Biomedical subjects

M A Rudek

Publications and source records attributed to M A Rudek.

7 recordsLinked to original sources

PubMed2004

Factors affecting pharmacokinetic variability following doxorubicin and docetaxel-based therapy.

Current dosing strategies for anticancer drugs result in wide interindividual pharmacokinetic variability. Here, we explored the influence of age, body size, concomitant drugs, dose, infusion duration, and sex on the clearance for doxorubicin and docetaxel in 243 individual patients. Patients received doxorubicin (n=110) or docetaxel (n=152) as monotherapy or in combination chemotherapy regimens. The mean (+/-S.D.) clearance was 63.6+/-22.7 L/h for doxorubicin and 42.8+/-14.9 L/h for docetaxel. Normalisation for body surface area (BSA) reduced the interindividual variability by only <1.7%. Doxorubicin clearance was significantly reduced when administered at doses >50 mg/m(2) or in combination with cyclophosphamide. Upper extremes of body size were associated with increased clearance for both drugs, whereas no consistent effect of age on clearance was discerned. Overall, these findings suggest that incorporation of variables in addition to BSA should be considered in routine dosing strategies for doxorubicin and docetaxel.

Adult↗

PubMed2001

Phase I clinical trial of oral COL-3, a matrix metalloproteinase inhibitor, in patients with refractory metastatic cancer.

PURPOSE: This phase I clinical trial was designed to determine the maximum-tolerated dose and dose-limiting toxicities of the matrix metalloproteinase (MMP) inhibitor COL-3 in patients with refractory solid tumors. PATIENTS AND METHODS: Thirty-five patients with different cancer types were enrolled. COL-3 doses were escalated from 36 mg/m2/d in successive cohorts of at least three patients. Circulating levels of MMP-2, MMP-9, vascular endothelial growth factor, and basic fibroblast growth factor were assessed during treatment. Pharmacokinetic parameters were assessed for single and multiple doses of drug. RESULTS: Cutaneous phototoxicity was dose-limiting at 98 mg/m2/d. With the use of prophylactic sunblock, COL-3 was well tolerated at 70 mg/m2/d. The dose of 36 mg/m2/d was well tolerated without the use of sunblock. Other toxicities that did not seem to be related to dose or pharmacokinetics included anemia, anorexia, constipation, dizziness, elevated liver function test results, fever, headache, heartburn, nausea, vomiting, peripheral and central neurotoxicities, fatigue, and three cases of drug-induced lupus. Disease stabilization for periods of 26+ months, 8 months, and 6 months were seen in hemangioendothelioma, Sertoli-Leydig cell tumor, and fibrosarcoma, respectively. There was a potentially statistically significant relationship between changes in plasma MMP-2 levels and cumulative doses of drug when progressive disease patients were compared with those with stable disease or toxicity (P = .042). CONCLUSION: COL-3 induced disease stabilization in several patients who had a nonepithelial type of malignancy. Phototoxicity was dose-limiting. We recommend the dose of 36 mg/m2/d for phase II trials.

Adult↗

PubMed2001

Reversible sideroblastic anemia associated with the tetracycline analogue COL-3.

Eight of 35 patients with cancer receiving COL-3, a tetracycline derivative with antiangiogenic properties, developed anemia while on treatment. All of these patients were enrolled on an approved Phase I clinical trial at the National Cancer Institute. Three of these patients had bone marrow examinations that revealed ringed sideroblasts. This paper describes these cases. Am. J. Hematol. 67:51-53, 2001. Published 2001 Wiley-Liss, Inc.

Adenocarcinoma, Follicular↗

PubMed2001

Drug-induced lupus associated with COL-3: report of 3 cases.

BACKGROUND: Anti-angiogenesis is an exciting new approach to anticancer therapy. COL-3, a tetracycline derivative, is a novel anti-angiogenesis agent with potent preclinical anticancer activity. During the conduct of a phase 1 clinical trial for refractory metastatic cancer at the National Institutes of Health, we observed 3 individuals who developed phototoxicity followed by clinical and laboratory features of drug-induced lupus. OBSERVATIONS: Three of 35 patients treated with COL-3 developed sunburnlike eruptions accompanied by fever and a positive antinuclear antibody titer within 8 to 29 days of starting treatment. Two of 3 had positive antihistone antibody levels and arthralgia. One patient had marked systemic manifestations including pulmonary infiltrates and elevated erythrocyte sedimentation rate remittent for more than 1 year after discontinuing COL-3 treatment. The other 2 patients' symptoms and rash abated within 2 weeks of discontinuing therapy although the serologic markers remained abnormal for the duration of follow-up. CONCLUSIONS: COL-3 is the second tetracycline derivative to be implicated in the development of drug-induced lupus. A sunburnlike eruption immediately preceded or accompanied the systemic and serologic changes in these 3 patients. The rapid onset and the phototoxic appearance of the accompanying eruptions might suggest that damage to the keratinocytes caused the formation of neoantigens to which autoantibodies formed.

Administration, Topical↗

PubMed2000

Endostatin inhibits microvessel formation in the ex vivo rat aortic ring angiogenesis assay.

Endostatin has demonstrated potent antiangiogenic and antitumor activity in mouse models. We have investigated the ex vivo rat aortic ring assay and a human vein model to assess the biological activity of murine and human endostatin. Rat aortic rings were exposed to recombinant murine endostatin (Spodoptera frugipera; Calbiochem, San Diego, CA) or recombinant human endostatin (Pichia pastoris; EntreMed, Rockville, MD). After 5 days, murine endostatin (500 microgram/ml) demonstrated inhibition of microvessel outgrowth with dose-dependent effects (down to 16 microgram/ml). No significant inhibition was observed with human endostatin in the rat assay. Human endostatin at 250 and 500 microgram/ml inhibited outgrowths from human saphenous vein rings after a 14-day incubation. Electron microscopy assessed the formation of basal lamina, confirming that the microvessels were progenitors of patent vessels. Immunostaining for Factor VIII or CD34 demonstrated that the microvessel cells were endothelial. BrdU incorporation assays supported the presence of proliferating endothelial cells, correlating with neovascularization from the aortic wall. We conclude that the rat aortic ring assay confirms the antiangiogenic activity of murine but not human endostatin, suggesting that the model may have species specificity. However, the human form shows biological activity against human vascular tissue.

Angiogenesis Inhibitors↗

PubMed2000

A high-performance liquid chromatography method using ultraviolet and fluorescence detection for the quantitation of UCN-01, 7-hydroxystaurosporine, from human plasma and saliva.

UCN-01, 7-hydroxystaurosporine, is an antagonist of protein kinase C, as well as causing cell cycle arrest. We developed and validated an HPLC assay method for the quantitation of UCN-01. Plasma and saliva standard curves were prepared at concentrations ranging from 0.2 to 20.0 microgram/mL and 4.0 to 200.0 ng/mL, respectively. The sample preparation consisted of acetonitrile precipitation. Separation was accomplished on a phenyl column and a C-18 precolumn insert utilizing a gradient-profile consisting of ammonium acetate and acetonitrile. UV detection was set at 295 nm for UCN-01 and 323 nm for umbelliferone, the internal standard. For fluorescence detection, excitation occurred at 290 nm, while emission was at 400 nm. The retention times were around 4 min for umbelliferone and 9.1 for UCN-01. Inter- and intra-assay errors of accuracy were less than 7. 0% and 10.7%, respectively, for the plasma standard curve and less than 7.1% and 6.7%, respectively, for the saliva standard curve. The recoveries of UCN-01 and umbelliferone from saliva were 81.4 +/- 0. 9% and 106.3 +/- 10.2%, respectively. The recovery of UCN-01 from plasma was 97.9 +/- 7.1% and for umbelliferone was 103.3 +/- 2.3%. This method is suitable for quantifying UCN-01 in patient samples and further characterizing the clinical pharmacology of this compound. Published in 2000 by John Wiley & Sons, Ltd.

Alkaloids↗

PubMed2000

High-performance liquid chromatography with mass spectrometry detection for quantitating COL-3, a chemically modified tetracycline, in human plasma.

COL-3, 6-deoxy-6-demethyl-4-dedimethylamino-tetracycline, is a matrix metalloproteinase inhibitor. A specific and sensitive analytical method was necessary to quantitate the analyte in human plasma. High-performance liquid chromatography with atmospheric pressure chemical ionization mass spectrometry detection was utilized to quantitate COL-3 from 30 to 10,000 ng/ml in two calibration curves: 30-1,500 and 400-10,000 ng/ml. The sample preparation consisted of acetonitrile precipitation for all plasma samples. COL-3 is separated on a Waters Symmetry C-18 (2.1 x 150 mm) column with oxalic acid (0.01 M, pH 2.2)-acetonitrile mobile phase. The total run time was 23 min. Identification of COL-3 and the internal standard was through positive chemical ionization and selective ion monitoring. A quantifying and qualifying ion for COL-3 is used to verify the presence of COL-3 in patient samples. Inter- and intra-run mean percent errors for all of the quality controls were less than 18.3', and relative standard deviations were all less than 14.9'% Recovery of COL-3 and the internal standard was approximately 55 and 72', respectively. Freeze thaw stability of COL-3 was variable. This method is suitable for quantifying COL-3 in patient samples and to further characterize the clinical pharmacology of this compound.

Antibiotics, Antineoplastic↗