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Biomedical subjects

V A Levin

Publications and source records attributed to V A Levin.

At least 199 records · Page 11Linked to original sources
PubMed1979

The effect of phenobarbital pretreatment on the antitumor activity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) and 1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl-1-nitrosourea (PCNU), and on the plasma pharmacokinetics and biotransformation of BCNU.

Many patients being treated for primary and secondary brain tumors receive phenobarbital as an anticonvulsant. The effects of chronic oral administration of phenobarbital on the antitumor activity of BCNU, CCNU and PCNU against the intracerebral 9L tumor in rats were determined. Phenobarbital pretreatment eliminated the antitumor activity of BCNU and reduced the activity of PCNU and CCNU. Pretreatment with phenytoin, sodium methylprednisolone succinate and dexamethasone had little or no effect. Pharmacokinetic data for i.v. BCNU in the plasma of rats showed an increase in drug clearance for phenobarbital pretreated animals, compared to a control group. Larger differences were observed when BCNU was given i.p. The half-life of BCNU in sera from pretreated and control group rats was similar. Finally, the in vitro rate of BCNU disappearance in 9000 X g supernatants and microsomes from the livers of pretreated rats was 5-fold faster than the rate of disappearance of BCNU in supernatants from normal animals. We conclude that the chronic oral administration of phenobarbital induces a change in liver enzymes, which accelerates the clearance of BCNU, thereby reducing the antitumor activity of BCNU and the other nitrosoureas. Phenobarbital pretreatment reduces systemic BCNU toxicity.

Alkylating Agents↗
PubMed1978

Quantitative high-pressure liquid chromatographic procedure for the determination of plasma and tissue levels of 2,4-diamino-5-(3,4-dichlorophenyl)-6-methylpyrimidine (metoprine) and its application to the measurement of brain capillary permeability coefficients.

A high-pressure liquid chromatographic assay for metoprine levels in aqueous media, serum, and tissue extracts has been developed that can measure concentrations of the drug in the 25-100 ng range with accuracy, reproducibility, and ease. The half-time for metoprine disappearance from rat plasma and capillary permeability coefficients for metroprine in rate brain tissue determined with this method are in excellent agreement with values determined for related drugs using labeled compounds.

Animals↗
PubMed1978

Correlations between experimental chemotherapy in the murine glioma and effectiveness of clinical therapy regimens.

Intracerebral murine glioma 26 was used as a model system for evaluating two-drug combinations of antitumor agents, BCNU was combined with either procarbazine, dianhydrogalactitol, or ellipticine. CCNU was combined with procarbazine. All combinations were more active than the individual drugs alone. The most potent combinations achieved 85-100% tumor "cure" at 120 days, with combined toxicity indices of 0.25 (CCNU-procarbazine) to 1.30 (NCNU-dianhydrogalactitol). The experimental data were compared to clinical studies with CCNU, procarbazine, and vincristine, and BCNU-procarbazine.

Animals↗
PubMed1978

Relationship of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) pharmacokinetics of uptake, distribution, and tissue/plasma partitioning in rat organs and intracerebral tumors.

To obtain a clearer definition of the relationship between the structure of BCNU and CCNU and their antitumor activity, we determined the uptake, distribution, and tissue/plasma partition ratios of both compounds in normal organs and intracerebral (ic) 9L tumors in rats. Greater uptake, distribution, and tissue/plasma partition ratios were obtained for parent CCNU in fat, liver, and brain, and for parent BCNU in kidney. CCNU distributes more rapidly and extensively than BCNU only in fatty tissues. BCNU distributed more extensively in kidney and liver. Rats received bolus IV injections of 14C-labeled BCNU or CCNU in increasing doses; measurements taken 30 min after injection showed that three- to fourfold more BCNU than CCNU was bound to nucleic acids in brain and ic 9L tumor tissue. Because the chloroethyl group is the alkylating moiety for both drugs, these findings implied that BCNU biotransformed to its reactive intermediate more rapidly than did CCNU. These observations, together with previous findings, indicate that one reason for the greater effectiveness of BCNU than CCNU against ic 9L tumors is its superior ability to form an intermediate that can bind to ic 9L tumor cell nucleic acids.

Animals↗
PubMed1978

Pharmacokinetics of intracarotid artery 14C-BCNU in the squirrel monkey.

A comparison of intravenous to intracarotid artery (ICA) administration of 14C-BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea) was made in squirrel monkeys. Radioactivity was measured as soluble drug products and as RNA-, DNA-, and protein-bound radioactivity. The ICA administration of BCNU achieved 190% to 280% higher brain nucleic acid-bound drug levels than use of the intravenous route in the infused hemisphere and 130% to 280% higher levels than in the noninfused hemisphere. In addition, some brain regions directly subserved by the middle cerebral artery had bound drug levels four- to fivefold greater than those found in regions of noninfused brain. The data suggest that a need for BCNU dose reduction due to myelotoxicity may be an indication for ICA therapy in selected brain-tumour cases.

Animals↗
PubMed1978

Chemotherapy of recurrent medulloblastoma with combined procarbazine, CCNU, and vincristine.

Seventeen patients with recurrent medulloblastoma were treated with a combination of three drugs: procarbazine, CCNU, and vincristine (PCV). Tumor recurrence was documented at varying periods following surgery and radiotherapy. Among 16 evaluable patients, ten showed a response to PCV on the basis of subjective neurological improvement and a decrease in tumor size by radiological criteria. Five patients were designated as having stable disease on the basis of no change in neurological status and tumor size. One patient showed uninterrupted progression of disease. The median time to progression for all patients was 45 weeks. Significnat myelotoxicity, exacerbated by prior spinal irradiation, compromised therapy. After an initial response, it was often necessary to reduce the higher doses of CCNU and procarbazine that caused concomitant bone-marrow toxicity; as a consequence of the lowered doses, tumor progression was then frequently observed. The authors conclude that PCV is an effective form of palliative therapy for recurrent medulloblastoma.

Adolescent↗
PubMed1978

BCNU-5-fluorouracil combination therapy for recurrent malignant brain tumors.

Twenty-nine patients with recurrent malignant brain tumors were evaluated. BCNU (180 mg/m2) was administered iv on Day 1 and 5-fluorouracil (1 g/m2/day) was given by continuous infusion on Days 15--17. Courses were repeated every 6 weeks until tumor progression occurred. Before each course, a neurologic examination and radionuclide and computerized tomographic scans were performed. Response and progression were defined as improvement or deterioration, respectively, in at least two of the three tests. Nine of 29 patients (31%) responded to therapy, five of 29 (17%) showed progression, and 15 of 29 (52%) had disease stability. The estimated median time to progression was 27 weeks for all patients, 34 weeks for the response group, and 25 weeks for the stable group. Of all 29 patients, 24 (83%) had tumor progression arrested; 40% with response and 6% with stable disease were continuing therapy after 1 year. The stable disease group was larger and the duration of stability was longer than that seen in previous studies. Evaluated by time to progression, a BCNU-5-fluorouracil combination is superior to either BCNU alone or a BCNU-procarbazine combination.

Astrocytoma↗
PubMed1978

Analysis for 1,3-bis(2-chloroethyl)-1-nitrosourea by chemical ionization mass spectrometry.

We used chemical ionization mass spectrometry to quantify the cancer chemotherapeutic agent 1,3-bis(2-chloroethyl)-1-nitrosourea in biological fluids. A stable isotope-labeled internal standard was added to the fluid being analyzed. Protonated molecular ion intensity ratios were determined by selected ion monitoring of sample extracts inserted directly into the chemical ionization source. Peak ratios were calculated for chlorine isotope ratios in their natural abundance, to verify the integrity of the data acquired, and to compute the drug concentration. The assay was applied to measure the compound in rat blood and plasma and in human plasma, and to monitor in vitro metabolism in rat-liver microsomal preparations. For the analyses we used a quadrupole mass spectrometer interfaced to a commercial computer system. Data-system characteristics are described.

Animals↗
PubMed1978

Pharmacokinetics of BCNU in man: a preliminary study of 20 patients.

Using the technique of direct sample insertion selected ion monitoring chemical ionization mass spectroscopy, BCNU levels were measured in vivo in patients and in vitro in serum, sera ultrafiltrates, and buffered Ringer's solution. The disappearance of BCNU in vitro was found to be first-order with a half-time of 11.6 minutes (+/- 0.5 SD) in volunteers and 15.6 minutes (+/- 2.3 SD) in patients. The disappearance from serum was catalyzed by a macromolecular component of the serum and was slowed by serum lipids. Analysis of the pharmacokinetics of BCNU in 20 patients using a two-compartment open model demonstrated a volume of distribution of 3.25 liters/kg (+/- 1.69 SD), a clearance of 56 ml/minute/kg (+/- 56 SD), and a transfer constant from the central compartment to the outside (K10) OF 0.0324 MINUTE-1 (+/- 41% SD), which was close to the decomposition rate observed for BCNU in serum in vitro. The pharmacokinetics of BCNU in patients may be affected by the percent of body fat and the lipid content of the serum.

Body Composition↗
PubMed1977

Brain-tumor chemotherapy. Pharmacological principles derived from a monkey brain-tumor model.

An implnated choriocarcinoma growing inthe brains of monkeys was used as a brain-tumor model for the study of the cerebral distribution of two commonly used physiological markers, inulin and albumin; tissue samples were obtained from the tumor, adjacent brain, and distant brain. An extravascular inulin space was calculated by subtracting the albumin (plasma) space from the total inulin spaces. The extravascular inulin space in the tumor was found to be 24%, a value significantly larger than that in distant brain (0.6%). The large inulin space of the tumor was probably the result of increases on both capillary permeability and the extracellular space within this area. Determination of the inulin space in 1 to 2-mm thick samples of tissue taken serially from the tumor center to the distant brain indicated a gradual decline in inulin concentration from the tumor's edge to distant brain. This distribution pattern could be the result of either a continuous decrease, running from the tumor to distant brain, in capillary permeability to inulin, or a diffusional flow of inulin from the tumor into the adjacent tissue. The failure of drugs to inhibit such a tumor in view of these observations is discussed.

Albumins↗
PubMed1977

Comparison of 1- and 2-hr delayed brain scans in patients undergoing chemotherapy for primary brain tumors.

Fifty-five patients receiving various forms of chemotherapy for primary brain tumors had brain scans performed at 1 hr and again at 2 hr following injection of the radionuclide. The images were compared for changes in lesion size, lesion intensity, and surgical flap intensity. Sixteen percent (9) of the patients showed a definite increase in size of the lesions and 29% (16) a definite increase in intensity from 1-hr to the 2-hr scan. Fifty-one percent (28) of the patients showed fading in surgical flap intensity. One case of primary neoplasm, one case of meningeal spread of tumor, and one case of subdural hematoma were detected only on the 2-hr view. In addition, changes in the so-called doughnut sign were observed. These findings demonstrate a need for strict adherence to a specified time between injection and imaging in studying brain lesions receiving chemotherapy, and emphasize the superiority of the 2-hr scan for evaluation of these patients.

Astrocytoma↗
PubMed1976

Single-agent chemotherapy of brain tumors. A five-year review.

Identification of effective single chemotherapeutic agents for brain tumors must precede the rational use of multiple drug combinations. In phase 2 trials beginning in 1968, 158 patients with intrinsic brain tumors (mostly recurrent malignant astrocytomas) were considered evaluable. The larger trials with more effective drugs produced these results: carmustine (BCNU) response rate, 47%, with median duration of nine months; lomustine (CCNU), 44%, with median duration of six months; procarbazine hydrochloride, 52%, with median duration six months; carmustine and vincristine sulfate combined, 44%, with median duration of only four months; and BIC (5-[3,3-bis(2-chloroethyl)-1-triazeno]imidazole-4-carboxamide), 38%, with median duration of five months. Administration of glucocorticoids was not found to bias the frequency of response. Forty-seven patients, 26 of whom had responded to the initial drug, received a second drug. Among 26 patients who were evaluable, only four responded to the second drug.

Astrocytoma↗
PubMed1976

Dianhydrogalactitol (NSC-132313): pharmacokinetics in normal and tumor-bearing rat brain and antitumor activity against three intracerebral rodent tumors.

Dianhydrogalactitol (DAG; NSC-132313), a hexitol epoxide, was used to treat intracerebral rodent tumors. DAG was most active against the murine ependymoblastoma [treated/controls (T/C)greater than 440%], less active against murine glioma 26 (T/C approximately 112-150%), and least active against rat 9L gliosarcoma (T/C approximately 100%). Application of a two-compartment open model for plasma disappearance of 14C-DAG in rats gave a volume of distribution at steady state of approximately 872 ml, a clearance of approximately 9.4 ml/minute, and an elimination constant of 0.025/minute. Entry of 14C-DAG was more rapid into the 9L tumor than into the normal brain. When a two-compartment series model for brain and tumor entry was applied, the t1/2 (half-time) for compartmental equilibrium was approximately 22 and 105 minutes in the brain, and 4 and 56 minutes in the 9L tumor. The drug rapidly entered the brain and tumor intracellular compartments. Binding to RNA was linear with time, and the absolute amount of binding was approximately six times greater for RNA than for DNA.

Animals↗