Search PubMed⌕ Search

Biomedical subjects

J L Marshall

Publications and source records attributed to J L Marshall.

At least 37 records · Page 2Linked to original sources
PubMed1999

A Phase I and pharmacokinetic study of TNP-470 administered weekly to patients with advanced cancer.

A Phase I study of angiogenesis inhibitor TNP-470 was conducted in patients with advanced cancer. TNP-470 (25-235 mg/m2) was administered i.v. over 4 h once a week to patients who had solid tumors refractory to the best available treatment or with a high risk of recurrence and who had normal renal, hepatic, and hematological function and no evidence of coagulopathy. The aims of the study were to determine the maximum tolerated dose, dose-limiting toxicities (DLTs), and the pharmacokinetics of TNP-470 given on a once-weekly schedule. Thirty-six patients, ages 23-75 (median, 54 years), with an Eastern Cooperative Oncology Group performance status of 0-2 were treated. The number of patients at each dose level (mg/m2) were 6 (25), 3 (50), 3 (75), 3 (100), 3 (133), 12 (177), and 6 (235). The principal toxicities of TNP-470 were dizziness, lightheadedness, vertigo, ataxia, decrease in concentration and short-term memory, confusion, anxiety, and depression, which occurred at doses of 133, 177, and 235 mg/m2. Two patients treated at 235 mg/m2 experienced DLT in the form of grade III cerebellar neurotoxicity after 6 weeks of treatment. Overall, these neurological symptoms were dose-related, had an insidious onset, progressively worsened with treatment, and resolved completely within 2 weeks of stopping the drug. One patient with malignant melanoma had stabilization of the previously growing disease for 27 weeks while on the treatment. Two patients, one with adenocarcinoma of the colon and the other with a soft tissue sarcoma, had no clinically detectable disease but were at high risk for recurrence at the initiation of treatment and received 13 months and > 3 years of treatment, respectively, with no evidence of disease recurrence. The remaining patients had progression of their disease after 1-6 months of treatment. The mean plasma half-life (t(1/2)) of TNP-470 and its principal metabolite, AGM-1883, were extremely short (harmonic mean, t(1/2) of 2 and 6 min, respectively) with practically no drug detectable in the plasma by 60 min after the end of the infusion. MII, an inactive metabolite, had a considerably longer t(1/2) of approximately 2.6 h. Mean peak TNP-470 concentrations were > or = 400 ng/ml at doses > or = 177 mg/m2. On the basis of this study, the maximum tolerated dose of TNP-470 administered on a weekly schedule was 177 mg/m2 given i.v over 4 h. The principal DLT was neurotoxicity, which appeared to be dose-related and was completely reversible. On the basis of the short plasma t(1/2) of TNP-470, exploration of a prolonged i.v. infusion schedule is warranted.

Adult↗
PubMed1999

Docetaxel and gemcitabine combinations in non-small cell lung cancer.

Docetaxel and gemcitabine have been shown to be active as single agents in a variety of solid tumors. These two agents have been studied in combination with several different treatment schedules. Two phase I studies used a novel 2-week administration schedule that involved a 1-hour infusion of 35 mg/m2 to 65 mg/m2 docetaxel and gemcitabine administered as either a 30-minute infusion (2,000 to 4,000 mg/m2) or a 10 mg/m2/min infusion (1,000 to 1,200 mg/m2 total dose). Another novel phase I study evaluated the effect of drug sequence on toxicities. Patients received 30 to 40 mg/m2 docetaxel and 800 to 1,250 mg/m2 gemcitabine on days 1 and 8 every 21 days. Two phase I studies of a monthly docetaxel regimen have been conducted. Patients received 800 mg/m2 gemcitabine on days 1, 8, and 15 and 100 mg/m2 docetaxel on day 1 of a 28-day cycle. Finally, in a phase II study, patients received 900 mg/m2 gemcitabine on days 1 and 8 and 100 mg/m2 docetaxel on day 8, with granulocyte colony-stimulating factor administered on days 9 through 15. In these studies, antitumor responses were observed in lung cancer as well as a number of other histologies. Neutropenia was the most frequent dose-limiting toxicity and no difference in clinical toxicity was observed with either sequence of administration. The emerging evidence suggests, therefore, that the combination of gemcitabine and docetaxel is active in a variety of solid tumors and is well tolerated.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Determination of the antitumor agent depsipeptide in plasma by liquid chromatography on serial octadecyl stationary phases.

A high-performance liquid chromatographic assay has been developed and validated for the determination of the antitumor agent depsipeptide (FR-901228) in plasma samples from patients with advanced cancer. After the plasma proteins were precipitated with acetonitrile, the supernatant was extracted with ethylacetate. Depsipeptide was chromatographed on two serial octadecylsilica stationary phases using a mobile phase consisting of acetonitrile-potassium phosphate buffer (0.03 M, pH 3) (27:73, v/v), at a flow-rate of 2.0 ml/min and at ambient temperature. The method was linear over a 50 to 2000 ng/ml range and the intra- and inter-day coefficients of variations were less than 8%. The method was applied to the determination of the plasma concentration-time profile for 14 patients with advanced cancer receiving from 1 to 7.5 mg/m2 of depsipeptide per day as a continuous 4-h infusion.

Anti-Bacterial Agents↗
PubMed1998

Phase I study of 9-cis-retinoic acid (ALRT1057 capsules) in adults with advanced cancer.

9-cis-Retinoic acid (9-cis-RA) and all-trans-RA (ATRA) are naturally occurring hormones. The nuclear receptors that mediate the effects of retinoids are the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). ATRA binds RAR with high affinity but does not bind to RXR, whereas 9-cis-RA, an isomer of ATRA, is a ligand that binds and transactivates both RARs and RXRs. The goals of this study were to determine the safety, tolerability, pharmacokinetics, and metabolic profile of 9-cis-RA in advanced cancer patients. Forty-one patients received oral 9-cis-RA (ALRT1057; Panretin capsules) at doses ranging from 5-140 mg/m2/day. Twenty-six patients were treated once daily with up to 140 mg/m2; a subsequent cohort of 15 patients were treated twice daily (b.i.d.) at 100-140 mg/m2/day (50, 60, and 70 mg/m2 b.i.d.) to evaluate a b.i.d. dosing regimen. Headache was the most frequent adverse event and was dose limiting in 3 of 41 patients. Skin toxicity was the next most common toxicity and was seen in 11 of 41 patients; it was typically mild and limited to skin dryness and erythema. Other toxicities included conjunctivitis, flushing, diarrhea, transaminitis, hypercalcemia, and asymptomatic hypertryglyceridemia. Toxicities were typically dose related, occurred primarily above 83 mg/m2/day, and were not ameliorated by b.i.d. dosing. No tumor responses were observed. The mean day 1 area under the plasma concentration-time curve and peak plasma concentration values were dose-proportional over all dose levels, whereas day 15 area under the plasma concentration-time curve and peak plasma concentration values were nonlinear above 83 mg/m2/day, suggesting that 9-cis-RA induced its own metabolism at doses equal to and above 140 mg/m2/day. 9-cis-RA is a retinoid receptor pan agonist with a more favorable pharmacokinetic and toxicity profile than that observed with previously studied retinoids and merits further investigation.

Administration, Oral↗
PubMed1997

TNM staging of pancreatic carcinoma using helical CT.

OBJECTIVE: The purpose of this study was to determine the accuracy of helical CT scanning in predicting the stage of carcinoma of the exocrine pancreas using TNM staging guidelines and in predicting resectability of carcinoma of the exocrine pancreas. MATERIALS AND METHODS: Twenty-six patients with proven adenocarcinoma of the pancreas underwent uniphasic or biphasic helical CT scanning. Two observers unaware of the patient's surgical stage evaluated the CT examinations using the TNM system (with specific assessment and description of disease sites). In addition, the two observers rated confidence of nonresectability using a 5-point scale (ranging from 1, definitely resectable, to 5, definitely not resectable). Observer results and preoperative interpretations were compared with surgical findings. RESULTS: Nineteen of 26 patients had nonresectable disease. The combined observer scores showed correct determination of T stage in 77% of patients, of N stage in 58%, and of M stage in 79%. The overall accuracy in determining lack of resectability was 96% and 84% for the two observers. All errors in determining resectable versus nonresectable disease occurred when the observer was not maximally confident of his or her diagnosis. CONCLUSION: Helical CT is an effective screening technique for assessing T and M stages of pancreatic carcinoma. However, helical CT is poor at detecting regional lymph node involvement. In patients with equivocal T-stage findings (such as questionable venous involvement), other studies such as endoscopic sonography may be of value.

Adenocarcinoma↗
PubMed1997

Phase I trial of orally administered pentosan polysulfate in patients with advanced cancer.

Tumor angiogenesis is critically important to tumor growth and metastasis. We have shown that pentosan polysulfate (PPS) is an effective inhibitor of heparin-binding growth factors in vitro and can effectively inhibit the establishment and growth of tumors in nude mice. Following completion of our Phase I trial of s.c. administered PPS, we performed a Phase I trial of p.o. administered PPS in patients with advanced cancer to determine the maximum tolerated dose (MTD) and toxicity profile and to search for any evidence for biological activity in vivo. Patients diagnosed with advanced, incurable malignancies who met standard Phase I criteria and who did not have a history of bleeding complications were enrolled, in cohorts of three, to receive PPS p.o. t.i.d., at planned doses of 180, 270, 400, 600, and 800 mg/m2. Patients were monitored at least every 2 weeks with physical exams and weekly with hematological, chemistry, stool hemoccult, and coagulation blood studies, and serum and urine samples for PPS and basic fibroblastic growth factor (bFGF) levels were also taken. The PPS dose was escalated in an attempt to reach the MTD. Eight additional patients were enrolled at the highest dose to further characterize the toxicity profile and biological in vivo effects of PPS. A total of 21 patients were enrolled in the three cohorts of doses 180 (n = 4), 270 (n = 3), and 400 (n = 14) mg/m2. The most severe toxicities seen were grade 3 proctitis and grade 4 diarrhea; however, 20 of the 21 patients had evidence of grade 1 or 2 gastrointestinal (GI) bleeding. These toxicities became evident at a much earlier time point as the dose was increased, but their severities were similar at all dose levels. There were no objective responses, although three patients had prolonged stabilization of previously progressing disease. Pharmacokinetic analysis suggested marked accumulation of PPS upon chronic administration. Serum and urine bFGF levels failed to show a consistent, interpretable pattern; however the data suggested an inverse relationship between PPS and bFGF levels in vivo. A MTD could not be determined using the daily t.i.d. dosing schedule due to the development of grade 3/4 GI toxicity (proctitis) at all dose levels studied. PPS, administered p.o. at doses of 400 mg/m2 t.i.d., did not cause significant systemic toxicity, but most patients developed moderate-to-severe GI toxicity within 1-2 months. The cause of the GI toxicity was unclear, but it was readily reversible upon cessation of the agent. The suggestion of an inverse relationship between PPS and bFGF supports further study of PPS as an antiangiogenic agent. The tested doses and schedule cannot be recommended for further study. Subsequent murine experiments showed PPS to be more effective as an anticancer agent when it is given intermittently. We propose a study of PPS given on a weekly schedule in further clinical trials.

Administration, Oral↗
PubMed1996

Biochemical modulation in the treatment of advanced cancer: a study of combined leucovorin, fluorouracil, and iododeoxyuridine.

Multiple studies have shown that leucovorin-fluorouracil regimens are modestly superior to fluorouracil alone in the treatment of advanced colorectal cancer. Laboratory data suggest that iododeoxyuridine could further enhance the efficacy of leucovorin-fluorouracil regimens. This report describes the Phase I clinical evaluation of a leucovorin-fluorouracil-iododeoxyuridine chemotherapy regimen. Twenty-four patients received treatment with leucovorin (500 mg/m2), fluorouracil (500 mg/m2), and iododeoxyuridine (escalating doses) on days 1 and 8 of a 21-day cycle. The maximum tolerated dose of iododeoxyuridine was 1200 mg/m2, with a recommended Phase II dose of 1000 mg/m2. Myelosuppression (leukopenia) was dose limiting; other commonly observed treatment toxicities were nausea/vomiting, mucositis, and hyperlacrimation. Although the 1200 mg/m2 dose was tolerated during the initial few cycles of therapy, chronic administration could not be maintained secondary to dose-limiting neutropenia. Since neutropenia was dose limiting, in a follow-up study, 10 patients received a modified regimen (treatment on days 1 and 6 instead of days 1 and 8) with the addition of granulocyte colony-stimulating factor (days 8-19). The addition of granulocyte colony-stimulating factor, however, did not permit further escalation of the iododeoxyuridine dose. Three partial responses and six minor responses were observed. Phase II studies of this regimen are ongoing in advanced colorectal and advanced pancreatic cancer to determine response rates in these diseases.

Adult↗
PubMed1995

The clinical experience with antiangiogenic agents.

Antiangiogenic agents have been recently recognized to be potentially useful in the treatment of malignant processes. There has been a resulting flood of these agents into the clinical research field, forcing researchers to consider the unique problems which these agents pose. As these are agents with a novel, angiostatic mechanism of action, new clinical trial designs may become necessary to move these agents from the phase 1 level on to clinical use. Currently, several of these agents are being or have been tested in clinical trials. In this article, we review the available clinical data with antiangiogenic agents from other investigators, and our own experience with pentosan polysulfate.

Clinical Trials as Topic↗
PubMed1995

Preclinical and clinical experience with cisplatin resistance.

Despite the general lack of clinical evidence supporting the preclinical data, there have been many attempts to overcome cisplatin resistance in clinical situations. These efforts have focused on both the proposed mechanisms of resistance as well as novel approaches to renew efficacy. In this article, the authors summarize the available clinical studies that have intentionally or serendipitously uncovered modulators of cisplatin sensitivity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Clinical pharmacokinetics and pharmacology of trimetrexate.

Trimetrexate represents one of a number of new antimetabolites that have been studied in malignant, rheumatological and infectious disease. Methotrexate, the classical antifolate agent, is active in a broad spectrum of clinical settings, but its use is limited ny pre-existing or acquired cellular resistance. Trimetrexate is an agent that does not require uptake by the folate carrier transport system, a major mechanism of cellular resistance both in vitro and in vivo. Both dihydrofolate reductase inhibition and high performance liquid chromatography (HPLC) assays can be used to determine drug concentrations. Clearance of trimetrexate has been reported to follow biphasic or triphasic patterns. Elimination is primarily by biotransformation with less than 5% of the drug excreted renally in an unchanged form. Both active and inactive metabolites have been found, but the precise metabolic pathways have yet to be defined. The role of trimetrexate in the treatment of Pneumocystis carinii pneumonia is limited to compassionate use, as clinical studies have shown cotrimoxazole (trimethoprim-sulfamethoxazole) to be superior to trimetrexate. However, in a wide spectrum of malignant processes, trimetrexate appears to have a role either as a high-dose single agent, with calcium folinate (leucovorin calcium) rescue, or in combination with other antineoplastic agents. However, further trials are needed to fully establish the efficacy of trimetrexate in these settings. Increased knowledge of the pattern of resistance for individual tumours and tumour types may result in trimetrexate becoming more widely used clinically.

Animals↗
PubMed1993

Partition of sodium dodecyl sulfate into stratum corneum lipid liposomes.

Synthetic detergents produce deleterious effects on human skin as the result of being taken up by the stratum corneum (SC). The present study aimed to determine to what extent a typical detergent enters the SC lipid lamellae, and what effect this might have on the physical properties of the lipids. These effects were studied in large unilamellar liposomes prepared from SC lipids (50% by weight of epidermal ceramides, 28% cholesterol, 17% free fatty acids, and 5% cholesteryl sulfate) by extrusion through successive polycarbonate filters of decreasing pore size, finally 400 nm. Freeze-fracture electron microscopy and light-scattering particle size analysis indicated a uniform liposome diameter averaging 230 nm. Partitioning of sodium dodecyl sulfate (SDS) into the lipid phase from aqueous buffer solutions was measured using the SC lipid liposomes and [U-14C]SDS. The partition coefficient was 416, 450, and 588 at pH 8.5 and 524, 507, and 807 at pH 7 for three different concentrations (0.1%, 0.02%, and 0.004%) of SDS. This high degree of partitioning into the liposomes is consistent with the high level of SDS partitioning seen in full SC. At the maximum, the SDS represented 18% of the liposomal lipids. Preparation of stable liposomes from SC lipids to which 10% or 20% of SDS had been added confirmed the ability of the liposomes to survive these high concentrations of surfactant. The permeability of the liposomes was enhanced as a result of SDS partitioning into the bilayers, as measured by the increased release of trapped [U-14C]glucose from these vesicles, and by their increased permeability to water in osmotic shock experiments.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Vesicoureteric reflux in children: prediction with color Doppler imaging. Work in progress.

Unlike gray-scale sonography, color Doppler ultrasonography allows reliable visualization of the ureteric jet phenomenon. A study was undertaken to determine whether any measurable parameter predicts the presence of vesicoureteric reflux. Measurements of mean urine jet velocity, longitudinal angle, transverse angle, and distance of the origin of the jet from the midline of the bladder were obtained on 31 infants and children (62 ureters) with a proved urinary tract infection. Of these measurements, only the distance of the ureteric orifice from the midline of the bladder was found to correlate with vesicoureteric reflux (mean distance in the reflux group, 10.25 mm +/- 2.40 (standard deviation [SD]); in the nonreflux group, 7.98 mm +/- 2.40 [P = .004]). The authors conclude that the more laterally positioned the ureteric orifice, the more likely it is to reflux. Color Doppler ultrasound measurement of the laterality of the ureteric orifice may be useful for predicting which children with a urinary tract infection would benefit from voiding cystourethrography.

Child↗
PubMed1988

A clinical and radiographical analysis of 127 anterior cruciate insufficient knees.

The progression from chronic anterior cruciate instability to degeneration of the knee has been well documented in animal studies. However, the literature is unclear as to the overall consequences with respect to the development of osteoarthritis. The long-term consequences of the anterior cruciate insufficient knee with or without associated medial collateral ligament insufficiency was investigated in 127 consecutive patients. The effects of meniscal injury and/or meniscectomy in the presence of ligamentous insufficiency was correlated with roentgenographic observations. A scoring system was devised and found to show that anterior cruciate insufficiency naturally progresses toward degenerative osteoarthritis. Meniscectomy with and without an associated medial collateral ligament insufficiency hastens the degenerative process. Progressive functional deterioration was shown to correlate with roentgenographic evidence of degenerative changes. The ultimate success of surgical repairs and reconstructions of the anterior cruciate ligament will not be based only upon functional return to activity or objective stability, but will also depend on the procedure's ability to prevent later development of degenerative osteoarthritis.

Adult↗
PubMed1986

Identification of major prognostic subgroups of patients with large-cell lymphoma treated with m-BACOD or M-BACOD.

One hundred twenty-one patients with diffuse large-cell lymphoma treated with m- or M-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone) were evaluated for pretreatment characteristics predictive for response and survival. Two characteristics, poor performance status and massive bulky disease, were negatively associated with response rate in a multivariate analysis. These two characteristics were also negatively associated with survival in multivariate analysis, as was another factor, an increased number of extranodal sites of disease. These three pretreatment characteristics were used to construct a model containing 12 categories of patients at increasing risk for relapse and shortened survival. These categories divided naturally into three broad groups of patients with respective 5-year survival rates of 68%, 55%, and 24%.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1984

Characterization of the covalent mercury (II)-NADPH complex.

Mercury (II) forms a covalent, 1:1 complex with NADPH which is indicated by the disappearance of the chromophore at 340 nm. With the use of NMNH as an analogue, the spectral changes were attributed to the reaction of Hg(II) with the nicotinamide ring. This reaction is reversed by the addition of sulfhydryl groups or other metal-chelating agents. The structure of the Hg(II) . NADPH complex was determined with 1H and 13C NMR spectroscopy and homonuclear decoupling and was shown to have Hg covalently attached to C-5 of the nicotinamide ring. From these results, we propose that Hg(II) reacts with the double bond between C-5 and C-6 to form a mercuronium ion which is opened by the nucleophilic attack of water on C-6. Two conformations of the Hg(II) . NADPH complex were detected, corresponding to the formation of the mercuronium ion on either the a or b side of the nicotinamide ring. Fluorescence quenching studies with the Hg(II) . NADPH complex and the flavoenzyme mercuric reductase showed that the complex could effectively bind (Kd = 2.3 microM), but could not reduce the enzyme.

Adenosine Diphosphate↗