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Biomedical subjects

B R Goldspiel

Publications and source records attributed to B R Goldspiel.

At least 19 recordsLinked to original sources
PubMed1998

Standardizing the expression and nomenclature of cancer treatment regimens. American Society of Health-System Pharmacist (ASHP), American Medical Association (AMA), American Nurses Association (ANA).

Guidelines for describing cancer chemotherapy regimens in all aspects of drug development, including treatment protocols, order forms, and product labels, are proposed. To complement the approaches to reducing medication errors that have been recommended by ASHP and others, pharmacists at the National Institutes of Health and the National Cancer Institute, with the input of oncology pharmacists from diverse areas of practice, developed guidelines for expressing chemotherapy dosage schedules and treatment regimens. The guidelines present standards that are broadly applicable and can be adopted by other institutions. Clear and unambiguous expression of all medication orders and consistency of treatment descriptions are suggested. Written treatment plans and orders should contain enough information to allow health care providers from diverse disciplines to compare them with published treatment descriptions and investigational protocols and must therefore include planned dosages and schedules expressed in patient-specific units. In general, drug dosages should be expressed as the amount of drug administered from a single container. When ordering drugs that are part of complex or combination-drug regimens, prescribers should write as many of the orders at one time as is possible, so that continuity might be preserved. Standard rules are proposed for describing chemotherapy regimens.

American Medical Association↗
PubMed1998

A review of paclitaxel (Taxol) administration, stability, and compatibility issues.

The purpose of this article is to review information relative to the administration, stability, and compatibility of paclitaxel (Taxol, Mead Johnson Oncology Products, Princeton, NJ). The unique formulation used to solubilize paclitaxel has led to an increased awareness of plasticizer-leaching issues, paclitaxel stability in solution, and paclitaxel compatibility with other medications. Particularly with longer paclitaxel infusion schedules (greater than 48 hours), both drug stability in solution and pump apparatus congruence require careful consideration to minimize plasticizer-leaching problems and to ensure optimum drug delivery. Despite knowledge of the physical compatibility of paclitaxel with numerous drugs, a paucity of research has documented the specifics of paclitaxel's chemical compatibility with other medications.

Antineoplastic Agents, Phytogenic↗
PubMed1996

Phase I study of paclitaxel in combination with cyclophosphamide and granulocyte colony-stimulating factor in metastatic breast cancer patients.

PURPOSE: In vitro data suggest that prolonged exposure to paclitaxel enhances breast cancer cytotoxicity. Our objective in this phase I study was to determine the tolerability of paclitaxel administered by 72-hour continuous intravenous (i.v.) infusion (CIVI) in combination with high-dose cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) in the ambulatory setting to metastatic breast cancer patients. PATIENTS AND METHODS: Paclitaxel was administered over 72 hours by CIVI and cyclophosphamide was given daily by i.v. bolus on days 1, 2, and 3, followed by G-CSF every 21 days. The availability of ambulatory infusion pumps and paclitaxel-compatible tubing permitted outpatient administration. RESULTS: Fifty-five patients with metastatic breast cancer who had been previously treated with a median of two prior chemotherapy regimens were entered onto the study. Dose-limiting toxicity of grade 4 neutropenia for longer than 5 days and grade 4 thrombocytopenia occurred in three of five patients treated with paclitaxel 160 mg/m2 CIVI and cyclophosphamide 3,300 mg/m2 followed by G-CSF. The maximum-tolerated dose (MTD) was paclitaxel 160 mg/m2 CIVI and cyclophosphamide 2,700 mg/m2 in divided doses with G-CSF. Nonhematologic toxicities were moderate and included diarrhea, mucositis, and arthalgias. Although hemorrhagic cystitis developed in six patients, recurrence was prevented with i.v. and oral mesna, which permitted continued outpatient delivery. One hundred seventy-four cycles were safely administered in the ambulatory setting using infusional pumps and tubing. Objective responses occurred in 23 (one complete and 22 partial) of 42 patients with bidimensionally measurable disease (55%; 95% confidence interval, 38% to 70%), with a response rate of 73% (11 of 15) seen at the highest dose levels. CONCLUSION: Paclitaxel by 72-hour CIVI with daily cyclophosphamide followed by G-CSF can be administered safely in the ambulatory setting, has acceptable toxicity, and is an active regimen in the treatment of metastatic breast cancer.

Adult↗
PubMed1995

A pilot study of amiodarone with infusional doxorubicin or vinblastine in refractory breast cancer.

Increasing evidence suggests that P-glycoprotein (Pgp) expression can mediate drug resistance in refractory breast cancer. We studied 33 patients with refractory breast cancer enrolled in a pilot study of oral amiodarone as a Pgp antagonist given in combination with infusional doxorubicin or vinblastine. Whenever possible, tumors were biopsied and Pgp expression was assayed. Patients received either 60 mg/m2 doxorubicin over 96 h or 8.5 mg/m2 vinblastine over 120 h by continuous intravenous infusion. Beginning with the second cycle of chemotherapy, 600-800 mg amiodarone was given orally each day. Patients who experienced toxicity due to amiodarone but were responding to chemotherapy were placed on quinidine. Partial responses were observed in 9 of 33 patients on study and were sometimes observed after the first cycle of chemotherapy, before amiodarone was given, suggesting that some patients may have responded to treatment because of the infusional schedule. Toxicities were primarily the known side effects of the antineoplastic agents and of amiodarone. The major amiodarone toxicity was gastrointestinal, with nausea, vomiting, anorexia, or diarrhea being noted in 21 patients. Biopsy samples were obtained from 29 patients and in 21 cases, viable tumor tissue was present and the results were interpretable. Of the 21 samples, 9 had Pgp expression as determined by immunohistochemical staining; 12 were considered negative. The presence of Pgp expression was associated with an acceleration of the time to treatment failure. Whereas normal-tissue toxicities related to the combination of a Pgp antagonist with chemotherapy were not observed, amiodarone was associated with too many untoward effects to be utilized as a drug resistance-reversing agent.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Phase II study of paclitaxel in relapsed non-Hodgkin's lymphomas.

PURPOSE: To assess the efficacy and toxicity of paclitaxel administered as a 96-hour infusion to patients with relapsed non-Hodgkin's lymphomas (NHLs). PATIENTS AND METHODS: Eligible patients had relapsed NHL and measurable disease and were considered incurable. Paclitaxel was infused at a dose of 140 mg/m2 every 3 weeks. Premedications to prevent paclitaxel hypersensitivity reactions were not administered and no patients received corticosteroids. Expression of the multidrug resistance (mdr-1) gene was determined in tumor from 17 patients by mRNA quantitative polymerase chain reaction (PCR). RESULTS: Thirty-one patients received a total of 99 cycles of paclitaxel. Two patients were not assessable for response. The median age was 50 years, 71% had stage IV disease, and intermediate/high-grade histology was present in 65% of patients. Patients had received a median of three prior chemotherapy regimens, and 68% of patients had responded to the previous chemotherapy (chemotherapy-sensitive). Of 29 assessable patients, five (17%) achieved a partial response (PR). With a median potential follow-up time of 17 months, the median event-free and overall survival durations were 1.6 and 7.5 months, respectively. No correlation was found between response to paclitaxel and extent of prior treatment or response. The mdr-1 gene was easily detectable in 14 of 17 tumor biopsies, but was low in all but one sample. The most serious toxicity was grade 4 neutropenia, which occurred during 14% of cycles. CONCLUSION: Paclitaxel was well tolerated, but had a low response rate in patients with relapsed NHLs. There was no clear association between response to paclitaxel and extent of our response to prior treatment. Most patients had chemotherapy-sensitive disease, which suggests that the low response rate to paclitaxel was probably not due to general chemotherapy resistance. Paclitaxel provided good palliation in a minority of patients and is a reasonable agent to consider for use in patients who have failed to respond to standard chemotherapy.

Adult↗
PubMed1994

Pharmaceutical issues: preparation, administration, stability, and compatibility with other medications.

In conclusion, paclitaxel, a very active anticancer agent, is dissolved in a polyoxyethylated castor oil/alcohol vehicle, which poses some interesting challenges for drug preparation and administration. Physicians, nurses, and pharmacists should become knowledgeable about solution containers, intravenous administration sets, in-line filters, and access devices compatible with paclitaxel administration. Chemical stability studies show that paclitaxel diluted to clinically used concentrations in customary infusion fluids is stable for at least 27 hours at room temperature, which enables a 24-hour supply to be prepared in a single container. Paclitaxel has been demonstrated to be visually and turbidimetrically compatible with many other drugs during Y-site simulation studies; however, evidence of chemical compatibility for the majority of these combinations is lacking.

Diethylhexyl Phthalate↗
PubMed1994

Paclitaxel in doxorubicin-refractory or mitoxantrone-refractory breast cancer: a phase I/II trial of 96-hour infusion.

PURPOSE: A phase I study of paclitaxel infused over 96-hours was performed to determine toxicity, maximum-tolerated dose (MTD), and pharmacokinetics in patients with incurable lymphomas and solid tumors. A phase II study was performed at the MTD of paclitaxel in patients with doxorubicin/mitoxantrone-refractory metastatic breast cancer. PATIENTS AND METHODS: In the phase I study, paclitaxel dose levels ranged from 120 to 160 mg/m2, administered on a 21-day cycle. Patients with metastatic breast cancer who had either no response or a partial response (PR) to doxorubicin or mitoxantrone and had measurable disease were eligible for the phase I and II studies. Expression of the multidrug resistance (mdr-1) gene was determined in tumor biopsies by mRNA quantitative polymerase chain reaction. RESULTS: Twelve patients received a total of 73 cycles of paclitaxel on the phase I study. Dose-limiting mucositis and/or grade IV granulocytopenia was reached at 160 mg/m2, and 140 mg/m2 was selected as the phase II dose. Thirty-six consecutive patients with metastatic breast cancer were treated, of whom three were not assessable. The median age was 49 years, with disease in the liver and/or lung in 76%. Patients received a median of two prior regimens for metastatic disease, and 73% had no response to prior doxorubicin or mitoxantrone. Of 33 patients treated with paclitaxel, 16 patients (48%) achieved a PR and five (15%) achieved a minor response (MR). With a median potential follow-up duration of 60 weeks, the median progression-free and overall survival durations were 27 and 43 weeks, respectively. No correlation was found between extent of prior treatment or prior response to doxorubicin/mitoxantrone, and response to paclitaxel. Paclitaxel pharmacokinetics showed a correlation between both granulocyte and mucosal toxicity, and serum steady-state concentrations (Css) more than 0.07 mumol/L. Patients with liver metastases had significantly decreased paclitaxel clearance and higher paclitaxel Css. Levels of mdr-1 were uniformly low in all tumor biopsies studied. CONCLUSION: The recommended phase II dose of paclitaxel is 140 mg/m2 in patients without liver metastases and 105 mg/m2 in patients with liver metastases. Ninety-six-hour infusions of paclitaxel were effective and well tolerated in patients with doxorubicin/mitoxantrone-refractory breast cancer. Prolonged infusion schedules may be more effective than shorter schedules and deserve further study.

Adult↗
PubMed1993

Administration of pentosan polysulfate to patients with human immunodeficiency virus-associated Kaposi's sarcoma.

BACKGROUND: Neovascularization induced by basic fibroblast growth factor (basic FGF) or FGF-like cytokines is thought to play a substantial role in the pathogenesis of human immunodeficiency virus (HIV)-associated Kaposi's sarcoma. Pentosan polysulfate has been shown to inhibit basic FGF and FGF-like dependent tumor growth both in vitro and in vivo. Moreover, it has been found to inhibit the growth of Kaposi's sarcoma-derived spindle cells in vitro. These observations suggested that pentosan polysulfate might be worth exploring as a potential agent for the treatment of Kaposi's sarcoma. PURPOSE: The purpose of this phase 1 clinical trial was to determine the maximum tolerated dose of pentosan polysulfate in patients with HIV-associated Kaposi's sarcoma and whether or not this compound had activity against this neoplasm. METHODS: Sixteen HIV-seropositive patients with Kaposi's sarcoma received pentosan polysulfate via continuous venous infusion for 3-6 weeks and then received a subcutaneous dose three times per week. Three different doses of pentosan polysulfate were administered: 2 mg/kg per day by infusion followed by 2 mg/kg per dose given subcutaneously (six patients), 3 mg/kg per day by infusion followed by 3 mg/kg per dose given subcutaneously (five patients), and 4 mg/kg per day by infusion followed by 4 mg/kg per dose given subcutaneously (five patients). Five of the 16 patients in the study also received injections of 1 mg of pentosan polysulfate into two different lesions two times a week for 3 weeks, followed by intralesional therapy once weekly. After receiving pentosan polysulfate for 6 weeks, patients were administered 100 mg zidovudine (AZT) orally every 4 hours in conjunction with pentosan polysulfate. RESULTS: The maximally tolerated dose of pentosan polysulfate given by continuous venous infusion was found to be 3 mg/kg per day. No patient had an objective clinical antitumor response to either systemic or intralesional pentosan polysulfate administration; however, three patients had stable Kaposi's sarcoma for 3-27 weeks. No statistically significant effect on CD4 cells or serum HIV p24 antigen was noted during pentosan polysulfate administration. Dose-limiting toxic effects were characterized by anticoagulation and thrombocytopenia and were reversible. CONCLUSION: Pentosan polysulfate was well tolerated in this patient population. However, no objective tumor response or evidence of anti-HIV activity was noted; therefore, no claim of activity can be made in this trial. IMPLICATION: Continued investigation into the use of angiogenesis inhibitors with improved activity and toxicity profiles or different mechanisms of action is warranted.

Adult↗
PubMed1993

Phase II study of fazarabine (NSC 281272) in patients with metastatic colon cancer.

Fazarabine (Arabinofuranosyl-5-azacytosine) is a synthetic pyrimidine nucleoside which combines the arabinose sugar of cytosine arabinoside with the triazine base of 5-azacytidine. It has demonstrated activity against a variety of human solid tumor xenografts including colon, lung and breast cancers. Eighteen patients with refractory metastatic colon cancer were enrolled in a phase II trial of fazarabine. The drug was administered as a 72 hr continuous infusion every 3-4 weeks; the starting dose was 2 mg/m2/hr as established in a previous phase I study. The major toxicity was neutropenia, as predicted from the phase I study. The median time to nadir for cycle 1 was 20 days, with a median granulocyte count of 437/microliters (range 36-1600/microliters); recovery was within 2-4 days, with only one incidence of fever and neutropenia in 42 cycles. Especially noted for their absence were thrombocytopenia, nausea, vomiting and stomatitis. No objective clinical responses were seen; one patient had stabilization of rapidly growing liver metastases for a period of 7 months. In view of fazarabine's narrow range of toxicities, future dose intensification trials utilizing fazarabine in combination with hematopoietic growth factors are worthy of consideration.

Adenocarcinoma↗
PubMed1993

Taxol: a history of pharmaceutical development and current pharmaceutical concerns.

Taxol, a unique diterpene anticancer compound derived from the bark of the Taxus brevifolia (Pacific yew) tree, induces cytotoxicity by a novel mechanism of action. An antimicrotubule agent, Taxol promotes the formation and stabilization of the tubulin polymer unlike other anticancer agents that induce microtubule disassembly. Because of its poor aqueous solubility, Taxol is formulated as a solution in 50% Cremophor EL and 50% dehydrated alcohol, USP. The Cremophor EL and dehydrated alcohol vehicle used in the formulation of Taxol creates some interesting challenges for its preparation and administration. The pharmaceutical concerns associated with the preparation and administration of Taxol are discussed.

Animals↗
PubMed1993

Human gene therapy.

Current concepts in gene transfer and its application to the treatment of human genetic disorders, cancer, and other diseases are discussed. Gene therapy is a technique in which a functioning gene is inserted into a human cell to correct a genetic error or to introduce a new function to the cell. Many methods, including retroviral vectors, have been developed for ex vivo and in vivo gene insertion into cells. Some pharmacists have likened gene therapy to a sophisticated form of drug delivery and have envisioned an active role for the pharmacy profession. There are several safety and ethical issues related to manipulating the human genome that need to be understood. Current gene therapy efforts focus on gene insertion into somatic (nongerminal) cells only. Gene therapy has the potential to revolutionize the treatment of genetic disorders, diseases associated with a genetic component (e.g., cystic fibrosis), cancer, AIDS, and many other diseases. Gene transfer may also be used to better understand the biology of disease processes, such as the source of relapse in bone marrow transplant patients. The human genome project will undoubtedly lead to the identification, characterization, and understanding of genes that are responsible for many human diseases, and gene therapy trials are sure to expand accordingly. To date, over 40 clinical trials have been approved and more than 110 patients have been entered in gene therapy studies. There are still many technical obstacles to overcome before gene therapy can have widespread application. Injectable vectors need to be developed to simplify foreign gene administration. Perhaps the biggest problem to overcome will be engineering the target cells to be able to regulate gene expression according to physiologic needs. Pharmacists should become knowledgeable about gene transfer techniques and possible clinical applications of gene therapy to keep abreast of the newest trends in medicine.

Animals↗
PubMed1992

Adaptive control with feedback strategies for suramin dosing.

Suramin, a drug used in the treatment of parasitic diseases, is currently being evaluated in clinical trials as an antineoplastic agent. The use of therapeutic drug monitoring and adaptive control with feedback in clinical trials of suramin was initially motivated by an association between acute neurologic toxicity and plasma suramin concentrations in excess of 350 micrograms/ml. We have prospectively examined the performance of both two- and three-compartment population pharmacokinetic models in controlling plasma suramin concentrations and have found that a three-compartment model best describes this drug. No correlation was found between the clearance of suramin and creatinine clearance, as had been previously hypothesized. The low systemic clearance of suramin and the number of parameters required to describe the three-compartment model suggest the need for a bayesian approach to the estimation of individual pharmacokinetics.

Adrenal Gland Neoplasms↗
PubMed1991

Ondansetron: a serotonin receptor (5-HT3) antagonist for antineoplastic chemotherapy-induced nausea and vomiting.

Ondansetron represents a new class of drugs that exert their antiemetic activity by selective inhibition of a serotonin receptor subtype (5-HT3). Ondansetron has marked activity against emesis associated with cisplatin and other highly emetogenic drugs. Compared with high doses of metoclopramide, the antiemetic "gold standard," it demonstrates equal or superior efficacy. Although ondansetron is moderately well absorbed after oral administration, only a parenteral formulation will initially be available. Ondansetron is eliminated almost entirely by hepatic metabolism; less than five percent of an intravenously administered dose is recovered intact in urine. The half-life of ondansetron is approximately 3.5 hours; slightly shorter in children and prolonged in the elderly. Neither clinical efficacy nor adverse effects have correlated with serum concentrations. Ondansetron is generally well tolerated. Clinically relevant adverse effects include headache, diarrhea or constipation, sedation, and transient minor elevations of liver function tests. It is not associated with extrapyramidal reactions. Ondansetron is indicated as prophylaxis for nausea and vomiting associated with emetogenic chemotherapy. Studies to further evaluate and define its use are ongoing.

Animals↗