Biomedical subjects

S B Howell

Publications and source records attributed to S B Howell.

At least 199 records · Page 11Linked to original sources

PubMed1985

Nephrotoxicity of high-dose intracavitary cisplatin with intravenous thiosulfate protection.

Sodium thiosulfate has been shown experimentally to protect against cisplatin-induced renal insufficiency by inactivating the nephrotoxic as well as cytotoxic properties of the agent. However, significant plasma levels of 'active' cisplatin have been demonstrated following high-dose intracavitary cisplatin administration with simultaneous intravenous thiosulfate delivery. At the UCSD Cancer Center 131 patients have been treated with a total of 485 courses (median per patient, 3; range 1-18) of intrapleural or intraperitoneal cisplatin with intravenous thiosulfate protection. Seventy-six patients (58%) had previously been treated with intravenous cisplatin. A total of 14 courses (2.9%) of intracavitary therapy were complicated by a serum creatinine rise to greater than 1.5 mg% which, in all but three cases, returned to the normal range within 1 month following treatment. All but one patient demonstrating clinical evidence of nephrotoxicity had been heavily pretreated with cisplatin. We conclude that thiosulfate can protect against clinically significant cisplatin-induced nephrotoxicity by cisplatin delivered in high doses via the intracavitary route.

Acute Kidney Injury↗

PubMed1985

Daily intraperitoneal administration of cytarabine in a patient with peritoneal mesothelioma.

A 58 year old male with advanced peritoneal malignant mesothelioma was treated with the daily (5 days/week) intraperitoneal administration of cytarabine in a large treatment volume (1-2 liters) for 7 weeks. While a clinical benefit was not observed, there was no systemic toxicity (except for mild emesis) during or following the intraperitoneal treatment program. Long-term exposure of slow growing solid tumors in the peritoneal cavity to a cell-cycle phase-specific agent with limited systemic exposure and toxicity is an innovative and potentially important means of rationally utilizing this class of anti-neoplastic drugs.

Cisplatin↗

PubMed1985

Maintenance of peritoneal catheter function by the intraperitoneal administration of 32% dextran 70.

Thirty-two percent dextran 70 was administered to 53 patients receiving intraperitoneal (i.p.) chemotherapy in an attempt to better maintain catheter function. One hundred milliliters of 32% dextran 70 was administered i.p. at the time of catheter placement and at the completion of each course of chemotherapy (every 3 to 4 weeks). Analysis of the functional survival of the dextran treated catheters and 20 historical controls was performed. The cumulative probabilities of catheters maintaining bi-directional function in the dextran treated and control groups were 0.75 and 0.50 respectively. This difference was statistically significant at p = 0.051 by two-tailed Wilcoxon analysis. The difference between survival of dextran treated and control catheters increased if patients who received intraperitoneal doxorubicin were factored out (p = 0.035 by two-tailed Wilcoxon analysis). Plasma and peritoneal dextran levels were measured on 9 courses in 8 patients. Dextran was detectable in the peritoneal cavity up to 7 days after administration. The "apparent half-life" of dextran 70 in the peritoneal cavity was 36 hours. Plasma dextran concentrations increased for 2 days following i.p. administration and then decreased with an apparent half-life of 36 hours. One patient experienced chills and another had an anaphylactoid reaction following administration of the dextran. This study suggests that i.p. administration of 32% dextran 70 may be an effective means of minimizing peritoneal catheter failures.

Adult↗

PubMed1985

Pilot study of intra-arterial floxuridine, mitomycin and doxorubicin in combination with degradable starch microspheres to treat primary and metastatic tumors of the liver.

Concurrent administration of degradable starch microspheres and cytostatic agents into the hepatic artery results in decreased systemic exposure and increased hepatic exposure to drug compared to intra-arterial administration of drug alone. Degradable starch microspheres 210 mg/m2 mixed with floxuridine 500 mg/m2, doxorubicin 40 gm/m2, and mitomycin 10 mg/m2 were administered through hepatic artery catheters to eleven patients with primary or metastatic cancer of the liver. Toxicity was acceptable and consisted of severe myelosuppression (5%), duodenal/gastric ulceration (9%), mild to moderate nausea and vomiting (17%) and alopecia (86%). There were no responses among the eleven patients; 7 of 7 patients with colo-rectal carcinoma had stable disease while on study. Minimal activity was observed in 7 patients with colo-rectal carcinoma. The use of degradable starch microspheres offers a new approach to the regional treatment of cancer and warrants further study.

Adult↗

PubMed1985

Intrapericardial instillation of cisplatin in a patient with a large malignant effusion.

Cisplatin (10 mg in 50 ml normal saline) was administered daily for five days directly into the pericardial cavity of a patient with metastatic nonsmall cell lung cancer and a malignant pericardial effusion. No systemic or local side effects were observed. A dramatic decrease in reaccumulation of pericardial fluid was noted which persisted until the patient's death four months later. On the basis of this experience, further investigation of the intrapericardial administration of cisplatin as treatment to control malignant pericardial effusions appears warranted.

Adenocarcinoma↗

PubMed1985

The intraoperative intraperitoneal administration of cisplatin: a case report.

A 63-year-old female with endometrial carcinoma who had received prior extensive systemic chemotherapy and pelvic radiotherapy was administered intraoperative cisplatin (100 mg/m2) by the i.p. route. The method and timing of chemotherapy administration were chosen to optimize delivery of the antineoplastic agent to tumor remaining following debulking surgery. There was no evidence of excessive or unexpected local or systemic toxicity. The intraoperative i.p. instillation of chemotherapeutic agents has the theoretical potential of improving to a limited degree the problem of insuring adequate drug distribution over i.p. chemotherapy.

Cisplatin↗

PubMed1985

High-dose cisplatin with sodium thiosulfate protection.

Nephrotoxicity frequently limits the dose of cisplatin to less than 120 mg/m2 per injection. Sodium thiosulfate is a neutralizing agent for cisplatin that protects against renal damage. To determine whether injection of thiosulfate would permit larger doses of cisplatin to be administered, a fixed 9.9-g/m2 dose of thiosulfate was given intravenously over three hours concurrently with escalating doses of cisplatin. Cisplatin was administered over the last two hours of the thiosulfate infusion. Using this technique, it was possible to escalate the cisplatin dose to 225 mg/m2 before dose-limiting toxicities were encountered. Comparison of cisplatin pharmacokinetics in patients treated with 202.5 mg/m2 plus thiosulfate to those in patients treated with 100 mg/m2 without thiosulfate indicated that there were no changes in the elimination rate constant, volume of distribution, or total body clearance of cisplatin. The total drug exposure for the plasma was approximately twofold at the higher cisplatin dose. This study demonstrates that concurrent administration of thiosulfate permits at least a twofold increase in dose and total exposure to cisplatin.

Adolescent↗

PubMed1985

Pharmacokinetics of 5-fluorouracil during hyperthermic pelvic isolation-perfusion.

The pharmacokinetics of 5-fluorouracil (5-FU) injected into a surgically isolated pelvic circuit during hyperthermic perfusion was studied in five patients with local recurrence of anorectal cancer. 5-FU doses ranged from 11 to 23 mg/kg. The geometric mean ratio of peak plasma 5-FU in the isolated to systemic circuits was 10, the ratio at the end of the 45-minute perfusion was 12.5. The mean half-life of 5-FU in the isolated circuit was 18.5 minutes. Total drug exposure for the isolated circuit was 7.8-fold greater than for the systemic compartment. These results demonstrate a large pharmacologic advantage for the use of the isolation-perfusion technique.

Adenocarcinoma↗

PubMed1985

Intraperitoneal chemotherapy with high-dose cisplatin and cytosine arabinoside for refractory ovarian carcinoma and other malignancies principally involving the peritoneal cavity.

Sixty-two patients with refractory ovarian carcinoma or other malignancies principally confined to the peritoneal cavity were treated with an intraperitoneal combination chemotherapy regimen consisting of cisplatin (100 mg/m2 or 200 mg/m2) and cytosine arabinoside (4 X 10(-3) mol/L or 10(-2) mol/L). Sodium thiosulfate was simultaneously administered intravenously (IV) to protect against cisplatin-induced nephrotoxicity. Sixteen of 52 evaluable patients demonstrated evidence of a clinical response including 14 (36%) of 39 with refractory ovarian carcinoma. Systemic toxicity was not severe except for cisplatin-induced emesis and a single episode of major renal insufficiency. Dose-limiting toxicity was bone marrow suppression with cytosine arabinoside administered at 10(-2) mol/L. We conclude that combination intraperitoneal therapy with high-dose cisplatin and cytosine arbinoside can be safely administered with objective tumor responses observed in patients with ovarian carcinoma refractory to front-line chemotherapy and in occassional individuals with other malignancies principally confined to the peritoneal cavity.

Adult↗

PubMed1985

Modulation of the activity of PALA by dipyridamole.

PALA is thought to inhibit an early step in de novo pyrimidine synthesis, causing depletion of intracellular pyrimidine nucleotides. Dipyridamole, a nucleoside transport inhibitor which can block restoration of nucleotide levels via the salvage pathway, was tested for its ability to augment the cytotoxicity of PALA against normal and malignant human cells in vitro. At the clinically relevant concentration of 1 microM, dipyridamole increased the cytotoxicity of PALA against a melanoma, a colon carcinoma, a promyelocytic leukemia (HL-60), and normal marrow (CFU-GM) in clonogenic assays. Dipyridamole produced 50% inhibition of uridine uptake in these cells at concentrations of less than 0.1 microM and reduced the LD50 of PALA by approximately 50% in mice. These results indicate that dipyridamole can markedly potentiate the activity of PALA in vitro and in vivo.

Animals↗

PubMed1985

Intraperitoneal chemotherapy: the use of concurrent systemic neutralizing agents.

There is a very great pharmacologic advantage to the intraperitoneal administration of many agents active against human ovarian carcinoma. In principle, the use of a systemic neutralizing agent can further improve the therapeutic index of this approach. In the case of the cell cycle phase-specific antimetabolite methotrexate, systemic administration of leucovorin permits very long duration exposure to methotrexate. In the case of cisplatin, systemically administered thiosulfate appears to provide relatively specific protection for the kidneys, and this in turn permits a doubling of the plasma exposure to unneutralized cisplatin. These concepts are now ready for phase II trial.

Animals↗

PubMed1985

Pharmacokinetics of hexamethylmelamine administered via the Ip route in an oil emulsion vehicle.

Saline and Intralipid were compared as vehicles for the ip administration of hexamethylmelamine (HMM) in mice. The drug proved stable over at least 7 weeks in solution and 2 years in crystal form. Fiftyfold higher concentrations of HMM could be achieved in Intralipid than in saline. The peritoneal pharmacokinetics were first-order and linear over the concentration range of HMM in Intralipid from 50 to 2000 micrograms/ml. The mean peritoneal half-life of HMM in Intralipid was 12.5-fold greater than the mean half-life of HMM in saline at the same concentration. Peritoneal concentration X time drug exposure, as measured by the area under the curve in single-dose elimination experiments, was 1200-fold greater for HMM at 2000 micrograms/ml in Intralipid than at 50 micrograms/ml, near saturation, in saline. The steady-state peritoneal to plasma concentration ratios were 96-104 for HMM in Intralipid at concentrations of 300-2000 micrograms/ml, and the peritoneal concentration that could be maintained by the constant ip infusion of HMM at 2000 micrograms/ml in Intralipid was at least 1600-fold greater than that maintainable with HMM in saline. The mean peritoneal clearance calculated by two independent methods and at three different concentrations of HMM in Intralipid was 0.112 +/- 0.016 ml/minute. HMM in Intralipid is a stable formulation that can be used to increase peritoneal exposure to HMM and may potentially be used iv as well.

Altretamine↗

PubMed1985

Mechanism of synergy between N-phosphonacetyl-L-aspartate and dipyridamole in a human ovarian carcinoma cell line.

Previous results from our laboratory have shown that the nucleoside transport inhibitor dipyridamole (DP) markedly augmented both the in vitro and in vivo activities of the pyrimidine antimetabolite N-phosphonacetyl-L-aspartate (PALA). In a human ovarian carcinoma cell line (2008), DP increased the activity of PALA by 1 to 2 logs in growth rate and clonogenic assays while exhibiting no cytotoxicity of its own. The concentration of DP used (1 microM) in these assays resulted in over 80% reduction in uridine uptake in the 2008 cells at the end of 1 h. The activity of PALA and PALA plus DP was completely antagonized by the addition of exogenous uridine in a dose-dependent manner. Addition of other nucleosides to concentrations as high as 1000 microM failed to rescue the ovarian cells from the drug combination, and combining two nucleosides together did not antagonize PALA and PALA plus DP activity to any greater extent. Cellular nucleotide pool analysis by anion-exchange high-performance liquid chromatography revealed that dipyridamole further reduced the already depressed uridine triphosphate and cytidine triphosphate pools of cells exposed to PALA, while the guanosine triphosphate pool was slightly elevated. Uridine supplementation resulted in partial replenishment of the uridine triphosphate and cytidine triphosphate pools, but the absolute levels remained below control values. The acute drug-induced changes in nucleotide pools in 2008 xenografts growing in athymic mice paralleled those observed in vitro. Evidence presented here supports the ability of DP to potentiate PALA activity against a human ovarian carcinoma cell line. The mechanism of synergy relates to the inhibition of pyrimidine salvage in the tumor cells via the blockade of uridine uptake.

Antineoplastic Agents↗

PubMed1985

Intracavitary cisplatin chemotherapy for mesothelioma.

A feasibility study of intracavitary cisplatin was conducted in eight patients with mesothelioma. Cisplatin, 90 mg/m2, was instilled weekly for 3 weeks, followed by a 3-week rest; thiosulfate was given iv to reduce nephrotoxicity. In 50 courses there was no chemical serositis; the major toxic effect was myelosuppression. One patient with measurable disease had a complete response; three others had objective responses.

Adult↗

PubMed1985

Differential potentiation of alkylating and platinating agent cytotoxicity in human ovarian carcinoma cells by glutathione depletion.

We have determined the effect of glutathione (GSH) depletion on the cytotoxicity of three nitrogen mustards, six platinum complexes, and mitomycin C in a human ovarian carcinoma cell line. GSH levels in COLO 316 cells were depleted by exposure of cell monolayers to 0.5 mM D,L-buthionine-S,R-sulfoximine. GSH depletion significantly potentiated the cytotoxicity of L-phenylalanine mustard, chlorambucil, and mechlorethamine as determined by clonogenic assay on plastic plates. The dose modification factors were 2.6, 2.6, and 1.9, respectively. The same level of GSH depletion had a minimal effect on the cytotoxicity of cis-diamminedichloroplatinum(II) (cis-DDP), carboplatin, dichloro(ethylenediamine)platinum(II), 1,2-diaminocyclohexylplatinum(II) malonate, and iproplatin. The dose modification factors of GSH depletion for these drugs were 1.4 or less. trans-Diamminedichloroplatinum(II) was, however, markedly potentiated by GSH depletion with a dose modification factor of 2.7. Mitomycin C was minimally potentiated by GSH depletion. We have also generated cis-DDP-resistant cells from COLO 316 and 2008 human ovarian carcinoma cells by in vitro selection with cis-DDP. These cis-DDP-resistant cells had identical levels of GSH as the parental cells. GSH depletion sensitized these cells only to the same degree as the parental cells and did not reverse the resistant phenotype. Our results indicate that intracellular GSH levels are not an important determinant of the cytotoxicity of cis-platinum(II) or cis-platinum(IV) complexes in COLO 316 and 2008 cells. In addition, altered GSH metabolism does not appear to be a component of the cis-DDP-resistant phenotype in these cells.

Alkylating Agents↗

PubMed1984

A high-performance liquid chromatographic assay with improved selectivity for cisplatin and active platinum (II) complexes in plasma ultrafiltrate.

cis-Diamminedichloroplatinum(II) (DDP) was measured in plasma ultrafiltrate following derivatization with sodium diethyldithiocarbamate (DDTC) by quantitation against a nickel chloride internal standard. A chloroform extract containing the Pt(DDTC)2 and Ni(DDTC)2 complexes was separated by reversed-phase high-performance liquid chromatography on a C18 radial compression column. The complex was eluted with methanol/water, 4/1, at a flow rate of 1.5 ml/min, and was detected at 254 nm. The limit of sensitivity was 0.1 microgram/ml DDP in the ultrafiltrate. This analytical approach was validated by comparison to graphite furnace atomic absorption spectrophotometric determinations of duplicate samples. There was clearly a component of the ultrafiltrable platinum present that was resistant to derivatization by DDTC. Evidence is presented that this component, presumably Pt(II) complexed with endogenous small molecules, is non cytotoxic and, hence, that this method may be selective for "active Pt(II)." This method offers an advantage over atomic absorption determination of total platinum in ultrafiltrate which does not discriminate between active and inactive forms, and over off-line FAA detection of parent DDP in HPLC eluates which ignores other active forms. Using this technique we have measured the pharmacokinetics of DDTC-reactive Pt(II) in humans after either i.v. infusion or infusion of DDP into the peritoneal cavity of patients with ovarian carcinoma.

Chromatography, High Pressure Liquid↗

PubMed1984

Anaphylactic reaction to cytarabine: in vitro evidence that the response is immunoglobulin E mediated.

A 48-year-old female developed significant bronchospasm on two occasions after being treated with cytarabine (Ara-C) by the intraperitoneal route. In this report we present the first in vitro evidence that such a reaction to cytarabine can be associated with the release of histamine and therefore might be immunoglobulin E (IgE) mediated. In addition, this report emphasizes the fact that, while uncommon, severe allergic reactions to this useful chemotherapeutic agent do occur and must be considered in the differential diagnosis of anaphylaxis and related symptoms in patients receiving this drug.

Anaphylaxis↗

PubMed1984

Pharmacokinetics and toxicity of 5-day continuous infusion of vinblastine.

Ten patients with advanced cancer were treated in a phase-I trial with monthly cycles of a 5-day infusion of vinblastine. Serum drug levels were relatively constant after 24 h and there was no correlation between drug level and myelosuppression or toxicity. Previously undescribed toxicities were observed, including one hypersensitivity reaction and three cases of severe, only slowly reversible, sensorimotor neuropathy. Two patients showed objective tumor regression during the vinblastine infusion therapy.

Aged↗