Clinical pharmacology of L-asparaginase was compared by intramuscular and intravenous injections in 12 patients with metastatic cancer or leukemia. Following a single intramuscular injection at the gluteal site of L-asparaginase (10,000 IU/m2), the enzyme appeared in plasma as measured initially at 1 hour, but plateau levels were not reached in plasma until 14 to 24 hours after drug administration. The peak plasma level was 1.12 IU/ml, only one fourth of that seen when L-asparaginase was given intravenously at equal doses. However, the enzyme level decrease in the plasma after intramuscular injections was slower, with a half-life ot 46 hours, compared to 7 to 28 hours for intravenously administered drug. The apparent volume of distribution indicated that the intravenously injected enzyme was mostly distributed in plasma, whereas the intramuscularly injected enzyme yielded a much larger volume of distribution (63 versus 245 ml/kg). In addition, only 19 per cent of the intramuscularly injected dose was in plasma, and the area under the curve (C X t) was only 1/24 that by intravenous route (20 versus 487 IU/ml.hr). No enzyme was measurable in patients' urine samples collected for three days after intramuscular injections of the enzyme, and only a trace (less than 1 per cent) of the enzyme was detected in urine after intravenous administration.

Asparaginase↗

PubMedDate not supplied

In vitro assessment of sulbactam plus cefoperazone in the treatment of bacteria isolated from cancer patients.

Cefoperazone is a broad-spectrum cephalosporin that has been used extensively to treat infections in cancer patients. A recent survey demonstrated only a 6% resistance to this drug among Gram-negative bacteria. The combination of cefoperazone plus sulbactam was studied in vitro against consecutive isolates causing bacteremia in cancer patients as well as those selected for resistance to cefoperazone. Both a fixed ratio of sulbactam/cefoperazone (2:1 w/w) and selected concentrations of sulbactam (2, 4, 8, and 16 micrograms/ml) were studied. Sulbactam was shown to increase the susceptibility of various unselected Gram-negative bacilli; this effect increased with larger concentrations of sulbactam. The addition of sulbactam at optimum concentration levels made 29 of 65 cefoperazone-resistant Gram-negative bacilli susceptible. This effect was seen most markedly for Acinetobacter spp.

Bacterial Infections↗

PubMedDate not supplied

Susceptibility surveillance among gram-negative bacilli at a cancer center.

We conducted a survey of susceptibility among 758 gram-negative bacilli (GNB; collected from cancer patients over a 3-month period) to commonly used antibiotics. The overall resistance among GNB was least for piperacillin/tazobactam and meropenem (5 and 6%, respectively) followed by cefepime (8%), imipenem (9%), amikacin (12%), ofloxacin (13%), ciprofloxacin, ceftazidime and ticarcillin/clavulanate (14% each), aztreonam (18%) and tobramycin (24%). In comparison to data on antibiotic resistance to ceftazidime, imipenem, ciprofloxacin and aztreonam in similar studies in 1985 and 1994, resistance has significantly increased to all four antibiotic classes. Based on our current study, meropenem, cefepime, imipenem and piperacillin/tazobactam would be the most appropriate choices in our institution for empiric therapy of GNB infections in febrile neutropenic patients.

Anti-Bacterial Agents↗

PubMedDate not supplied

Survey of antibiotic susceptibility among gram-negative bacilli at a cancer center.

A survey of the susceptibility of gram-negative bacilli isolated from cancer patients to broad-spectrum antimicrobial agents was conducted. The organisms were isolated from all patient specimens submitted to the microbiology laboratory during a 3-month study period. Overall, the least resistance was observed against cefoperazone/sulbactam, ciprofloxacin, and imipenem. Of these, cefoperazone/sulbactam has had limited usage at our institution. Drugs used more frequently (piperacillin, aztreonam, cefoperazone, ceftazidime) were associated with greater levels of resistance. Imipenem and ciprofloxacin have enjoyed wide usage but the level of resistance remains low.

Acinetobacter↗

PubMedDate not supplied

L-asparaginase for the treatment of cancer.

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Asparaginase↗

PubMedDate not supplied

Clinical pharmacology of combined oral uracil and ftorafur.

Phase I clinical trials of the combination of oral uracil with ftorafur (Ft) were conducted in patients with solid tumors over either a 5-day (345 mg/m2/day) or a 28-day (160 mg/m2/day) period. The uracil dose, which was four times the Ft dose (molar basis), was previously shown to be optimal at inhibiting the degradation of 5-fluorouracil (5-FU). Pharmacology was performed on the first dose of the first day of therapy. Ft was measured by HPLC, whereas uracil and 5-FU were measured using GC/MS. Plasma levels were highest for Ft, followed by uracil and 5-FU at all time points. Peak and trough levels after selected subsequent doses were also measured; these varied in the individual from day to day. Maximum plasma levels (Cpmax) for Ft, uracil, and 5-FU except in one patient were achieved at 0.6-2.1 hr, 0.6-4.1 hr, and 0.7-2.0 hr, respectively. Generally, lower doses yielded more rapid decay of 5-FU and uracil levels than did higher doses. No correlation was observed between myelotoxicities (granulocytopenia and leukopenia) and the Cpmax and AUC0-6hr of Ft (p > 0.2). However, after the highest uracil and Ft dose (approximately 300 mg/m2/Ft study dose), the Cpmax and AUC0-6hr values of 5-FU revealed significant differences (p < 0.05) in three patients each with and without myelotoxicity. These associations were similarly observed with uracil. Our findings thus indicate that measuring plasma uracil and more importantly, the 5-FU levels, may predict hematological toxicity and enable subsequent dose adjustments.

Administration, Oral↗

PubMedDate not supplied

Clinical pharmacology of 1-beta-D-arabinofuranosyl-5-azacytosine (fazarabine) following 72-hour infusion.

The clinical pharmacology of fazarabine (1-beta-D-arabinofuranosyl-5-azacytosine), a structural analogue of 1-beta-D-arabinofuranosylcytosine (ara-C) and 5-azacytidine, was assessed in 14 patients with various malignancies during a phase I trial. Since the starting dose for the protocol was low (0.2 mg/m2/hr over a 72-hr continuous iv infusion), a radioimmunoassay (RIA) using commercially available ara-C antibody and [3H]ara-C was developed to measure the anticipated low plasma drug levels. The assay could be used to measure fazarabine accurately in plasma and urine with a sensitivity of 0.08 ng/ml. The RIA does not require extraction of samples. Using both RIA and HPLC, similar results were obtained in plasma samples from a patient receiving a high dose (180 mg/m2/hr) of fazarabine. The assay is simple, sensitive, reproducible, and specific. Following the infusion, plasma levels declined triphasically with a terminal half-life of 5.7 +/- 2.0 hr. The AUC was linearly related to dose. When the various doses were normalized to 1.75 mg/m2/hr (the maximum tolerated dose as determined from the phase I trial) the mean AUC value was 4232 +/- 987 (ng/ml)hr. Plasma steady-state drug levels (CPss) were achieved in 2-4 hr and were linearly dependent to dose. Also, when normalized, the mean CPss was 58 +/- 13 ng/ml, which is within the reported concentration range necessary for inhibiting malignant cell growth. Total clearance was rapid, 528 +/- 138 ml/(m2.min), and not dose-related.

Adult↗

PubMedDate not supplied

Enzymatic conversion of 5-fluoro-2'-deoxyuridine to 5-fluorouracil or 5-fluoro-2'-deoxyuridine 5'-monophosphate in human tissues.

The relative activities and Km values of pyrimidine nucleoside phosphorylase (PNPase) and thymidine (TdR) kinase were compared in postsurgical human tissues. TdR kinase, which activates 5-fluoro-2'-deoxyuridine (FUdR), was higher in normal liver than in other tissues examined. PNPase, which cleaves FUdR, was higher in normal spleen and liver and lowest in kidney. In normal lung tissue, almost all of the FUdR was cleaved at a high concentration since PNPase activity was much higher than TdR kinase activity. The affinity of TdR kinase as indicated by Km was greater in normal than in cancerous lung tissue. At a low concentration, FUdR is relatively well activated in the normal tissue; thus it may not be suitable for chemotherapy of lung cancer. When comparing normal versus cancerous colon tissues, no difference was seen in either TdR kinase affinities or TdR kinase and PNPase activities. However, the PNPase affinity for FUdR was significantly higher in normal than in cancerous colon tissue. When FUdR is maintained at low concentrations, it might have a selective cytotoxicity for colon cancer tissue since it is well cleaved in normal colon.

Biotransformation↗

PubMedDate not supplied

Pharmacologic studies of cyclocytidine and arabinosylcytosine in dogs.

Cyclocytidine (cyclo-C) and arabinosylcytosine (ara-C) were compared as to distribution and metabolism in dogs after administration by the intravenous, subcutaneous, intramuscular, and oral routes. After cyclo-C, two metabolites were found in the plasma and urine--a hydrolytic product, ara-C, and its deaminated product, arabinosyluracil (ara-U). The urinary excretion of cyclo-C is rapid; Five hours after parenteral administration, 60% of the given drug is excreted; 45% as cyclo-C, 10% as ara-C, and about 5% as ara-U. In contrast, after similar injections of ara-C, 45% of the drug is excreted; 33% as ara-C and 12% as ara-U. When compared with those in human and mouse tissues, the deoxycytidine deaminase levels in dog tissues are extremely low. This agrees with the finding of low ara-U levels in dog plasma and urine after administering cyclo-C or ara-C. Regardless whether cyclo-C or ara-C is injected, the plasma decay curve of the resultant ara-C is biphasic, with calculated half-lives of 40 min and 2-2.5 hr. However, if ara-C is given, the plasma ara-C peak level is higher. Higher ara-C levels are also maintained throughout the measured 5 hr. There are no differences in pharmacologic disposition after iv, sc, or im administration of ara-C. This is also true for cyclo-C. These findings suggest that for both drugs, the above routes of administration may be equally effective. Neither cyclo-C nor ara-C is well absorbed after oral administration, and the drug concentration in the plasma is too low to be measurable. Whether the dog is fasted overnight or fed, the drug is excreted slowly. In 5 hr. no more than 3% is excreted, and by 12 hr. only 10% is excreted.

Administration, Oral↗