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Biomedical subjects

L Baltzer

Publications and source records attributed to L Baltzer.

24 records · Page 2Linked to original sources
PubMed1993

Midazolam in patients receiving anticancer chemotherapy and antiemetics.

Benzodiazepines lessen anxiety and improve comfort in cancer patients. Midazolam is an effective benzodiazepine with a rapid onset and short duration of action, properties that could permit its use in outpatient areas or in short but stressful situations. Two consecutive trials were undertaken to study midazolam as an adjunct in patients receiving anticancer chemotherapy. Each studied midazolam given as a short infusion 30 min prior to chemotherapy at dose levels ranging from 0.01 to 0.05 mg/kg. Trial I determined the safety, sedation, and dose of midazolam in patients receiving chemotherapy of low to moderate emetic potential. Twenty-two patients were entered. No significant respiratory depression or oxygen desaturation was observed. At the optimal dose level (0.04 mg/kg), sedation began a median of 3 min following administration and continued for a median of 38 min. Sixty-four percent of patients experienced mild sedation. Trial II studied the same doses of midazolam when used in combination with intravenous metoclopramide and dexamethasone in patients receiving cisplatin > or = 100 mg/m2. Nineteen patients were entered; 79% experienced mild sedation. At the 0.04-mg/kg dose level, sedation began a median of 18 min following administration and continued for a median of 170 min. Midazolam can be given safely to patients receiving chemotherapy with and without concomitant antiemetics. The predictability and duration of its sedative effects suggest it can be used in outpatients.

Adult↗
PubMed1991

Clinical pharmacology of deoxyspergualin in patients with advanced cancer.

Pharmacokinetic studies were carried out in 25 patients with advanced cancer receiving deoxyspergualin (DSG), a candidate anticancer agent, in a dose-finding Phase I study. The dosage range explored was 80 to 2160 mg/m2/day for 5 days by continuous i.v. infusion. The drug levels in plasma and urine were measured by high-performance liquid chromatography with postcolumn derivatization and fluorescence detection. One drug metabolite was demonstrated in plasma and urine of treated patients. This metabolite was extracted from urine and purified to homogeneity; thereafter, it was examined by high-performance liquid chromatography, nuclear magnetic resonance, and fragmentation mass spectrometry and was demonstrated to be identical to chemically synthesized desaminopropyl-DSG. The mean steady state plasma concentrations of DSG ranged from 0.28 to 11.1 microM at, respectively, the 80- and 2160-mg/m2 dosage levels. The plasma concentration at steady state and the area under the plasma concentration versus time curve of DSG were proportional to dose (r = 0.97). Following discontinuance of the infusion, DSG was cleared from the plasma in a biexponential fashion. The mean total body clearance was 364 +/- 78 ml/min/m2. Desaminopropyl-DSG was formed extensively at all dosage levels; mean steady state plasma levels of this metabolite reached a plateau 2.65 microM at a dose of 720 mg/m2/day and did not rise with further dose increments. The urinary content of DSG was examined in 20 patients over the dosage range from 160 to 960 mg/m2/day; in this group less than 10% of the administered dose was excreted as DSG. In four patients at the 720- and 960-mg/m2/day dosage levels, the total DSG plus metabolite excretion ranged from 7 to 18% of the administered dose, with comparable quantities occurring as the parent drug and desaminopropyl-DSG.

Animals↗
PubMed1990

Phase I clinical and pharmacological study of merbarone.

Merbarone, a nonsedating derivative of thiobarbituric acid, has demonstrated excellent activity against certain murine tumors, including L1210 and P388 leukemias, B16 melanoma, and M5076 sarcoma. Preclinical studies suggested that the antitumor effects of this drug were schedule dependent, since repeated dosing increased killing of tumor cells when compared to intermittent injections. We have completed a Phase I clinical and pharmacological study of merbarone in which the drug was administered both as a 2-h infusion and as a continuous i.v. infusion over 24 h. In view of the increased toxicity observed in animals following bolus injections and the possibility of schedule-dependent anticancer activity, a schedule of drug administration daily for 5 days was selected. Fifty patients with advanced cancer were treated at dose levels that ranged from 100 to 1500 mg/m2/day. When the drug was administered by peripheral vein, phlebitis was observed at the infusion site at daily doses greater than or equal to 150 mg/m2. Therefore, all patients who received drug doses greater than or equal to 200 mg/m2 were treated by continuous i.v. infusion using central venous catheters. Renal insufficiency, initially observed at a dose of 1000 mg/m2/day, was the dose-limiting toxic reaction at 1500 mg/m2/day. Three of five patients treated at the highest dose level were unable to complete the infusion due to this effect. Marked hypouricemia was observed in all patients. Other toxic effects were mild and included nausea, fatigue, leukopenia, thrombocytopenia, and anorexia. Alopecia was noted in several patients who received doses greater than or equal to 1000 mg/m2/day. No major antitumor effects were observed. Dose-dependent, steady-state plasma concentrations of merbarone were reached within 24-48 h after beginning the continuous i.v. infusion. Elimination of drug from plasma followed a two-compartment model, with a t1/2 alpha of 4.2 h and a t1/2 beta of 15.3 h. Renal excretion of merbarone and its major metabolites accounted for less than 30% of the administered dose. We conclude that merbarone is relatively well tolerated with few constitutional symptoms. The current formulation of the drug causes phlebitis when administered by peripheral vein, and renal insufficiency is commonly observed at daily doses which exceed 1250 mg/m2. The recommended dose for extended Phase II evaluation is 1000 mg/m2/day daily for 5 days administered by central venous catheter.

Adult↗
PubMed1988

Phase I trial and clinical pharmacological evaluation of hexamethylene bisacetamide administration by ten-day continuous intravenous infusion at twenty-eight-day intervals.

We have treated 33 patients with different types of advanced cancer by 10-day continuous i.v. infusion courses of hexamethylene bisacetamide (HMBA), a drug that produces differentiation of a variety of transformed cell lines on prolonged exposure in vitro to drug concentrations of 3 to 5 mM. In this dose-finding and pharmacokinetic study, five dosage levels were explored from 12 to 28 g/m2/day. Patients who had not shown progression of disease were given repeat courses of therapy at 28-day intervals. Seventy-two courses of therapy were administered; 17 patients received one course; eight patients received two; six patients received three; and one patient each received four and 17+ courses, respectively. The maximal tolerated dose was 28 g/m2/day for 10 days; the dose-limiting toxic effects were thrombocytopenia with hemorrhage and central nervous system dysfunction manifesting as disorientation and confusion. Based on these studies the recommended dosage for Phase II studies by the 10-day schedule is 24 g/m2/day. Pharmacokinetic studies demonstrated rapid clearance of HMBA from plasma; the decay phase data fit a one compartment model with a mean plasma half-life of 2.5 h and a range from 0.6 to 5.8 h. Mean plasma steady-state levels in our patients were 0.37, 0.58, 0.86, 0.88, and 1.42 mM, at the 12-, 16-, 20-, 24-, and 28-g/m2/day dosage levels, respectively. The data indicate that plasma HMBA concentrations of 1 mM can be maintained for 10 days with acceptable patient tolerance, but that HMBA concentrations in excess of 1.4 mM for 10 days are associated with substantial hematological and central nervous system toxicity. Objective antitumor effects were observed in five patients; one woman with non-small cell lung cancer, who has received 17+ courses over a period of 28+ mo, achieved a partial remission that continues at 28+ mo on therapy. Transient regression of cutaneous metastases was observed in three patients with breast carcinoma and one patient with colorectal carcinoma.

Acetamides↗
PubMed1986

Gd(DOTA): an alternative to Gd(DTPA) as a T1,2 relaxation agent for NMR imaging or spectroscopy.

Methods have been devised for obtaining gadolinium(III) complexes of the ligands NOTA (1,4,7-triazacyclononane-N,N',N''-triacetic acid), DOTA (1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid), TETA (1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid), and DTPA (diethylenetriaminepentaacetic acid) as solids for use as pharmaceuticals. Their effectiveness as in vitro and in vivo contrast agents for NMR imaging or T1,2 relaxation agents for spectroscopy has been investigated. The Gd(DOTA) complex was shown to be a more stable alternative to Gd(DTPA) by serum stability studies and measurement of stability constants. Images of tumors grown in athymic mice were obtained by NMR after injection of Gd(DOTA) and Gd(DTPA).

Animals↗