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Biomedical subjects

S Madajewicz

Publications and source records attributed to S Madajewicz.

At least 37 records · Page 2Linked to original sources
PubMed1988

Phase I clinical trial and human pharmacokinetics of 2,4-diamino-5-adamantyl-6-methyl pyrimidine ethane sulfonate (DAMP-ES): a lipid-soluble antifolate.

A phase I and pharmacokinetic study of a novel lipid-soluble antifolate, 2,4 diamino-5-adamantyl-6-methyl pyrimidine ethane sulfonate (DAMP-ES) has been carried out on two schedules: I--daily x5; II--24-h continuous infusion. In schedule I, doses of 10-90 mg/m2 per day were evaluated. Dose-limiting toxicity was hematologic, but nausea and vomiting, skin rash, diarrhea, anorexia, alopecia, mucositis, and neurotoxicity were also noted. In schedule II, doses of 192 and 240 mg/m2 were evaluated. Dose-limiting toxicity was neurotoxicity, but hematologic toxicity was also marked. Recommended starting doses for phase II studies are 75 mg/m2 per day for 5 days or 192 mg/m2 by continuous infusion for 24 h. Pharmacokinetic studies indicated a beta-phase plasma half-life of 12.4-24 h and a large and variable volume of distribution.

Adamantane↗
PubMed1987

Phase I clinical trial of ethyl 6-deoxy-3,5-di-O-methyl 6-(3 methyl-3-nitrosoureido)-alpha-D-glucofuranoside (CGP 6809).

A phase I study of single i.v. doses of a new sugar containing nitrosourea 6-deoxy-3,5 di-O-methyl 6-(3 methyl-3-nitrosoureido)-alpha-D-glucofuranoside (CGP 6809, EDMN) has been carried out in 47 patients with advanced solid tumors. Nine dose levels between 200 and 4500 mg/m2 were examined. Nausea and vomiting were seen in most patients but were controlled with antiemetics. Myelosuppression was minimal. The dose-limiting toxicity was hepatotoxicity, occurring early (peak at days 2-4) and resolving rapidly. No cumulative toxicity was seen with an every 6 weeks schedule. Other toxicities were abdominal pain, diarrhea, arm pain, restlessness, and headache. Pharmacokinetic studies in 20 patients using an HPLC assay and in 5 patients using [14C]EDMN showed a short half-life, rapid plasma clearance, rapid metabolism, and minimal excretion of unchanged drug. There was one partial response in a patient with colon carcinoma. The recommended dose for phase II studies in 3750 mg/m2 every 6 weeks.

Adult↗
PubMed1987

Phase I clinical trial of 1-(2-[2-(4-pyridyl)-2-imidazoline-1-yl]-ethyl)-3-(4-carboxy-phenyl) urea (CGP 15720A).

A phase I clinical trial of the intravenous administration of a novel pyridyl imidazoline ethyl carboxy phenyl urea was carried out in 42 patients with advanced solid tumors. Five schedules were evaluated: I, daily X 5; II, daily X 10; III, daily X 15; IV, continuous infusion for 5 days; V, continuous infusion for 7 days. Toxicity was not seen in schedule I (maximum dose 3 g/m2/day) and was minimal in schedule IV (6 g/m2/day). In schedule II it was seen at 2 and 3 g/m2/day, in schedule III at 2 g/m2/day and in schedule V at 6 g/m2/day. Dose-limiting toxicity consisted of a syndrome of lethargy and fatigue. There were no definitely drug-related changes in hematologic or serum chemistry parameters. No responses were seen, but relief of pain in three patients with prostate cancer was noted. Pharmacokinetics indicate a short half-life, limited volume of distribution, and rapid renal clearance. The recommended dose for phase II studies is 3 g/m2/day X 10 or 2 g/m2/day X 15 days.

Adult↗
PubMed1987

Biologic modulation of 5-fluorouracil with high-dose leucovorin and combination chemotherapy of 5-fluorouracil and cisplatin in metastatic colorectal adenocarcinoma.

The data from an ongoing 3-arm prospective study of 72 patients with advanced colorectal carcinoma is presented. The 3 regimens are as follows: Regime 1 (every 4 weeks)--5-fluorouracil (FUra) (450 mg/m2 iv bolus daily for 5 days, then 200 mg/m2 iv bolus every other day for 6 doses); regime 2 (every week for 4 weeks, then every other week)--methotrexate (MTX) (50 mg/m2 in a 4-hour infusion) followed by FUra (600 mg/m2 iv bolus); regime 3 (weekly for 6 weeks followed by a 2-week rest period)--D,L-leucovorin (D,L-CF) (500 mg/m2 in a 2-hour infusion) with FUra (600 mg/m2 iv bolus) 1 hour after the D,L-CF infusion began. All monitoring lesions except lung were documented by tissue biopsy. Thirteen of 18 patients in the FUra + D,L-CF arm were evaluable for response. Six of the 13 patients (46%) have had a partial response. The duration of the 6 responses has been 11, 8, 7, 4, 3 and 3 months. In patients with liver metastases as the monitoring lesion, a dramatic improvement in liver function tests has been seen during the first 2 courses (12 weeks) of treatment, but this was not sustained. The toxicity of FUra + D,L-CF was predominantly gastrointestinal; unlike with FUra alone, myelosuppression was not predominant.

Adenocarcinoma↗
PubMed1986

Clinical development of iproplatin (CHIP).

The clinical development of the second generation platinum complex iproplatin (CHIP) is reviewed. The compound was virtually non-nephrotoxic in preclinical toxicology studies and had myelosuppression as its dose-limiting toxicity in rats and dogs. A phase I study of 20-350 mg/m2 given every 3-4 weeks showed the compound to have myelosuppression as its dose-limiting toxicity in humans, with thrombocytopenia being the most prominent feature. Nausea and vomiting were almost universal, but were less severe than with cisplatin. Diarrhoea and skin rash were also noted but nephrotoxicity, neurotoxicity and ototoxicity were not seen. The maximum tolerated dose was 350 mg/m2, with or without pretreatment hydration. In pharmacokinetic studies three platinum-containing species were measured: total Pt, non-protein bound Pt and unchanged iproplatin. Plasma decay of total Pt was biphasic with a beta-phase half-life of 69.3 h. Plasma decay of unchanged iproplatin was monophasic with a half-life of about 1.17 h. Plasma decay of filterable Pt followed a monophasic pattern at low doses and a biphasic pattern at high doses. Urinary excretion of Pt was widely variable and incomplete. Early data from phase II studies indicate a high degree of activity in small-cell lung cancer; high activity in ovarian carcinoma has been reported by others.

Antineoplastic Agents↗
PubMed1985

Human pharmacokinetics of 1-[2-[2-(4 pyridyl)-2-imidazolinyl-(1)]-ethyl]-3-(4-carboxyphenyl) urea (CGP 15720A).

Pharmacokinetics of CGP 15720A have been studied in patients receiving this drug in a short I.V. infusion during its phase I clinical trial. Plasma decay was biphasic with a mean t1/2 beta of 4.9 +/- 2.47h. The drug was cleared rapidly from plasma (7.02 +/- 5.95 L/h). Renal clearance (4.13 +/- 1.65 L/h) appears to be the major clearance pathway. The steady state volumes of distribution of the drug indicate limited tissue distribution for the drug. Studies with plasma and urine of patients receiving 14[C] GCP 15720A indicate that the drug is not metabolized. CGP 15720A could be measured in cerebrospinal fluid.

Aged↗
PubMed1985

Evaluation of the nephrotoxicity of iproplatin (CHIP) in comparison to cisplatin by the measurement of urinary enzymes.

Levels of three enzymes, leucine aminopeptidase (LAP), N-acetyl-beta-D-glucosaminidase (NAG), and beta-glucuronidase (BGA) were measured in the urine of patients receiving hematologically toxic doses of iproplatin (a) with or (b) without pretreatment hydration. The maximum post-treatment increases in the levels of each of the enzymes were compared between these two groups of patients. In addition, the maximum increases in urinary enzyme levels in iproplatin-treated patients were compared with those in patients treated with 40 mg/m2 cisplatin, a known nephrotoxic agent. Increases in LAP levels after cisplatin treatment in the periods studied are significantly higher than those after iproplatin treatment (P less than 0.05). No differences were found in the increases in BGA and NAG levels between iproplatin treatment and cisplatin treatment. No differences were found in the increases in levels of any of the enzymes between patients receiving iproplatin with pretreatment hydration and no prior hydration.

Acetylglucosaminidase↗
PubMed1985

Phase-I clinical trial of sodium cyanate in patients with advanced colorectal carcinoma.

Sodium cyanate, a drug that selectively suppresses amino acid incorporation for protein synthesis in tumor tissue, was given to patients with advanced colorectal carcinoma who had failed to conventional therapy, with the purpose of assessing a maximum tolerable oral dose. At 35 mg/kg p.o. daily, the drug had to be stopped in approximately half (4) of the patients because of gastrointestinal toxicity (nausea, vomiting) and neurologic toxicity (hallucinations, disorientation). However, in 5 other patients, at the same dose, the drug was well tolerated for up to 147 days and for a total cumulative dose of 308 g. In this group of patients, sodium cyanate was stopped because of evidence of tumor progression. No hematologic toxicity was observed. We observed no therapeutic effects. We therefore recommend a starting dose of 30 mg/kg p.o. if a phase-II study is considered.

Adult↗
PubMed1985

Effect of renal function impairment of iproplatin pharmacokinetics and relation to toxicity.

The pharmacokinetics of iproplatin, a quadrivalent second-generation platinum complex the dose-limiting toxicity of which is myelosuppression, was studied in patients with different degrees of renal function impairment. The drug was administered in a 30-min i.v. infusion. The plasma decay of iproplatin was biphasic, with an overall median terminal phase half-life of 3.16 +/- 2.6 (SD) h. The overall mean volume of distribution (Vss) was 39.9 +/- 25.0 liters, with a total body clearance of 14.25 +/- 3.99 liters/h. The total body clearance of iproplatin showed a linear correlation, with renal function measured as creatinine clearance. The toxicity of the drug, expressed as percentage of reduction in platelet count, correlated linearly with the area under the concentration X time curve.

Antineoplastic Agents↗
PubMed1984

Malignant melanoma brain metastases. Review of Roswell Park Memorial Institute experience.

One-hundred twenty five of 700 patients with malignant melanoma treated at Roswell Park Memorial Institute from 1972 to 1978 were found to have brain metastases. Seventy-three percent of the patients had multiple brain metastases. Male to female ratio was 1.9:1. The median survival of the untreated group of patients was 3 weeks as compared with that of 6 weeks for the patients maintained on steroids only, 9 weeks for those who received radiotherapy, 11 weeks for the patients treated with intraarterial chemotherapy, and 26 weeks for the patients who underwent successful surgical excision of a solitary lesion.

Autopsy↗
PubMed1984

New potential treatment modalities for disseminated prostatic cancer.

The authors consider treatments that are applicable to disseminated prostatic cancer. Several types of potential developments in systemic therapy for prostatic cancer are considered: new hormonal agents, new cytotoxic agents, modulation of the antitumor efficacy or toxicity or both of standard agents, biologic response modifiers, drug delivery systems, and systems for prediction of response.

Androgen Antagonists↗
PubMed1984

Phase I-II trial of high-dose calcium leucovorin and 5-fluorouracil in advanced colorectal cancer.

Twenty-six patients with metastatic colorectal adenocarcinoma were entered into a Phase I-II study of 5-fluorouracil (5-FUra)-high-dose leucovorin (CF). The starting dose of 5-FUra was 300 mg/sq m with escalation to 750 mg/sq m/week in 6 doses given by rapid i.v. injection midway during a 2-hr infusion of CF, 500 mg/sq m. Partial responses were seen in 9 of 23 patients (6 of 12 who had had previous 5-FUra). Complete normalization of liver enzymes was seen in two of these patients. Side effects were seen sporadically with 5-FUra doses up to 600 mg/sq m. At a 600-mg/sq m 5-FUra dose, 8 of 18 patients had diarrhea, and 2 of 18 had white blood cell counts less than 3000/microliter. At a 750-mg/sq m dose of 5-FUra, 6 of 11 patients had severe diarrhea and 6 of 11 had white blood cell counts less than 3000/microliter. Other toxicities were mild conjunctivitis and lacrimation, thinning of the nails, and alopecia. In bioavailability studies of CF p.o., no plasma CF could be detected. After CF i.v., mean plasma peak was 111.3 +/- 40.3 (S.D.) microM. 5-FUra-CF appears to be effective in patients clinically resistant to 5-FUra. This study is being extended to randomized trial of 5-FUra-CF versus 5-FUra alone.

Adult↗
PubMed1983

Pharmacokinetics of cis-dichloro-trans-dihydroxy-bis-isopropylamine platinum IV (CHIP) in patients with advanced cancer.

The pharmacokinetics of a second-generation platinum (Pt) analog cis-dichloro-trans-dihydroxy-bis-isopropylamine platinum IV (CHIP) have been studied in 12 patients at doses from 20 to 350 mg/m2. Three Pt species have been measured: total Pt and non-protein-bound Pt by atomic absorption spectrophotometry, and unchanged CHIP by separation on high-performance liquid chromatography followed by atomic absorption spectrophotometry. Plasma decay of total Pt was biexponential at all doses with a beta-phase half-life of 32.1-124 h. Plasma decay of filterable Pt was monoexponential at low doses but biexponential at high doses, with a terminal-phase half-life of 17.8-54.6 h. Plasma decay of unchanged CHIP was monoexponential at all doses, with a half-life of 0.64-1.27 h. Excretion of Pt after CHIP was rapid up to 10 h after the end of infusion and then slow. The total recovery of Pt was 15%-61% of the dose at 24 h in 19 patients. The data indicated that essentially all plasma Pt after 12 h is in the form of metabolites, most of which are protein-bound. The most striking difference between CHIP and reported data for cisplatin is the biexponential decay of non-protein-bound Pt.

Antineoplastic Agents↗
PubMed1983

Phase I clinical trial of cis-dichloro-trans-dihydroxy-bis-isopropylamine platinum(IV) (CHIP).

cis-Dichloro-trans-dihydroxy-bis-isopropylamine platinum(IV) (CHIP), a second-generation platinum complex with little or no nephrotoxicity in preclinical studies, has undergone phase I clinical testing and initial pharmacokinetic evaluation in 26 patients with solid tumors who received 40 courses of treatment. Doses of 20-350 mg/m2 were evaluated as single 2-hr infusions given every 3 weeks for two doses, with 2 L of pretreatment hydration (but no diuretics) in all but five patients. Nausea and vomiting was almost universal but was severe in only three courses. The dose-limiting toxic effect was myelosuppression, with a median wbc count nadir of 2500/mm3 and a median platelet count nadir of 32,000/mm3 at the maximum tolerated dose of 350 mg/m2. No increase in serum creatinine or decrease in creatinine clearance was seen. No pretreatment hydration was given in five of the seven patients treated at 350 mg/m2. Two cases of hypersensitivity were seen. No hearing loss was observed and no other toxic effects were noted. Plasma decay of total platinum was biexponential with a prolonged beta phase. Recovery of platinum in the urine was rapid up to 8-10 hrs and slow thereafter. Recoveries were incomplete and variable (16.5%-62% of the dose at 48 hrs).

Adult↗