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Biomedical subjects

L B Grochow

Publications and source records attributed to L B Grochow.

At least 91 records · Page 5Linked to original sources
PubMed1988

Clinical pharmacology of oral and i.v. N-methylformamide: a pharmacologic basis for lack of clinical antineoplastic activity.

N-Methylformamide (NMF) has been an agent of considerable interest to oncologists because of its broad spectrum of preclinical antitumor activity, tumor-differentiating abilities, and radiosensitizing and chemosensitizing properties. In this report, the pharmacokinetics of NMF are described, based on data from two phase I studies exploring both iv and oral routes of administration. Mean peak NMF plasma concentrations at recommended phase II doses were 0.46 mmol/L for NMF administered orally, 600 mg/m2 three times/week X 4 weeks every 6 weeks, and 2.78 mmol/L for NMF administered as a weekly iv bolus at 2,000 mg/m2 X 3 weeks every 4 weeks. These NMF concentrations were significantly lower than the concentrations that have been demonstrated to induce antineoplastic and relevant biologic effects in preclinical studies. Plasma disappearance curves were biphasic in the majority of patients; however, 25% of the curves were best fit by a monoexponential kinetic model. Mean alpha half-life and beta half-life values (+/- SE) were 10 +/- 2 and 732 +/- 93 min, respectively. Volumes of distribution for the theoretical central compartment (Vc) and at steady-state (Vss) were 13.8 +/- 1.1 L/m2 and 18.7 +/- 1.1 L/m2, respectively. The mean plasma clearance of NMF was 19.1 +/- 2.1 mL/min per square meter, and the relative contributions to parent compound disposition by respiratory and renal routes were insignificant. No metabolites were identified. Gastrointestinal absorption of oral NMF was rapid and nearly complete; oral bioavailability was calculated to be 0.87. Pharmacodynamic associations were observed between the magnitude of the area under the plasma disappearance curves and hepatotoxicity, the dose-limiting toxic effect of iv NMF, and the symptom complex of nausea, vomiting, and malaise, which precluded dose escalation of oral NMF.

Administration, Oral↗
PubMed1988

Determination of busulfan in human plasma by gas chromatography with electron-capture detection.

A simple and highly sensitive gas chromatographic method has been developed for the determination of busulfan in human plasma. After extraction of plasma specimens (clinical or spiked) with ethyl acetate, busulfan and the internal standard [1,8-bis(methanesulfonyloxy)octane] were derivatized with 2,3,5,6-tetrafluorothiophenol to yield compounds monitored by a 63Ni electron-capture detector. Sample recoveries from extraction and derivatization were greater than 78 and 91%, respectively. The limit of quantitation was 0.01 microgram/ml (0.04 microM) in 1 ml of plasma with a linear relationship over the 0.01-1.0 micrograms/ml (0.04-4 microM) concentration range. The method has been applied to analyze the plasma versus time profile of busulfan in human subjects following administration of an oral dose of 4 mg/kg per day as a marrow ablative chemotherapy for bone marrow transplantation.

Biological Availability↗
PubMed1987

Clinical and pharmacologic effects of high dose single agent busulfan with autologous bone marrow support in the treatment of solid tumors.

A Phase I-II clinical trial of high dose single agent busulfan (16-20 mg/kg) administered over a 4-day period was undertaken. Pharmacokinetic measurements reveal that steady state total plasma busulfan levels between 2 and 10 microM were achieved by the second day and maintained through the remaining treatment period. Urinary excretion of mutagenic activity monitored by the Salmonella mutagenesis assay persisted for up to 48 h following the last dose of busulfan. The treatment showed specificity for myelocytic precursors as evidenced by selective depression of granulocytes with relative sparing of lymphocytic elements, and by differences in DNA damage as measured by a nucleoid sedimentation assay. Dose limiting toxicity was mucositis, anorexia, and hepatic toxicity. Transient autoimmune disorders were observed in three of the six patients. Partial responses were seen in two of five patients with melanoma, but these lasted for only 2 and 3 months. High dose busulfan represents an alkylating agent with marked myelocytic selectivity and may be useful for inclusion in intensive combination regimens.

Adult↗
PubMed1987

Prolonged infusion of hexamethylene bisacetamide: a phase I and pharmacological study.

Hexamethylene bisacetamide (HMBA, NSC 95580), a potent polar-planar differentiating agent in vitro, was studied in a phase I trial as a 10-day continuous infusion administered every 4 weeks. Since preclinical evidence had demonstrated that the duration of HMBA exposure was an important variable in the induction of differentiation, and HMBA steady-state concentrations (Css) achieved during 5-day infusions were minimally effective at inducing in vitro differentiation, this study was conducted to evaluate the feasibility of maintaining HMBA Css for 10 days similar to levels achieved and maintained for 5 days. Twelve patients received 17 evaluable courses at three dose levels, 12, 15.8, and 20 g/m2/day. Platelet toxicity limited further dose escalation. Mean nadir and percentage of decrement in platelet counts were 175,000/microliter and 66%, and 43,500/microliter and 83%, at 15.8 and 20 g/m2/day, respectively. In this 10-day study, the percentage of decrement of platelet counts was linearly related to mean HMBA Css and to the area under the plasma concentration versus time curve (AUC). However, when combined platelet and pharmacological data from both 5- and 10-day studies were analyzed, it was apparent that the duration of HMBA exposure was an additional significant variable in predicting the magnitude of thrombocytopenia. Renal and metabolic toxicities that precluded dose escalation in previous 5-day trials of HMBA were mild and insignificant in this study. Mean HMBA Css were 0.65 +/- 0.09 mmol/liter at 15.8 g/m2/day, and 0.99 +/- 0.22 mmol/liter at 20 g/m2/day. Depletion of intracellular polyamines in peripheral blood mononuclear leukocytes was noted during several courses that were associated with profound myelosuppression, but no clear relationships were apparent between the magnitude of polyamine changes and toxicity or between fluctuations in polyamines and the magnitude of mean HMBA Css values. Based on this study, the maximum tolerated and recommended phase II doses for HMBA administered on this schedule were 20 and 15.8 g/m2/d, respectively. The administration of HMBA by a ten-day infusion at the maximum tolerated dose resulted in the delivery of lower daily doses and lower HMBA Css than on the 5-day schedule. The major toxicities differed on these schedules with thrombocytopenia being most prominent on the 10-day schedule and metabolic and CNS toxicities on the 5-day schedule.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetamides↗
PubMed1987

Unusual opioid withdrawal syndrome. A case-report.

In a patient with advanced cancer, neurosurgery relieved severe pain that had been uncontrolled by very high doses of opioids. On reduction of opioid dosage he had visual and auditory hallucinations and showed deterioration of consciousness progressing to coma. Naloxone worsened his mental state whereas morphine restored it to normal. This syndrome may be related to opioid withdrawal at receptors other than the mu receptors that have been linked to analgesia and drug abuse.

Aged↗
PubMed1987

A reservoir model for repeated CSF access in the rabbit.

A simple, reliable and inexpensive subcutaneously implanted reservoir-catheter system method was developed for repeated sterile access to the rabbit brain ventricular system. The system provides an avenue for the repeated intrathecal administration of drugs and for the withdrawal of cerebrospinal fluid (CSF). Reservoirs were subcutaneously implanted under the scalp and connected to tubing inserted into the cisterna magna or the lateral ventricle. The systems successfully functioned in 38 of 41 animals (12 with cisternal magna catheters and 29 with lateral ventricle catheters), for up to 12 weeks following implantation. Patency of the systems were documented with X-rays and radiopaque injected contrast medium.

Animals↗
PubMed1987

Venoocclusive disease of the liver following bone marrow transplantation.

Review of 235 consecutive patients undergoing bone marrow transplantation was performed in order to define the clinical syndrome of venoocclusive disease of the liver (VOD) in these patients. Analysis of all patients with histologically proven VOD revealed a consistent clinical syndrome of liver dysfunction occurring within the first 3 weeks after marrow infusion. This was characterized by hyperbilirubinemia peaking at greater than or equal to 2 mg/dl with at least 2 of 3 other findings: hepatomegaly, ascites, and 5% or greater weight gain. VOD developed in 22% (52 of 235). A persistently elevated aspartate aminotransferase (SGOT) prior to transplant was associated with an increased risk of developing VOD by multivariate analysis (P = 0.0003), and acute leukemia in first remission was associated with a decreased risk (P = 0.02). Neither the preparative regimen (busulfan and cyclophosphamide versus cyclophosphamide and total body irradiation) nor the type of graft (allogeneic versus autologous) influenced the occurrence. Twenty-four of these 52 patients (47%) died with VOD (10% of the entire group). This makes VOD the third leading cause of death in our allogeneic graft recipients, and the second leading cause in our patients receiving autologous transplants. VOD is a common complication of bone marrow transplantation and has a specific clinical presentation, which usually allows diagnosis without the need of liver biopsy.

Bone Marrow Transplantation↗
PubMed1987

A phase I study of menogaril in patients with advanced cancer.

Menogaril (7-con-O-methylnogarol) is a semisynthetic anthracycline analogue of nogalamycin that has shown good activity against a variety of experimental tumor systems as well as decreased cardiac toxicity when compared with doxorubicin in preclinical studies. Forty-one patients with refractory solid tumors received menogaril during a phase I trial at The Johns Hopkins Oncology Center (Baltimore). Menogaril was administered as an intravenous (IV) infusion on days 1 and 8 of a 28-day cycle in doses of 8 to 140 mg/m2. Eastern Cooperative Oncology Group (ECOG) grade 3 and 4 leukopenia was the principle dose-limiting toxicity and was occasionally accompanied by thrombocytopenia. Both WBC and platelet nadirs occurred between days 15 and 22. Anemia requiring transfusion was occasionally seen. Nonhematologic toxicities observed included frequent anorexia and malaise that was not dose related and postinfusion phlebitis that was dose related and occasionally dose limiting. Gastrointestinal toxicity and alopecia were infrequent and mild in severity. Three patients with cumulative doses of menogaril greater than 1,400 mg/m2 had no significant changes in ejection fractions as determined by serial gated blood pool scans. Two patients had greater than 10% decrements in ejection fractions without clinical changes at total doses of 128 and 288 mg/m2. One patient with prior anthracycline therapy and chest irradiation decreased her left ventricular ejection fraction from 52% to 30% and developed respiratory failure after two cycles of therapy in the setting of disease progression. No responses to menogaril therapy were observed. The recommended phase II dose for menogaril on this day 1 and 8 schedule is 140 mg/m2. A starting dose of 90 mg/m2 should be considered for heavily pretreated patients. In comparing results of this phase I schedule with those of other schedules, evidence for schedule-dependent toxicity differences should be sought.

Adult↗
PubMed1987

High-performance liquid chromatographic assay for taxol in human plasma and urine and pharmacokinetics in a phase I trial.

Taxol is a unique antineoplastic agent which appears to exert its cytotoxic action as a result of interference with microtubular structure and function. Clinical development of this drug will be facilitated by the availability of sensitive and specific methods for its quantitation in biological fluids. We have developed a reverse-phase high-performance liquid chromatographic assay for taxol capable of detecting concentrations as low as 50 nM, which can be automated using readily available equipment. With this assay we have performed pharmacologic studies of taxol during the conduct of a phase I trial of this compound at The Johns Hopkins Oncology Center. Following a 60- to 360-minute infusion, the plasma disappearance is biexponential, with harmonic mean alpha half-life and beta half-life values of 16.2 minutes and 6.4 hours, respectively. Volumes of distribution for the theoretical central compartment (VDc) and at steady state (VDss) were 8.6 and 67.1 L/m2. Mean plasma clearance was 253 ml/minute/m2. Urinary clearance was 29.3 ml/minute/m2 and 5.9% +/- 8.8% of the drug was identified in 48-hour urine collections. No metabolites have been identified. Over the 18-fold dose range studied, there was no evidence of nonlinearity or dose-dependent behavior. A rough correlation between area under the plasma disappearance curve and hematologic toxicity was observed.

Alkaloids↗
PubMed1987

Phase I trial of taxol in patients with advanced cancer.

Taxol is a unique plant-derived antineoplastic agent that appears to exert its cytotoxic effect by interfering with microtubule structure and function. In this phase I trial, in which the drug was given as a brief iv infusion every 3 weeks, the dose-limiting toxicity was leukopenia, with thrombocytopenia being seen much less frequently. Sensory neuropathy was frequently seen at the highest dosage, with numbness and paresthesias appearing in a glove-and-stocking distribution. In some cases, this appeared to be a cumulative effect. Total alopecia was common. Other toxic effects observed included nausea and vomiting, mucositis, myalgias, and phlebitis. The frequent occurrence early in the study of acute cardiovascular and pulmonary toxicity suggestive of hypersensitivity reactions was decreased in frequency and severity by prolonging the infusions and premedication with corticosteroids and antihistamines. Two heavily treated patients appeared to respond to this agent, one with non-small cell lung cancer and one with ovarian cancer. Based on these data, we recommend a starting dose in phase II trials of 212 mg/m2 in patients with minimal prior therapy and 170 mg/m2 in heavily treated patients. At least initially, these trials should be carried out in institutions familiar with the use of this drug.

Alkaloids↗
PubMed1986

Phase I and pharmacologic study of hexamethylene bisacetamide in patients with advanced cancer.

Hexamethylene bisacetamide (HMBA, NSC 95580) has been demonstrated to be the most effective of the known and studied polar-planar compounds at inducing differentiation in a wide variety of leukemic and nonleukemic cell lines. Although HMBA demonstrated no antineoplastic activity in preclinical testing, it was selected for clinical development on the basis of its potent differentiating capabilities in vitro. In this phase I study, HMBA was administered as a continuous five-day infusion every 3 weeks to patients with advanced cancer. Twenty-three patients received 35 evaluable courses at doses that ranged from 4.8 to 33.6 g/m2/d. Dose-limiting toxicities included renal insufficiency, a hyperchloremic metabolic acidemia/acidosis, and CNS toxicities manifested by agitation and delirium, which progressed to coma in one patient who developed concomitant renal insufficiency. Moderate myelosuppression, mucositis, nausea, and vomiting were also observed. The pharmacokinetics of HMBA best fit a single compartmental model and disposition is primarily by renal elimination. Renal excretion of HMBA and of the primary metabolite, 6-acetoamidohexanoic acid, together account for the disposition of 66% to 93% (mean, 74%) of the infused drug. Based on this trial, the maximum tolerated and recommended phase II doses for HMBA administered on this schedule are 33.6 and 24 g/m2/d, respectively. However, since steady-state HMBA levels at these doses were in the range of 1 to 2 mmol/L, only approaching the lower limit demonstrated for in vitro differentiating effectiveness, and because of evidence suggesting that the exposure period is an important variable in the induction of differentiation, additional studies examining longer periods of infusion are warranted.

Acetamides↗
PubMed1985

Tastes associated with parenteral chemotherapy for breast cancer.

We employed a structured interview to retrospectively study tastes and vomiting associated with the parenteral components of cyclophosphamide, methotrexate, and 5-FU in 45 patients with stage II-IV breast cancer. Sixteen patients (36%) reported tastes which generally occurred in each cycle within 30 minutes of parenteral drug administration, lasted less than or equal to 1 hour, and were bitter. Five patients recalled that tastes seemed to produce vomiting. Tasting was significantly associated with postchemotherapy (P less than 0.01) but not anticipatory vomiting. Employing logistic regression techniques, tasting did not significantly improve prediction of anticipatory vomiting by postchemotherapy vomiting. Tastes may be produced by the action of plasma or salivary cyclophosphamide, methotrexate, and 5-FU on taste buds. While tastes might cause some vomiting, they are not necessary for it. Because this was a retrospective study with a small sample, these findings require confirmation.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1984

Acute anthracycline cardiotoxicity. Comparative morphologic study of three analogues.

Chemotherapeutic use of anthracycline antibiotics is limited by their cardiotoxic effects. A potential solution to this problem is the development of anthracycline analogues retaining antitumor efficacy but without cardiac toxicity. An isolated perfused rabbit heart model was used to compare the nature and extent of early ultrastructural effects on the myocyte of three anthracycline analogues purported to have lesser cardiotoxicity than Adriamycin (doxorubicin). Seventeen rabbit hearts were perfused with oxygenated Krebs-Ringer bicarbonate buffer at 39 degrees C containing either Adriamycin (4 mg/L), daunomycin (10.6 mg/L), aclacinomycin (8 mg/L), or rubidazone (17.6 mg/L). For comparison, three hearts each were exposed to phosphoramide mustard (14.7 mg or 25 mg/L) or 4-hydroperoxy cyclophosphamide (24 mg or 17 mg/L), two active congeners of cyclophosphamide, an agent interacting with DNA differently than the anthracyclines and which is known to be cardiotoxic in high dose. Two hearts were exposed to dactinomycin (0.1 mg or 0.2 mg/L) which intercalates with DNA in a manner similar to the anthracyclines but which is not cardiotoxic. Ten control hearts were perfused with oxygenated buffer solution only. Light microscopic study disclosed no differences between treated and control hearts. Electron microscopic examination showed a striking and distinctive clumping of nuclear chromatin with clearing of chromatin from the nuclear membrane in all anthracycline treated hearts but in no hearts treated with 4-hydroperoxy cyclophosphamide, phosphoramide Mustard, dactinomycin, or control hearts. The nuclear effects of the four anthracycline analogues were indistinguishable. Thus, all anthracycline analogues studied produced acute nuclear alterations which were distinctive from the changes produced by other DNA interactive chemotherapeutic agents. The relationship of the distinctive anthracycline nuclear changes to the late cardiomyopathy requires further definition.

Aclarubicin↗
PubMed1982

Improved rabbit brain tumor model amenable to diagnostic radiographic procedures.

The VX2 carcinoma was used to create a rabbit brain tumor model. VX2 tumors were chemically dissociated and suspended in liquid medium. Twenty-five microliters of the tumor suspension containing 3 X 10(3), 3 X 10(4), or 3 X 10(5) viable tumor cells were injected through cranial burr holes 6 mm into the right frontoparietal lobes of 17 rabbits. Fifteen of these developed histologically documented nodular intraparenchymal tumors. Tumors were demonstrable with cerebral computed tomographic scans and by cerebral angiography. The feasibility of surgical resection of lesions using the fluorescein staining technique was also demonstrated. This animal brain tumor model is suitable for neuro-oncology research focusing on imaging and therapeutic techniques.

Animals↗
PubMed1982

The course of nausea and vomiting after high-dose cyclophosphamide.

We studied the course of nausea and vomiting after high-dose cyclophosphamide (50-75 mg/kg) in 25 patients. Nausea was assessed with a visual analog scale and vomiting by patient report. The reliability and validity of these methods of assessment were established in separate studies of oncology patients. Nausea and vomiting developed between 6 and 12 hours after the start of a 1-hour cyclophosphamide infusion in about two thirds of the patients. Peak symptoms were at 12 hours. Vomiting had subsided in most of the patients by 24 hours, but nausea persisted. Although there was significant individual variation in the course of nausea and vomiting, we could identify no demographic, disease, drug, or treatment factors which were associated with more significant nausea and vomiting. Some of the variability in the onset, severity, and duration of nausea and vomiting may be related to individual differences in the metabolism of and susceptibility to cyclophosphamide. The visual analog scale may provide information about nausea not obtained by the more frequently employed categoric verbal rating scales. Suggestions for the treatment of nausea and vomiting after high-dose cyclophosphamide are made on the basis of the findings.

Adult↗