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Biomedical subjects

W D Ensminger

Publications and source records attributed to W D Ensminger.

At least 109 records · Page 6Linked to original sources
PubMed1983

Clinical pharmacology of hepatic arterial chemotherapy.

The techniques now exist to deliver drug infusions reliably through the hepatic artery to infuse the entire liver and tumor within the liver. Drug selection for use in these systems should be rational and include agents with short half-lives (high total body clearance) and some evidence of activity against the tumor type in question. Hepatic extraction and metabolism of the drug will in turn decrease systemic exposure or allow more drug to be given per set amount of systemic exposure. The dose-limiting toxicity of appropriate drug programs may well be regional and not systemic. Further pharmacokinetic studies and controlled clinical trials are needed to evaluate existing regimens and to design new regimens. Future advances are likely to involve the combination of effective drugs and the use of therapeutic microspheres to improve selectivity based on tumor microcirculation.

Antineoplastic Agents↗
PubMed1982

Cytokinetic evaluation of the four-drug combination of bleomycin, vincristine, mitomycin C, and methotrexate (BOMM) in cultured Burkitt's lymphoma cells and human bone marrow.

The four-drug combination of bleomycin, vincristine, mitomycin C and methotrexate produces a high response rate in patients with squamous cell carcinoma. In this study we have examined the cytokinetic effects of this drug combination in vitro and in human bone marrow in vivo. The in vitro analysis revealed that mitomycin C produces a concentration dependent slowing of S-phase transit with partial G2/M and G1/S blocks in cell cycle progression. A partially synchronized S-wave occurs 4-8 and 16-20 hours following a two-hour drug exposure. Bleomycin produces a dose dependent G2/M block during a 14-hour drug exposure. Drug removal did not result in appreciable cell cycle synchrony. In vitro exposure to the two drug combination resulted in loss of both the marked G2/M accumulation seen with bleomycin, and the partially synchronized S-phase waves seen following mitomycin C exposure. The sequential changes in bone marrow cytokinetics were determined in eight patients during and following administration of vincristine, mitomycin C and a continuous four-day infusion of bleomycin. The major cytokinetic changes observed were an increase in G2/M phase cells 18 hours following vincristine, and an increase in thymidine incorporation and S-phase cells 24 and 48 hours following the end of the bleomycin infusion. The clinical course of 24 patients was reviewed. Eleven patients who received methotrexate 36 to 42 hours following bleomycin had a subsequent median leukocyte nadir of 1.8 x 10(3)/mm3. Thirteen patients receiving methotrexate 60 to 72 hours after bleomycin had median leukocyte nadir of 3.9 x 10(3)/mm3. The objective response rates in the two groups was 75% and 80%, respectively. This study demonstrates that bone marrow cytokinetic analysis may allow schedule modification to avoid myelosuppression without loss of therapeutic activity.

Antineoplastic Agents↗
PubMed1982

Ocular toxicity associated with high-dose carmustine.

The ocular side effects of carmustine (a nitrosurea) are not well established. Evidence of delayed bilateral ocular toxicity developed in two of 50 patients treated with high dose intravenous (IV) carmustine (800 mg/sq m) with autologous bone marrow rescue. Symptoms or signs of ocular toxicity became apparent four weeks following IV treatment. Evidence of delayed ocular toxicity ipsilateral to the side of the infusion developed in seven of ten patients treated with intra-arterial carotid doses of carmustine to a cumulative minimum of 450 mg/sq m in two treatments. The ocular toxicity began two to 14 weeks (mean, six weeks) following intra-arterial treatment. In three of these patients, the visual loss progressed over one week to no light perception. The funduscopic manifestations of both groups included arterial narrowing, nerve fiber-layer infarcts, and intraretinal hemorrhages. Fluorescein angiography demonstrated segmental perivascular staining, wide-spread late capillary leakage, and optic disc hyperfluorescence. One patient had light and microscopic confirmation of cilioretinal artery occlusion and choroidal fibrin thrombi.

Adult↗
PubMed1982

Pharmacologic studies on the dibutyl and gamma-monobutyl esters of methotrexate in the rhesus monkey.

The pharmacokinetics and metabolism of dibutyl methotrexate (DBMTX) and gamma-monobutyl methotrexate (gamma-MBMTX) were studied in Rhesus monkeys. When a bolus IV dose of either [3H]DBMTX or [3H] gamma-MBMTX was given, the principal species in serum for up to 1 h was the monoester, with MTX accounting for less than 10% of the total radioactivity. Products other than gamma-MBMTX and MTX were formed in substantial amounts with DBMTX, but not with gamma-MBMTX. Total radioactivity recovered in the bile 5 h after [3H]DBMTX injection accounted for 32% of the administered dose, indicating high hepatic extraction for this lipophilic compound. Serum and CSF levels of unchanged gamma-MBMTX, as well as of MTX arising via esterase cleavage, were measured by HPLC after IV infusion of gamma-MBMTX (10 g/m2). Efflux of monoester from CSF was slower than disappearance from serum. However, gamma-MBMTX levels in CSF were no higher than could be attained by infusing MTX itself at the same dose rate. While CSF/serum ratios were ca. 10-fold higher for gamma-MBMTX than for MTX, this difference could be explained on the basis of the very different affinities of the two compounds for serum proteins. HPLC analysis of serum processed by methanol precipitation as opposed to ultrafiltration of the proteins showed gamma-MBMTX to be greater than 99% bound, whereas for MTX this value was 50% or less. When gamma-MBMTX and MTX levels measured after ultrafiltration were corrected for this difference in serum protein binding the total amount of the two drugs in serum became almost equivalent.

Animals↗
PubMed1982

New implantable continuous administration and bolus dose intracarotid drug delivery system for the treatment of malignant gliomas.

A totally implantable system for the continuous and bolus delivery of intra-arterial chemotherapeutic agents to patients with malignant gliomas is described. The system utilizes an Infusaid pump (Infusaid Corp., Sharon, Massachusetts), which discharges the drug directly into the internal carotid artery and is percutaneously refillable. This system has been utilized experimentally in primates and in the treatment of six patients with malignant gliomas. It seems that this system can be utilized safely as an experimental technique in the treatment of malignant gliomas.

Adult↗
PubMed1982

Benefit from and tolerance to continuous intrathecal infusion of morphine for intractable cancer pain.

A patient with painful bilateral metastatic lumbosacral plexopathy from cervical cancer was treated with levorphanol tartrate (Levo-Dromoran), 4 mg orally every 4 hours, with poor pain relief. A lumbar subarachnoid catheter was then placed percutaneously. A bolus of 1 mg of morphine gave complete pain relief for 17 hours. Over the next week, the dose requirement increased to 10 mg/day, infused by an external pump. A permanently implantable infusion pump with a 50-cc drug chamber and flow rate of 3.4 cc/day was placed in the abdomen and attached to the lumbar subarachnoid catheter. The pump was refilled by percutaneous injection. Morphine was infused continuously at 15 mg/day, affording the patient increased mobility and no pain for 7 days. When the pain returned, the morphine dose was increased to 17.5 mg/day, and the patient was allowed to take oral Levo-Dromoran for pain. The intrathecal morphine dose was constant within 2-week periods, but was increased from 17.5 to 96 mg/day because of inadequate pain relief. Oral Levo-Dromoran intake averaged 3.4 mg/day. Levo-Dromoran intake was less during the 1st week of each 2-week cycle than the last week (mean 15.0 versus 38.0 mg/wk, p less than 0.05). No sedation or respiratory depression was seen.

Adenocarcinoma↗
PubMed1982

Stability of cancer chemotherapeutic agents in a totally implanted drug delivery system.

The stability and compatibility of serveral chemotherapeutic agents with an implantable infusion device were evaluated. The totally implantable drug delivery system can be placed subcutaneously in an ambulatory patient to permit the regional administration of antineoplastic drugs. The in vitro method of assessing the stability of three chemotherapeutic agents with the pumping device involved placing the pumps, filled with cytarabine, dichloromethotrexate, and vinblastine, in a 37 degree C water bath with mild agitation. Control solutions placed in amber vials were maintained under simulated physiological conditions. Samples (1 ml) were removed periodically, frozen at -20 degrees C and later toward and batch assayed by high pressure liquid chromatography to determine drug concentrations. An in vivo assessment of the stability of floxuridine was also conducted in five patients receiving intra-arterial hepatic infusions by the device. The concentrations placed in the pump were compared with the contractions removed at the time of refill. Cytarabine and dichloromethotrexate showed no appreciable drug decomposition in the control vials or the pump over the 15-day and 28-day study periods, respectively. Vinblastine underwent a 48% and 20% drugs loss in the pump and control, respectively, during a 14-day period. In the vivo assessment of floxuridine, less than 5% drug degradation was found for infusion times ranging from four to 12 days. Cytarabine, dichloromethothrexate, and floxuridine were stable and compatible with the implantable infusion evice, and vinblastine was found to be unstable. The compatibility of all agents with the infusion device should be evaluated before clinical application.

Antineoplastic Agents↗
PubMed1982

Perfusion scintigraphy (Tc-99m MAA) during surgery for placement of chemotherapy catheter in hepatic artery: concise communication.

In 17 patients receiving regional hepatic chemotherapy, Tc-99m macroaggregated albumin imaging was used to aid arterial catheter placement and to assess perfusion patterns. Intraoperative imaging with a portable gamma camera allowed immediate monitoring of hepatic and extrahepatic perfusion patterns and assisted catheter manipulation when necessary to achieve optimal flow distribution. In all 12 patients with standard hepatic arterial anatomy, complete perfusion of both lobes of the liver was achieved, although three of them required intraoperative catheter manipulation and repeat imaging after initial placement. The remaining five patients had aberrant hepatic arterial anatomy, and complete perfusion was more difficult to achieve; they exemplified the need for dual catheters, ligation of accessory hepatic branches, and repeated imaging.

Adenocarcinoma↗
PubMed1982

High-dose doxorubicin: an exploration of the dose-response curve in human neoplasia.

Twenty-seven patients with advanced solid tumors (ten with lung cancer, eight with sarcoma, five with melanoma, four with miscellaneous tumors) were treated with high-dose doxorubicin (120 mg/m2) every 3 weeks for a total of 75 courses. As expected, marked myelosuppression was observed, with all patients having a granulocyte count nadir of less than 500 cells/mm3. The median platelet count nadir was 91 X 10(3)/mm3 following the first cycle and 50 X 10(3)/mm3 following the fourth cycle. Moderate or severe stomatitis was seen with 65% of the courses, and 46% of the courses were complicated by fever greater than 101 degrees F. Congestive heart failure was observed in only one patient after five cycles (600 mg/m2) of high-dose therapy. This patient has received 540 mg/m2 of doxorubicin 2 years previously. Radionuclide ventriculography (MUGA) performed serially in 12 patients (eight of whom received 480 mg/m2) and clinical evaluation did not suggest an increased risk of cardiotoxicity at this dose rate. Overall, 11 of 24 (46%) evaluable patients responded (58% if patients with malignant melanoma are excluded). Responses included one complete and three partial responses in eight evaluable patients with lung cancer, one complete and two partial responses in seven evaluable patients with sarcoma, and no objective responses in five patients with malignant melanoma. With appropriate supportive care, repetitive courses of doxorubicin at a dose of 120 mg/m2 can be given to patients of good performance status without a major increase in cardiotoxicity. However, the low complete remission rate, considering the observed toxicity, does not justify routine use of this regimen in patients with solid tumors.

Adult↗
PubMed1979

Technique for preclinical evaluation of continuous infusion chemotherapy with the use of WF rat acute myelogenous leukemia.

A technique was developed for continuous iv infusion chemotherapy in an inbred rat model of acute myelogenous leukemia. Polyethylene tubing was inserted surgically into the internal jugular vein of adult WF rats, burrowed sc to the base of the tail, and connected to an infusion pump. A flexible spring was sutured at the base of the tail and fastened to the cage wall; it protected the infusion catheter and allowed movement of the rat within the cage. This technique was used to compare bolus with continuous infusion therapy with adriamycin, cytosine arabinoside, and neocarzinostatin. Only small differences were noted in host toxicity and in antitumor effect against tumor grown as a subcutaneous myeloblastoma. Nearly three times more neocarzinostatin was required by continuous infusion for an effect equivalent to that of bolus injection. In contrast, continuous infusion of methotrexate with concurrent thymidine infusion prevented toxicity, enhanced the antitumor effect, and prolonged survival. This infusion system should facilitate rapid preclinical evaluation of drugs considered for constant iv infusion therapy.

Animals↗
PubMed1979

A Phase 1 study of high doses of aminopterin with leucovorin rescue in patients with advanced metastatic tumors.

We have conducted a Phase 1 study of aminopterin (AMT) with leucovorin (LV) in 17 patients. AMT was administered by bolus injection every 7 to 14 days in dosages from 25 to 425 mg/sq m. LV rescue was instituted at 24 hr and continued for 48 to 72 hr. At dosages above 50 mg/sq m, we observed nephrotoxicity defined as greater than or equal to a 25% increase in serum creatinine 24 hr after AMT administration, but its incidence was not strictly dose related. Urinary alkalinization and volume expansion appeared to reduce the incidence of nephrotoxicity. Nephrotoxic drug courses were associated with 24-hr plasma AMT levels [3.6 +/- 2.0 (S.D.) X 10(-6) M] which were significantly higher than nonnephrotoxic courses (1.6 +/- 1.0 x 10(-6) M) (p less than 0.05). In nonnephrotoxic courses, serum elimination pharmacokinetics appeared to be biphasic with a t1/2 alpha of 1.08 +/- 0.01 hr and t1/2 beta of 12.31 +/- 0.06 hr. Systemic toxicity (myelosuppression and mucositis) could be prevented in patients with impaired AMT clearance by the administration of LV at an increased dose rate. In several courses, systemic toxicity occurred in spite of apparently normal plasma clearance, suggesting that 24-hr plasma levels may not accurately reflect intracellular drug effects. Cytokinetic studies on bone marrow aspirates allowed determination of the rescue effect of LV and may prove useful in predicting marrow protection.

Aminopterin↗