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Biomedical subjects

M Todd

Publications and source records attributed to M Todd.

At least 19 recordsLinked to original sources
PubMed1995

Biochemical modulation of 5-fluorouracil with brequinar: results of a phase I study.

Biochemical modulation can increase the efficacy of 5-fluorouracil (5-FU). Pizzorno et al. have previously shown that brequinar, a de novo pyrimidine synthesis inhibitor, enhances the antitumor effect of 5-FU in vivo [Cancer Res 52: 1660-1665, 1992]. On the basis of their data, we conducted a phase I study of brequinar in combination with 5-FU in patients with refractory solid tumors. The initial dose (100 mg/m2) of brequinar was raised in 100-mg/m2 increments in cohorts of three assessable patients. The initial dose of 5-FU was 500 mg/m2, but escalation was allowed in patients who showed no significant toxic reaction. Brequinar was administered over 1 h and 5-FU over 2 h starting 18-20 h after the initiation of infusion of brequinar. Treatments were repeated weekly. Responses were evaluated after 4 weeks (one course) and then every 8 weeks thereafter. Pharmacokinetics of brequinar and determination of plasma uridine levels were performed in at least three patients at each dose level. Of the 25 patients registered in the study, 21 were assessable for toxicity studies. The dose of brequinar was escalated up to 600 mg/m2. In addition, the dose of 5-FU was increased to 600 mg/m2 as a result of a lack of a significant toxic reaction in the first nine patients. No objective responses were observed. One patient developed grade 3 stomatitis, and one developed grade 3 esophagitis at the 400 and 600 mg/m2 dose of brequinar, respectively. Brequinar produced a dose-dependent decrease in plasma uridine levels at doses up to 500 mg/m2. No additional decrease in plasma uridine occurred with higher doses of brequinar, thus suggesting a plateau effect. This observation prompted us to terminate the study before reaching the maximum tolerated dose of brequinar. Our data indicate that brequinar in doses > or = 400 mg/m2 results in significant biochemical modulation. The lack of toxicity seen at these doses of brequinar suggests that the initial dose of the effector agent 5-FU should be increased in future studies.

Adult↗
PubMed1995

Preventing intimal hyperplasia with photodynamic therapy using an intravascular probe.

The purpose of this study was to determine the efficacy of intravascular photodynamic therapy (PDT) to prevent the development of intimal hyperplasia. Anesthetized New Zealand white rabbits underwent placement of Fogarty balloon catheters introduced via femoral artery cutdowns. Catheters were passed retrograde 10 cm into the lower abdominal aorta, inflated six times, and withdrawn toward the inguinal ligament. Rabbits were then randomly assigned to one of the following groups: group 1, drug with no light; group 2, no drug with 240 joules of light; group 3, drug plus 120 joules of light; or group 4, drug plus 240 joules of light. Uninjured carotid arteries served as negative control vessels (N) and injured but non-PDT-treated iliac artery segments served as positive controls (P). Porfimer sodium (photofrin) was administered in a dose of 5.0 mg/kg. Light was provided by a fiberoptic probe with a 1 cm cylindric diffuser attached to an argon pumped dye laser tuned to 630 nm to provide 1 W of laser light for 120 or 240 seconds. One month after PDT, rabbits were killed, perfusion fixed with glutaraldehyde, and vessels removed and examined microscopically. Intimal thickness (mean +/- SD) was calculated and expressed as ratios of the intima/media at four equal positions. Results for N, P, and groups 1, 2, 3, and 4 were 0.02 +/- 0.00, 1.18 +/- 0.71, 0.76 +/- 0.33, 0.96 +/- 0.43, 0.14 +/- 0.22, and 0.36 +/- 0.16, respectively. Intimal thickness was significantly reduced in groups 3 and 4 when compared with P, group 1, and group 2 (p < 0.001, ANOVA). These results showed that intravascular PDT was effective in reducing intimal hyperplasia following arterial injury. This may be a practical method of delivering light for PDT.

Animals↗
PubMed1995

Novel squalestatins produced by biotransformation.

Microorganisms were screened for the ability to modify the squalene synthase inhibitor squalestatin 1. Biotransformation of 1 by two actinomycetes, S15106 and S15138, yielded three products hydroxylated on the 4,6-dimethyl-oct-2-enoyl side chain either at the 6 position (5) or 7 position (4 two diastereoisomers), and lacking the acetyl ester from the C-1 side chain. Many strains were found to hydrolyse the 4,6-dimethyl-oct-2-enoyl or acetyl esters to yield squalestatins 2 or 3. The 3-methyl ester (6) of 1 was obtained using Fusarium sp. F13945. This fungus also produced a farnesoic acid derivative, possibly in response to inhibition of its squalene synthase by 1. The biotransformation products of 1 all retained potent squalene synthase inhibitory activity.

Actinomycetales↗
PubMed1994

Polyethylene glycolated interleukin-2 as maintenance therapy for acute myelogenous leukemia in second remission.

Seven patients in second complete remission of acute myeloid leukemia (AML) aged 19-65 years were treated with polyethylene glycolated interleukin-2 (PEG IL-2), 1 x 10(6) U/M2 IV weekly as the sole postremission therapy. Second remission duration was in the range of 4-49+ months, and three patients had a second remission duration substantially longer than their first (6, 21+, and 42+ months). The results suggest that PEG IL-2 may prolong second remission duration in AML and that a prospective randomized study designed to test that idea is warranted.

Adult↗
PubMed1994

Preparation, characterization, and evaluation of a monoclonal antibody against the rabbit platelet glycoprotein IIb/IIIa in an experimental angioplasty model.

The deposition of platelets at the site of balloon angioplasty is thought to play a major role in the pathogenesis of restenosis. The antibody AZ-1, which binds to the rabbit platelet glycoprotein IIb/IIIa receptor and inhibits platelet function both in vitro and in vivo, was produced and tested in an experimental model of angioplasty. Atherosclerosis was induced by desiccation injury of the femoral artery, followed by a 28-day diet with 2% cholesterol and 6% peanut oil. Rabbits were randomized to receive an infusion of saline, a single infusion of 0.5 mg/kg of AZ-1, or an infusion of 0.6 mg/kg AZ-1 before angioplasty. The latter group received a second infusion of 0.6 mg/kg 72 hours later. Functional platelet inhibition was demonstrated by prolongation of the bleeding time in all treated animals. Angiography was performed at baseline, immediately after a standardized angioplasty, and again 28 days after angioplasty on a total of 42 vessels. There were no significant differences between the antibody-treated group and the control group in the mean angiographic minimum luminal diameter at any of the time points. There was also no difference in the initial improvement after angioplasty (acute gain), in the decrease in luminal diameter from immediately after angioplasty to 28 days after angioplasty (late loss), or in the overall improvement from before angioplasty to 28 days after angioplasty. Quantitative histological analysis confirmed the lack of a beneficial effect of AZ-1. There were no significant differences in the area of the intima, the media, or the combined intima and media between the antibody-treated groups and the control group. Thus, potent platelet inhibition for up to 6 days after balloon angioplasty using a monoclonal antibody that inhibits platelet aggregation did not reduce the response to vascular injury after balloon angioplasty in this rabbit model of experimental atherosclerosis.

Angioplasty↗
PubMed1994

Comparison of the efficacy of three dose levels of moexipril versus placebo as add-on therapy to hydrochlorothiazide in patients with moderate hypertension.

This parallel, double-blind trial was designed to evaluate the efficacy of three dose levels of moexipril versus placebo as add-on therapy to hydrochlorothiazide (HCTZ) in patients with uncomplicated moderate to severe hypertension. Two hundred patients (aged 25-74 years) with sitting diastolic blood pressure (DBP) between 95 and 114 mm Hg after 4 week treatment with HCTZ 25 mg once daily were randomized to placebo, or moexipril 3.75, 7.5 mg, or 15 mg. BP was measured at 22-26 h postdose at biweekly visits and at 1, 2, 3, and 4 h postdose after the first dose of double-blind medication. At endpoint, adjusted mean reductions from baseline sitting DBP were 8.4, 8.8, and 8.9 mm Hg in the moexipril 3.75-, 7.5-, and 15-mg groups, respectively, as compared with a reduction of 4.6 mm Hg in the placebo group (p = 0.003). The differences in systolic BP (SBP) reductions were statistically significant in favor of each of the moexipril groups over the placebo group at all trough time-points. Adjusted mean changes in sitting SBP were 10.9, 12.0, and 11.7 mm Hg, respectively, as compared with a reduction of 0.6 mm Hg in the placebo group (p < 0.001). Our results indicate that moexipril and HCTZ constitute a clinically valuable combination in treatment of patients with moderate to severe hypertension.

Adult↗
PubMed1991

Reduction in local cerebral blood flow induced by endothelin-1 applied topically to the middle cerebral artery in the rat.

The role of endothelin-1 (ET-1) in cerebral ischemic injury remains the subject of much debate. Vasoconstriction in large conduit vessels may not be associated with reductions in flow at the tissue level. We present two studies examining the effects on local cerebral blood flow of topical application of ET-1 to the surgically exposed middle cerebral artery (MCA) in adult male Sprague-Dawley rats. In the first series using 14C-iodoantipyrine autoradiography, 10 min following application of ET-1 (1 nmol) to the MCA, up to 80% reduction in blood flow in the territory of distribution of the MCA is seen (e.g., dorsolateral caudate nucleus--flow reduced from 131 +/- 3 ml/100 g/min to 29 +/- 25 ml/100 g/min). These levels of flow are comparable with those seen with permanent bipolar diathermy occlusion and division of the proximal MCA--a standard rat model of focal cerebral ischemia. In a second series using hydrogen clearance technique for measurement of local cerebral blood flow in the caudate nucleus, we have shown that flow ipsilateral to application of ET-1 (0.25 nmol) is significantly reduced compared with saline controls for 80 min. Such reduction of flow, at the tissue level, sustained over this duration is consistent with the induction of ischemic cell damage by ET-1.

Administration, Topical↗
PubMed1990

Reduction of local cerebral blood flow to pathological levels by endothelin-1 applied to the middle cerebral artery in the rat.

Endothelin-1 (1 nmol) was applied to the exposed left middle cerebral artery (MCA) in anaesthetised adult male Sprague-Dawley rats. Local cerebral blood flow (1CBF), using [14C]iodoantipyrine and quantitative autoradiography, was measured in 27 anatomically defined structures, 10 min after topical application of endothelin-1. In those areas supplied by the MCA, 1CBF was markedly reduced beyond the threshold for ischaemic damage (e.g. dorsolateral caudate nucleus reduced from 131 +/- 3 to 29 +/- 25 ml.100 g-1.min-1, sensorimotor cortex from 109 +/- 5 to 31 +/- 21 ml.100 g-1.min-1). Distant areas were not affected.

Animals↗
PubMed1990

In search of the perfect assessment.

Assessment tools are essential in planning individual care for people with learning difficulties, but nurses often lack confidence in using them. This article looks at why this is, and discusses 10 commonly used tools.

Child↗
PubMed1989

Comparison of one dose cefazolin versus one dose cefotetan for cesarean section prophylaxis.

During one year, 646 women who delivered by cesarean section entered into a prospective randomized clinical trial to determine if a single intraoperative dose of cefazolin was as effective as cefotetan in the prevention of postoperative endomyometritis. Of 336 patients receiving 2 gm cefazolin intravenously at the time of clamping of the cord, endomyometritis developed in 30 (8.91%), and of 310 patients who received 2 gm cefotetan intravenously at the time of clamping of the cord, endomyometritis developed in 36 (11.6%). There was no statistically significant difference in the incidence of endomyometritis between the two groups (p = .269). We conclude that since the two drugs are equal in efficacy 2 gm of cefazolin is a cost effective method of prophylaxis for cesarean section.

Adolescent↗
PubMed1984

A follow-up of a randomized study comparing two chemotherapy treatments for advanced diffuse histiocytic lymphoma.

In 1976 we began a randomized study for the treatment of patients with stage III and IV diffuse histiocytic lymphoma. The therapy was either ACOMLA (doxorubicin, cyclophosphamide, vincristine [oncovin], methotrexate with leucovorin rescue, and cytarabine) or CHOP-B (cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [oncovin], prednisone, and bleomycin). A complete response (CR) was achieved in 13 (65%) of 20 patients treated with ACOMLA and in 20 (71%) of the 28 patients treated with CHOP-B. Four patients achieving CR with ACOMLA and three patients treated with CHOP-B have relapsed for an overall relapse rate of 21%. Partial response (PR) was obtained in four patients treated with ACOMLA and five patients treated with CHOP-B. Median follow-up time is 36 months for the combined treatment groups. Multiple regression analysis demonstrated that those patients who were classified by the Lukes-Collins criteria as having histiocytic lymphoma not of follicular center-cell origin (combined T- and B-cell immunoblastic sarcoma) had a significantly worse survival as compared to patients classified with follicular center-cell origin lymphoma (large cell noncleaved, large cell cleaved, and large cell unclassified) with a 40% five-year survival versus an 80% five-year survival (P = .011). The CR rate however for these two large categories of patients was 63% v 73% respectively, and the relapse rates were equivalent. The increased survival in the follicular center-cell origin lymphomas may be related to a longer survival of PRs and relapsed patients as compared to the patients with nonfollicular center-cell lymphomas.

Adolescent↗
PubMed1983

Survival of women with metastatic breast cancer at Yale from 1920 to 1980.

The tumor registry at Yale--New Haven Hospital, which began recording data in 1920, was utilized to examine the ultimate outcome of all breast cancer patients who were initially diagnosed at Yale with metastatic breast cancer. Of the 5,898 patients with breast cancer seen from 1920 to 1980, 574 initially had metastatic cancer. The median survival of these patients increased steadily from 21 months in 1920 to 41 months in the decade from 1970 to 1980. The percentage of women actually surviving 5 years increased from 5% in the 1920s to approximately 25% in the 1960s. Despite the use of combination drug programs in the 1970s, the percentage of these patients remaining alive at 5 years remained near 25%. Firm conclusions cannot be made from a retrospective study spanning 60 years, although the trends depicted and lack of continued improvement indicate that our current therapeutic approach to metastatic breast cancer may not result in dramatic improvement in overall survival.

Breast Neoplasms↗