
Hepatic arterial infusion of Corynebacterium parvum and chemotherapy.
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Antineoplastic Agents↗
Phase 1 clinical investigation of 4'-(9-acridinylamino)methanesulfon-m-anisidide (NSC 249992), a new acridine derivative.
The compound 4'-(9-acridinylamino)methanesulfon-m-anisidide is a new derivative that was evaluated in a Phase 1 clinical trial. The schedule of drug administration consisted of daily i.v. injection for 3 consecutive days, repeated at 3-week intervals. Twenty-six patients received a total of 63 courses of 4'-(9-acridinylamino)methanesulfon-m-anisidide in a dose range from 4 to 50 mg/sq m/day. Hematopoietic toxicity was dose limiting, but it was of short duration and rapidly reversible. Mild nausea and vomiting were observed in 16% of the courses, and a mild degree of phlebitis was observed in 10% of the courses. Responses were observed in two patients with adenocarcinoma of the lung and one each of melanoma and acute myeloblastic leukemia. Phase 2 studies of 4'-(9-acridinylamino)methanesulfon-m-anisidide are planned at a starting dose of 40 mg/sq m/day for 3 days in good-risk patients and at 25 to 30 mg/sq m/day for 3 days in poor-risk patients. Course of treatment would be repeated at 21-day intervals.
Acridines↗
Phase I study of maytansine using a 3-day schedule.
Maytansine, a new ansa macrolide antitumor antibiotic, was administered to 60 patients as part of a phase I study. The doses given ranged from 0.01 (starting level) to 0.9 mg/m2 for 3 days. The toxic effects encountered consisted principally of nausea, vomiting, diarrhea, and occasionally, stomatitis and alopecia. Superficial phlebitis was also encountered and occurred when the drug was diluted in a volume of less than 250 ml. Myelosuppression occurred infrequently; it was almost regularly associated with abnormal liver function tests. Antitumor activity was detected in one patient each with melanoma, breast carcinoma; and head and neck clear cell carcinoma. Further studies are indicated with this compound since it has shown evidence of activity with little or no myelosuppression.
Blood Cell Count↗
Disposition and metabolism of 1-(tetrahydro-2-furanyl)-5-fluorouracil (ftorafur) in humans.
The pharmacology of high-dose 1-(tetrahydro-2-furanyl)-5-fluorouracil (FT) has been studied by radiochemical and chromatographic techniques in eight patients. Plasma disappearance of FT was exponential, with a half-life of 8.8 hr. Plasma concentrations of 5-fluorouracil (FUra) were sustained at 12.8 nmol/ml (1.7 microgram/ml) for at least 48 hr after FT administration. The concentrations of FUra derived from the administration of FT were considerably greater than were those achieved by constant infusion of FUra at the maximal tolerated dose of 1.1 g/sq m without causing unacceptable mucositis. The cumulative urinary excretion was 20% of the administered dose in 24 hr. FT underwent in vivo biotransformation to 2 hydroxytetrahydrofuranyl-5-fluorouracil derivatives in addition to anabolites and catabolites of FUra. High concentrations of FT and FUra were present in the cerebrospinal fluid, which could account for the severe central nervous system toxicity of FT at high doses. We conclude that the antitumor activity of FT is partially attributable to its slow release of FUra.
Animals↗