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Biomedical subjects

G Schwartsmann

Publications and source records attributed to G Schwartsmann.

At least 55 records · Page 3Linked to original sources
PubMed1997

Postangioplasty restenosis: a practical model in the porcine carotid artery.

Transluminal coronary angioplasty is a routine therapeutic intervention in coronary heart disease. Despite the high rate of primary success, restenosis continues to be its major limitation. Porcine models have been considered to be the most adequate experimental models for studying restenosis. One limitation of porcine models is the need for radiological guidance and the expenses involved. The objective of the present study was to adapt an experimental model of angioplasty in the porcine carotid artery that does not require radiological equipment. Eight animals were used to develop the technique of balloon injury to the common carotid artery by dissection without radiological guidance. This technique was then employed in six other animals. Under anesthesia, the left common carotid artery was dissected and incised at the carotid sinus for insertion of an over-the-wire angioplasty balloon towards the aorta. Overstretch injury of the carotid artery was performed under direct visualization. After 30 days, the arteries were excised and pressure-fixated. Uninjured carotid arteries from 3 additional animals were used as controls. A decreased luminal area associated with intimal hyperplasia and medial reaction was observed in all injured arteries. Immunohistochemistry identified the intimal hyperplastic cells as smooth muscle cells. Computerized morphometry of the ballooned segments revealed the following mean areas: lumen 2.12 mm2 (+/- 1.09), intima 0.22 mm2 (+/- 0.08), media 3.47 mm2 (+/- 0.67), and adventitia 1.11 mm2 (+/- 0.34). Our experimental model of porcine carotid angioplasty without radiological guidance induced a vascular wall reaction and permitted the quantification of this response. This porcine model may facilitate the study of vascular injury and its response to pharmacological interventions.

Angioplasty↗
PubMed1997

Decitabine (5-Aza-2'-deoxycytidine; DAC) plus daunorubicin as a first line treatment in patients with acute myeloid leukemia: preliminary observations.

The authors report on the preliminary results of an ongoing phase II trial whereby the combination of the new DNA hypomethylating agent, 5-Aza-deoxycytidine (DAC), plus daunorubicin was given as first-line induction therapy to non-pretreated patients with acute myeloid leukemia (except FAB M3). DAC was given as a 4-h intravenous infusion at the dose of 90 mg/m2 daily from days 1-5, while daunorubicin was administered at the dose of 50 mg/m2 on days 1-3. A maximum of two courses were given to the patients with an interval of 4-6 weeks. Up to now, eight patients were accrued, of those six were evaluable for toxicity and response. The main toxic effects were bone marrow suppression, mucositis, nausea and vomiting, and alopecia. All six patients achieved a complete remission after one (five cases) or two (one case) courses. The trial is open for patient accrual.

Adult↗
PubMed1997

A phase II study of doxorubicin/paclitaxel plus G-CSF for metastatic breast cancer.

This phase II trial was conducted to evaluate the percentage of objective responses and the toxicity profile of combination doxorubicin (Adriamycin) and paclitaxel (Taxol) with granulocyte colony-stimulating factor as first-line therapy for patients with metastatic breast cancer (MBC) not previously exposed to anthracycline-containing regimens. Patients with measurable, visceral-dominant MBC and a performance status of 0 to 2 were included in the study. Doxorubicin 60 mg/m2 was administered as a short intravenous infusion, followed by paclitaxel 250 mg/m2 as a 3-hour intravenous infusion on day 1. Granulocyte colony-stimulating factor 5 micrograms/kg/d was given prophylactically as a subcutaneous injection from day 2 until granulocyte recovery to > or = 1,500/mm3. Treatment was repeated every 21 days for a maximum of six courses. Dose reductions (to doxorubicin 50 mg/m2 and paclitaxel 175 mg/m2) and/or treatment delay were applied in case of severe toxicity. All 25 women who entered were evaluable for response and toxicity. The main grade 3/4 toxicities observed were leukopenia, thrombocytopenia, and mucositis. Alopecia occurred in all patients. No clinically relevant cardiovascular toxicity was observed. Severe myelosuppression and/or mucositis necessitated dose reductions at courses 2 or 3 in all but one patient. The complete response rate was 28%, and the partial response rate was 52% for an overall objective response rate of 80%. Median progression-free survival for complete responders was 11 months (range, 3 to 24 months), while the progression-free survival was 7+ months (range 2 to 14+ months) for partial responders and 5 months (range, 3 to 9 months) for nonresponders. This combination produces a high objective response rate in women with MBC, but dose reductions were necessary in almost all cases. Toxicity was manageable after dose reduction, allowing patients to be re-treated for two to six courses without life-threatening toxicity or toxic deaths. Unfortunately, the duration of response was limited even among complete responders. Further trials of this combination in patients with MBC should explore improvements in this study regimen.

Adult↗
PubMed1994

Malignant melanoma.

Explore the source record for details and available documents.

Antibodies, Monoclonal↗
PubMed1992

Phase I and pharmacokinetic study of rhizoxin.

Rhizoxin is a tubulin-binding cytotoxic compound, isolated from the fungus Rhizopus chinensis, with significant antineoplastic activity in several murine and human tumor models. In this Phase I study, the drug was administered by i.v. bolus injection at 3-wk intervals. Twenty-four patients with refractory solid tumors were treated; 60 courses of rhizoxin were given, at doses ranging from 0.8 to 2.6 mg/m2. Grade 3 mucositis, Grade 4 leukopenia, and Grade 3 diarrhea were dose limiting but reversible at 2.6 mg/m2, the maximum tolerated dose for both previously untreated and heavily pretreated patients. Alopecia and moderate discomfort at the injection site occurred at all doses. Other sequelae, including peripheral neuropathy, phlebitis, and nausea and vomiting, were sporadic and mild. Two heavily pretreated patients with recurrent breast cancer had minor responses to rhizoxin, one at 1.6 mg/m2 and the other at 2.6 mg/m2. Plasma concentrations of rhizoxin were measured by high-performance liquid chromatography. The drug was not detectable (less than 5 ng/ml) at doses of 0.8 mg/m2 and 1.6 mg/m2 and was not measurable 10 min after injection at 2.0 mg/m2. At 2.6 mg/m2, there was considerable intersubject variation in the plasma concentration-time profiles; the area under the curve ranged from 0.29 to 0.96 microgram/ml.min. Rhizoxin has shown some clinical activity in this Phase I study, and a dose of 2.0 mg/m2 is recommended for Phase II studies using this schedule.

Adult↗
PubMed1992

Comparative antitumour activity of vinblastine-isoleucinate and related vinca alkaloids in human tumour xenografts.

The antitumour activity of the investigational agent vinblastine-isoleucinate (V-LEU) was compared with vintriptol, another investigational agent of the same series of vinblastine-23-oyl amino acid derivatives, and vinblastine, their clinically active parent compound, in a panel of nine human tumour xenografts growing subcutaneously in nude mice. Compounds were administered intravenously at equitoxic doses twice weekly. As assessed by optimal tumour growth inhibition and tumour growth delay, vinblastine, V-LEU and vintriptol exhibited antitumour activity in 8/9, 7/9 and 4/7 human tumour xenografts, respectively. When growth curves and numbers of complete remissions were compared, V-LEU was the most active agent in two malignant melanoma lines (THXO and LOX p28) and two small cell lung carcinoma lines tested (LXFS 538 and WX 322), whereas vinblastine was more active against the two colorectal carcinomas (CXF 243 and CXF 280). Notably, the non small cell lung carcinoma (NSCLC) line AHXOL was resistant to the three agents. The results of this study suggest that V-LEU was as active as vinblastine in most tumour lines, exhibiting superior antitumour activity in malignant melanoma, SCLC and breast cancer lines. The decision to bring this compound into clinical trial shall await further confirmation of these preclinical results and the evaluation of its toxicity profile in relation to other vinca alkaloids.

Animals↗
PubMed1992

Preclinical antitumour activity and animal toxicology studies of rhizoxin, a novel tubulin-interacting agent.

Rhizoxin is a 16-membered antifungal macrocyclic lactone isolated from the plant pathogenic fungus Rhizopus chinensis. The compound binds to tubulin, preventing microtubule formation, and inhibiting mitosis. It possesses antitumour activity in vivo against various preclinical murine models, both leukaemias and solid tumours model, as well as in vincristine- and doxorubicin-resistant leukaemia lines. In the present study, cytotoxic activity was observed in human tumour cell lines in vitro at very low concentrations (+/- 10(-10) M) particularly against melanoma, colon, renal, non-small cell and small cell lung cancer. In vivo antitumour activity was demonstrated in murine P388 and L1210 murine leukaemias, solid tumour models B16 melanoma and M5076 sarcoma, and in 5 out of 9 human solid tumour xenografts: LOX melanoma, MX-1 breast cancer, non-small cell lung cancer A549, and small cell lung cancers LXFS 605 and LXFS 650. The absence of cross-resistance to vinca alkaloids was confirmed in vivo against the vincristine-resistant P388 leukaemia subline and the vincristine-resistant human small cell lung cancer LXFS 650. In addition, the antitumour activity of rhizoxin was improved by prolonged or repeated drug administration indicating a schedule dependency. In animal toxicology studies, transient changes in erythrocyte and leukocyte numbers, local phlebitis, diarrhea, and spermatogenic arrest were observed. The LD10 value of rhizoxin after a single intravenous injection was 2.8 mg/kg (8.4 mg/m2). One-tenth of the mouse equivalent LD10 (0.84 mg/m2), the starting dose for clinical phase I studies, was considered to be safe in rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Laboratory and phase I studies of new cancer drugs.

New drug discovery continues to follow the time-honored paths of screening and novel target identification combined with analogue development and serendipity. The agents selected here reflect these various approaches. They include drugs already showing significant antitumor activity, eg, anthrapyrazoles, temozolomide, camptothecin analogues, and taxotere, and updated information is provided on their development. Other drugs just entering or currently in phase I trials include rhizoxin, which seems capable of overcoming multidrug resistance; the novel bioreductive agent EO9 [corrected]; and bryostatin, a highly potent protein kinase C agonist. Sequence specificity could well prove to be an important factor in the development of DNA-interactive agents, and information is provided on the progress with distamycin mustard and the new cyclopropylpyrroloindole analogues carzelesin and adozelesin.

Antineoplastic Agents↗
PubMed1991

Phase II study of teniposide in patients with AIDS-related Kaposi's sarcoma.

Antitumour activity of cytotoxic agents, evaluated in patients with AIDS-related Kaposi's sarcoma (KS), is about 30-80%. However, responses are mostly partial and short. Experience with etoposide is similar. Teniposide has a longer elimination half-life and superior antitumour activity compared with etoposide in some experimental models. Thus a phase II trial was done in 25 patients with AIDS-related KS. Teniposide was given by 60-min infusion at 360 mg/m2 every 3 weeks. 10 (40%) showed a partial response, median duration of 9 (6-20) weeks. The main side-effects were leukopenia, thrombocytopenia, nausea and vomiting, alopecia and mucositis.

Acquired Immunodeficiency Syndrome↗
PubMed1990

In vivo inhibition of the pyrimidine de novo enzyme dihydroorotic acid dehydrogenase by brequinar sodium (DUP-785; NSC 368390) in mice and patients.

Little is known about the in vivo effects of inhibition of the mitochondrial pyrimidine de novo synthesis enzyme dihydroorotic acid dehydrogenase (DHO-DH). In mice a new inhibitor of DHO-DH, Brequinar sodium (DUP-785, NSC 368390) depleted the plasma uridine concentration to 40% within 2 h, followed by a small rebound after 7-9 days. The drug was subsequently evaluated in a Phase I clinical trial, during which it was possible to follow its biochemical effects in 24 patients (27 courses). In addition to the measurement of plasma uridine concentrations, we also measured in lymphocytes of 9 patients (10 courses) the duration of DHO-DH inhibition. Brequinar sodium was administered every 3 weeks as an i.v. infusion at dose levels of 15-2250 mg/m2. The biochemical effects were studied following the first administration of the drug. In sonicated extracts of lymphocytes from 7 healthy volunteers the activity of DHO-DH varied from 2.0 to 3.9 nmol/h per 10(6) cells, while in the lymphocytes of 9 patients obtained immediately before treatment this value was between 0.5 and 4.8 nmol/h per 10(6) cells. Within 15 min of drug administration DHO-DH activity was not detectable and was still low up to 1 week later. Duration of the inhibition appeared to be related to the extent of clinical toxicity, e.g., myelosuppression, nausea, vomiting, diarrhea, and mucositis. Severe lymphopenia was observed in patients receiving Brequinar sodium at the maximum tolerated dose. At dose levels of greater than or equal to 600 mg/m2, uridine depletion (40-85%) was observed between 6 h and 4 days, followed by a rebound of 160-350% after 4-7 days. The extent of the depletion and of the accompanying rebound of uridine levels and the extent and duration of DHO-DH inhibition in the individual patients could be partially associated with drug toxicity in these patients. This is the first report describing biological effects of DHO-DH inhibition in humans in relation to the degree and duration of inhibition of this enzyme.

Animals↗