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Biomedical subjects

W D Ensminger

Publications and source records attributed to W D Ensminger.

125 records · Page 7Linked to original sources
PubMed1978

Thymidine rescue of high-dose methotrexate in humans.

Thymidine rescue was administered following 63 courses of high-dose methotrexate in 20 patients. In the first part of this study, the methotrexate was given as a 24-hr infusion and the dose was escalated from 0.14 to 8.54 g/sq m; in the second part, methotrexate was infused to maintain a serum concentration of 15 micrometer for 30, 36, or 40 hr. Thymidine rescue was started immediately after the end of the methotrexate infusions, and consisted of 8 g/sq m/day for 3 days or until serum methotrexate was below a toxic level. Mucositis and myelosuppression were the major toxicities. Neither was dose related. Serum methotrexate levels were proportional to the logarithm of the methotrexate dose. There was a mean 6-fold increase in thymidine concentration during rescue. However, thymidine levels prior to and during rescue were not related to the incidence of subsequent toxicity. Recovery of DNA synthesis in bone marrow cells was evident by nucleoside precursor incorporation at 24 hr after the start of rescue. Two of 16 evaluable patients achieved partial responses. This study indicates that thymidine is an effective rescue agent for high-dose methotrexate in humans.

Adult↗
PubMed1978

Intra-arterial radionuclide infusion: a new technique to assess chemotherapy perfusion patterns.

A mechanical infusion pump was used to introduce 99mTc-sulfur colloid at a rate of 1 ml/minute into the hepatic arteries of six patients. The radiotracer distribution patterns were compared to those obtained with "bolus" radionuclide angiography and those seen with standard contrast angiography. In all cases, the slow flow rate radionuclide studies evidenced dramatic differences from the patterns obtained with rapid flow rate injections. The results indicate that standard, rapid-injection contrast techniques may not produce the most reliable information regarding potential flow distribution. It is concluded that radiotracers introduced at flow rates approximating those attained with infusion pumps will offer the best estimates of both initial catheter placement and subsequent patterns of hepatic distribution of chemotherapeutic agents.

Adult↗
PubMed1978

Hepatic arterial BCNU: a pilot clinical-pharmacologic study in patients with liver tumors.

BCNU at a dose of 200 mg/m2 was administered in a 60-minute hepatic arterial (HA) infusion to three patients with liver-predominant neoplastic disease. Nitrosourea blood levels were measured during the 60-minute infusion and for 30 minutes after completion of the infusion in samples obtained simultaneously from a hepatic venous (HV) catheter and a peripheral venous (PV) site. Direct extraction of blood with diethyl ether was used in order to remove quantitatively the nitrosourea from blood and thereby stabilize it against in vitro breakdown in blood prior to colorimetric analysis. As determined by blood levels, steady-state was achieved within 50 minutes of infusion. Mean HV levels at steady-state were 2.5-fold higher in the HV compared to PV samples. The higher HV compared to PV levels must reflect higher tumor exposure to nitrosourea with HA compared to the usual iv route of administration. No drug-related hepatic toxicity was noted. Myelosuppression was noted in only one patient in whom reversible leukopenia (granulocyte nadir, 500/mm3) and thrombocytopenia (platelet nadir, 20,000/mm3) developed.

Carmustine↗
PubMed1977

The prevention of methotrexate toxicity by thymidine infusions in humans.

Continuous i.v. thymidine (TdR) was given to 12 patients with metastatic cancer in an attempt to prevent methotrexate (MTX) toxicity. MTX was infused in 27 courses with progressive dose increase from 80 mg/sq m for 24 hr to 6 g/sq m for 72 hr. TdR at 8 g/sq m/day was infused concurrently and continued 24 to 48 hr beyond MTX infusion. The median pretreatment serum TdR level was 0.19 micron. With TdR infusion, the median level was 1.5 micronM. Serum TdR fell with a half-time of 8 to 10 min after a pulse dose or cessation of infusion. Spinal fluid TdR equaled serum TdR levels after 2 hr of infusion. Less than 2% of administered TdR appeared in urine. MTX serum levels were proportional to dose infused, ranging from 80 to 100 micronM with 2 g/sq m/day. The half-time for MTX clearance from serum was 4 to 8 hr. Spinal fluid MTX reached equilibrium at 3 to 12% of serum levels by 4 hr. Bone marrow dysfunction during MTX infusion was prevented by TdR as determined by labeling indices and cytofluorographic analyses. Toxicity was not seen in patients with normal MTX clearance using 48-hr infusions of MTX where TdR was continued for an additional 48 hr after the MTX infusion had ended. However, 3 of 6 courses of MTX at 6 g/sq m over 72 hr led to toxicity. Toxicity was reversible in 2 patients, 1 of whom was retreated with a similar dose duration of MTX without toxicity when TdR was continued beyond the end of the MTX infusion for 48 hr instead of the usual 24 hr. The 3rd patient with toxicity died of progressive disease and thrombocytopenia 19 days after treatment. No TdR-related toxicity or unusual MTX toxicity was detected. Antitumor effects were noted in 4 patients. TdR offers significant protection against MTX toxicity and deserves further clinical study.

Adult↗
PubMed1970

Inhibition of synchronized cellular deoxyribonucleic acid synthesis during Newcastle disease virus, mengovirus, or reovirus infection.

Cultures of L cells were synchronized with respect to deoxyribonucleic acid (DNA) synthesis with thymidine and 5-fluoro-2'-deoxyuridine (FUdR) and infected with Newcastle disease virus (NDV), mengovirus, or reovirus 3. Inhibition of incorporation of (3)H-cytidine into the DNA of synchronized cells is partially inhibited 2 hr after infection with NDV or mengovirus and nearly completely suppressed 4 hr after infection. With NDV and mengovirus, no evidence was obtained of differences in sensitivity of cells during early S phase as compared to later stages in DNA synthesis. When cells were infected with reovirus at the time of release from FUdR block, inhibition of cellular DNA synthesis was evident at 2 to 3 hr, and it was complete at 4 to 5 hr after infection. However, when cells were infected several hours prerelease, synthesis of DNA occurred in early S phase in spite of the fact that the cells had been infected for up to 6 hr. The results indicate that DNA synthesis in early S phase is relatively insensitive to the inhibitory function of reovirus. Colorimetric determinations (diphenylamine reaction) of the amounts of DNA produced in synchronized cells have substantiated the inhibition of DNA synthesis observed by isotope incorporation techniques.

Colorimetry↗
PubMedDate not supplied

Intraarterial infusion chemotherapy for head and neck cancer using a totally implantable infusion pump.

Intraarterial infusion chemotherapy has not been widely accepted for the treatment of head and neck cancer due to the high rate of complications it involves. To avoid these complications, a totally implantable infusion pump has been developed to achieve continuous low-level drug delivery for long periods of time. The pump is implanted in a subcutaneous pocket and connected to a permanent, indwelling, arterial catheter. It can be repeatedly refilled with chemotherapeutic agents by hypodermic needle injection through the skin and through a self-sealing septum located at the entry to the pump. Refilling the pump recharges an inexhaustible power source for the next delivery cycle. Preliminary results suggest that long term intraarterial infusion chemotherapy for the treatment of head and neck cancer is practical for outpatients.

Antineoplastic Agents↗
PubMedDate not supplied

Low infusion rate digital subtraction angiography to predict regional perfusion in hepatic arterial chemotherapy.

Digital subtraction angiography (DSA) with a low injection rate of contrast (0.5 ml/sec) was studied as a means of predicting the regional perfusion of percutaneously placed catheters for hepatic arterial chemotherapy. In 64 hepatic artery catheter placements, conventional injection rate angiography (3-5 ml/sec) and low infusion rate DSA exams were compared to conventional radionuclide perfusion studies performed with Tc-99m-MAA. In 58 of 64 cases (90.6%) the conventional arteriogram correctly predicted the extent of hepatic perfusion, whereas in 63 of 64 cases (98%), the low flow DSA exam correctly predicted hepatic perfusion. The conventional arteriogram correctly predicted the extent of extrahepatic perfusion in 32 cases (50%), with a sensitivity of 100%, but a specificity of only 39.6%. The DSA exam was correct in defining the presence or absence of extrahepatic perfusion in 57 of 64 cases for a sensitivity of 82% and a specificity of 91%. Despite the quantitative difference between the low infusion rate DSA study and the chemotherapy infusion (10 ml/hr), it is a useful tool to assist in the correct positioning of temporary catheters for hepatic arterial chemotherapy.

Angiography, Digital Subtraction↗
PubMedDate not supplied

Bleomycin, vincristine, and mitomycin C with or without methotrexate in the treatment of squamous cell carcinoma.

Forty-two patients with metastatic squamous cell carcinoma were treated with bleomycin, vincristine, and mitomycin C with or without methotrexate (BOM +/- M). The overall response rate of 64% (complete response [CR] rate, 19%) included 19 responses among 26 patients (seven CRs) with head and neck cancer, three responses among eight patients with cervical cancer, and three responses among five patients (one CR) with lung cancer. Six of 12 patients (two CRs) responded to BOM and 21 of 30 patients (six CRs) responded to BOMM. The median duration of response was 16 weeks. Toxic effects included nausea or vomiting in 33% of the patients, fever of > 101 degrees C in 26%, stomatitis in 29% and pulmonary toxicity in 19%. Four of eight cases of pulmonary toxicity were fatal and the incidence was related to the amount of both bleomycin and mitomycin C administered. The occurrence of pulmonary toxicity could not be predicted by serial determination of pulmonary function or blood gases. A wbc count nadir of < 2500/mm3 occurred in 15 of 42 patients. There were two episodes of sepsis with one death. A platelet count nadir of > 75,000/mm3 occurred in eight of 42 patients with no episodes of hemorrhage. BOMM produces a high objective response rate in patients with squamous cell cancer. However, the duration of remission is brief, and use of the regimen carries an increased risk of fatal pulmonary toxicity.

Adult↗
PubMedDate not supplied

Intra-arterial BCNU chemotherapy for the treatment of malignant gliomas of the central nervous system: a preliminary report.

We treated six patients with unilateral malignant astrocytomas with pulse doses of intra-arterial BCNU (200 mg/m2 initially, with escalating doses every 6-8 weeks) via transfemoral selective internal carotid catheterization. Four patients had had partial resections without prior radiation therapy and received no steroids. They had decreased tumor stain and surrounding edema after two to four cycles of chemotherapy. For one patient, results of the neurologic examination returned to normal, with total disappearance of her tumor as assessed by computerized tomographic scan. Objective tumor response continued for 7 months in three patients and for 3 months in one. In two of the four patients, chemotherapy was discontinued because of retinal toxicity and not because of treatment failure. Two patients had had partial resections and radiation therapy. One patient had stable disease for 4 months, and the second had progressive disease with gradual visual loss beginning in the infused eye 3 weeks after the second treatment. The catheterization procedure is safe; it was without immediate complication in 17 BCNU infusions. In summary, high-dose intra-arterial BCNU is well-tolerated and is an effective initial chemotherapeutic modality.

Adult↗
PubMedDate not supplied

Mutual kinetic interaction between 5-fluorouracil and bromodeoxyuridine or iododeoxyuridine in dogs.

The pharmacokinetics of 5-fluorouracil (FUra) were studied alone and in the presence of either bromodeoxyuridine (BrdUrd) or iododeoxyuridine (IdUrd) in five mixed breed hounds. FUra was administered intravenously over 1 min as a 5 mg/kg dose in all three treatments. BrdUrd or IdUrd was infused intravenously at 2.5 mg/hr.kg x 6 hr and FUra was given 3 hr into the 6-hr infusion of thymidine analog. Serial blood samples were obtained for 3 hr prior to and after FUra dosing. Plasma concentrations of FUra, BrdUrd and bromouracil (BrUra), and IdUrd and iodouracil (IUra) were measured by reversed-phase HPLC. Concomitant administration of BrdUrd or IdUrd resulted in substantial changes in the kinetics of FUra. In particular, the total plasma clearance of FUra was decreased and area under the plasma concentration-time curve was increased. There were also significant changes in the volume of distribution steady-state, and in the mean residence time and half-life of FUra. The data show that FUra had little or no effect on the disposition of BrdUrd or IdUrd. In contrast, FUra had a significant effect on the disposition of BrUra and IUra going to form catabolic products. The observed pharmacokinetic interaction in dogs is probably due to a competition between BrUra (or IUra) and FUra for the rate-limiting catabolic enzyme, dihydropyrimidine dehydrogenase. This kinetic interaction was mutual and of a smaller magnitude for FUra + BrdUrd than for FUra + IdUrd.

Animals↗