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Biomedical subjects

M G Kris

Publications and source records attributed to M G Kris.

At least 91 records · Page 5Linked to original sources
PubMed1993

Enhancing the effectiveness of the specific serotonin antagonists. Combination antiemetic therapy with dexamethasone.

Combinations of drugs have become standard therapy for the prevention of vomiting caused by anticancer drugs like cisplatin. Recently, a new class of antiemetic agents, the potent and specific 5-HT3 receptor antagonists such as ondansetron, granisetron, and tropisetron, have been shown to be more effective and better tolerated than metoclopramide. This report describes the rationale for combination antiemetic therapy, details the testing of metoclopramide-based regimens as a model for combination therapy development, reviews completed trials of ondansetron plus dexamethasone, and offers strategies to further alleviate vomiting during anticancer chemotherapy. The reported trials testing metoclopramide-based combinations were reviewed and that experience was applied to the ongoing studies of ondansetron when used with dexamethasone and other agents. Combinations of metoclopramide, dexamethasone, and lorazepam prevented acute emesis caused by high-dose cisplatin in 63% of patients, lessened side effects, and were convenient enough to administer to outpatients. Completed trials of ondansetron and dexamethasone demonstrated improved vomiting control over ondansetron alone while using less cumbersome schedules. Attempts to improve ondansetron-based antiemetic regimens by developing optimal drug doses and schedules and adding adjuvant and different classes of antiemetic agents are now in clinical testing. Based on previous experience and current results, combinations of a specific serotonin agonist and dexamethasone are the best treatment for prevention of vomiting induced by chemotherapy. Future clinical research should aim to refine antiemetic regimens and improve emetic control through the use of new antiemetic and adjuvant agents.

Antiemetics↗
PubMed1993

Constitutive variability in the pharmacokinetics of the natural retinoid, all-trans-retinoic acid, and its modulation by ketoconazole.

BACKGROUND: All-trans-retinoic acid (all-trans RA) induces complete remission in most patients with acute promyelocytic leukemia (APL). However, continuous oral dosing results in progressive decline in plasma drug concentrations, which is associated with relapse and resistance to this retinoid. We speculated that the decline in drug levels, indicating acquired resistance, resulted partly from inducible cytochrome-P450 oxidative enzymes, which can catabolize all-trans RA. PURPOSE: We studied the clinical pharmacology of all-trans RA in cancer patients to determine possible mechanisms of acquired resistance and evaluated the potential for reversal by ketoconazole, an inhibitor of cytochrome-P450 oxidative enzymes. METHODS: Serial plasma samples were obtained from 54 patients with APL or advanced lung cancer after a single oral dose of all-trans RA (45 mg/m2). In the 34 patients with advanced lung cancer, all-trans RA (45 mg/m2) was administered twice daily for 4 weeks, and, on days 2, 28, and 29, serial plasma samples were again obtained after a single 45-mg/m2 dose. One hour prior to drug administration on days 2 and 29, a single oral dose (200-1200 mg) of ketoconazole was administered. Endogenous plasma concentrations of all-trans RA and 13-cis-retinoic acid were measured in a subset of these patients and in 11 with early-stage lung cancer. RESULTS: The mean area under the curve for plasma drug concentration times time (AUC) for all-trans RA on day 1 varied substantially among patients. Compared with patients with APL, the 28 patients with advanced lung cancer who completed therapy demonstrated significantly lower AUC levels on day 1 (P = .06); a subgroup with levels less than 300 ng/mL per hour on day 1 had lower endogenous plasma all-trans RA concentrations than patients with APL or early-stage lung cancer or 14 normal subjects. Following continuous oral treatment, the mean day 28 AUC for all-trans RA was significantly lower than that on day 1 (213 ng/mL per hour versus 467 ng/mL per hour; P < .01), a decline significantly attenuated by ketoconazole, which increased the mean plasma all-trans RA AUC on day 29 to 375 ng/mL per hour (P < .01). CONCLUSION: Reported variability for the pharmacokinetics of all-trans RA may result from disease-related or population-based differences in basal catabolic rates influenced by genetic or environmental factors. However, the pattern of inducible catabolism of all-trans RA is not disease specific. Ketoconazole attenuates this accelerated catabolism, suggesting that oxidation by cytochrome-P450 enzymes is an important pathway for both constitutive and induced pathways of all-trans RA metabolism.

Carcinoma, Non-Small-Cell Lung↗
PubMed1993

Dose-ranging antiemetic evaluation of the serotonin antagonist RG 12915 in patients receiving anticancer chemotherapy.

BACKGROUND: RG 12915 is a potent, selective 5-HT3 receptor antagonist with a biologic half-life of 11-20 hours. RG 12915 prevents cisplatin-induced emesis in ferrets at doses of 0.03 mg/kg. Animal toxicology studies permitted safe testing in humans at doses of up to 2.0 mg/kg. This dose-ranging trial of intravenous RG 12915 was performed to determine the optimal dosage and adverse effects and to observe for antiemetic effects in patients receiving anticancer chemotherapy. METHODS: Twenty-six patients receiving chemotherapy likely to cause vomiting received a single intravenous dose of RG 12915 at a rate of 3 ml/minute beginning 60 minutes before chemotherapy. Four dose levels were explored: 0.25, 0.50, 1.0, and 2.0 mg/kg. RESULTS: No dose-limiting toxicities were observed. All adverse effects were mild and transient and included discomfort at the infusion site, hyperglycemia, headache, serum aspartate transaminase (AST) and alanine transaminase (ALT) elevations, and sedation. Antiemetic efficacy was seen in patients receiving cisplatin at doses of greater than or equal to 100 mg/m2. CONCLUSION: RG 12915 can be administered safely at the dose levels explored. Single intravenous doses of RG 12915 prevented or lessened emesis caused by chemotherapy, including cisplatin given at doses of greater than or equal to 100 mg/m2. RG 12915 warrants further testing. Of the doses tested, the 2.0 mg/kg dose is the most appropriate for further exploration.

Adolescent↗
PubMed1993

Dose-ranging antiemetic evaluation of the serotonin antagonist tropisetron in patients receiving anti-cancer chemotherapy.

BACKGROUND: Tropisetron (ICS 205-930) antagonizes the serotonin type 3 receptor and has antiemetic activity in animals given cisplatin. Its mean serum half-life in 11.1 hours. METHODS: In this dose-ranging trial, 22 patients undergoing anti-cancer chemotherapy received 24 courses of a single intravenous infusion of tropisetron beginning 30 minutes before chemotherapy. Four dose levels were explored (range, 12-48 mg/m2). RESULTS: Toxicities were mild and included headache, transient elevations of serum alanine transaminase and/or aspartate transaminase levels, and sedation. No akathisia or acute dystonic reactions were observed. Thirty-six percent of patients had no emesis, and 58% had two or fewer emetic episodes. Ten patients received high-dose cisplatin (dose, > or = 100 mg/m2) as initial chemotherapy. Of these, 30% had no emesis, and 60% had two or fewer episodes. CONCLUSIONS: Tropisetron can be administered safely in the doses tested with no dose-limiting toxicities. The encouraging antiemetic efficacy, mild toxicities, lack of extrapyramidal effects, and convenience of a single 15-minute infusion regimen make this drug appropriate for study in additional trials.

Adult↗
PubMed1993

Dose-ranging evaluation of the substituted benzamide dazopride when used as an antiemetic in patients receiving anticancer chemotherapy.

Dazopride, a substituted benzamide structurally related to metoclopramide, is a potent gastric prokinetic agent that prevents cisplatin-induced emesis in animals. Unlike metoclopramide, dazopride has no effect on dopamine receptors and therefore should not produce extrapyramidal side effects. In this dose-ranging trial, 23 patients with cancer receiving chemotherapy known to produce nausea and vomiting received three i.v. infusions of dazopride every 2 h beginning 30 min before the chemotherapy. Seven dose levels were explored ranging from 0.5 to 4.0 mg/kg in each of the three infusions. Toxicities were mild and included sedation, dizziness, visual disturbances, and headaches. All side effects were transient and were not dose-related. Antiemetic effects were observed. Dazopride can be safely given on this schedule at doses of up to 4.0 mg/kg to patients receiving chemotherapy. On the basis of the results of this trial, further studies of this agent are warranted.

Adult↗
PubMed1993

Phase II trial of gallium nitrate in previously treated patients with small cell lung cancer.

Gallium nitrate is a group IIIa metal that was found to be active in animal species. Gallium nitrate exerts its antitumor effects via a transferrin binding mechanism. This agent is of interest in small cell lung cancer since 26 of 27 small cell carcinoma cell lines tested had increased levels of transferrin receptors. In a phase I study using a continuous infusion, the dose limiting toxicity was nausea when gallium nitrate was given at doses of 400 mg/m2/day. Other effects included elevations of serum creatinine, hypocalcemia, hypomagnesemia, decreased hearing and paresthesias. Activity has been seen in pretreated patients with malignant lymphoma, bladder carcinoma and small numbers of patients with small cell lung carcinoma. To determine the activity of continuous infusion gallium nitrate, this phase II trial was undertaken in patients with small cell lung cancer previously treated with chemotherapy.

Adult↗
PubMed1993

Preoperative chemotherapy for stage IIIa (N2) lung cancer: the Sloan-Kettering experience with 136 patients.

From 1984 to 1991, 136 patients with histologically confirmed non-small cell lung cancer and stage IIIa (N2) disease received two to three cycles of MVP (mitomycin + vindesine or vinblastine + high-dose cisplatin) chemotherapy. All patients had clinical N2 disease, defined as bulky mediastinal lymph node metastases or multiple levels of lymph node involvement in the ipsilateral mediastinum or subcarinal space on chest roentgenograms, computed tomographic scans, or mediastinoscopy. The overall major response rate to chemotherapy was 77% (105/136). Thirteen patients had a complete response and 92 patients had a partial but major response (> 50%). The overall complete resection rate was 65% (89/136) with a complete resection rate of 78% (82/105) in patients with a major response to chemotherapy. There was no histologic evidence of tumor in the resected specimens of 19 patients. The overall survival was 28% at 3 years and 17% at 5 years (median, 19 months). For patients who had complete resection, the median survival was 27 months and the 3-year and 5-year survivals were 41% and 26%, respectively. There were seven treatment-related deaths, five of which were postoperative deaths. To date, 33 patients, all of whom had complete resection, have had no recurrence after treatment. These results demonstrate that (1) preoperative chemotherapy with MVP produces high response rates in stage IIIa (N2) disease, (2) high complete resection rates occur after response to chemotherapy, and (3) survival is longest in patients who have a complete resection after major response to chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Midazolam in patients receiving anticancer chemotherapy and antiemetics.

Benzodiazepines lessen anxiety and improve comfort in cancer patients. Midazolam is an effective benzodiazepine with a rapid onset and short duration of action, properties that could permit its use in outpatient areas or in short but stressful situations. Two consecutive trials were undertaken to study midazolam as an adjunct in patients receiving anticancer chemotherapy. Each studied midazolam given as a short infusion 30 min prior to chemotherapy at dose levels ranging from 0.01 to 0.05 mg/kg. Trial I determined the safety, sedation, and dose of midazolam in patients receiving chemotherapy of low to moderate emetic potential. Twenty-two patients were entered. No significant respiratory depression or oxygen desaturation was observed. At the optimal dose level (0.04 mg/kg), sedation began a median of 3 min following administration and continued for a median of 38 min. Sixty-four percent of patients experienced mild sedation. Trial II studied the same doses of midazolam when used in combination with intravenous metoclopramide and dexamethasone in patients receiving cisplatin > or = 100 mg/m2. Nineteen patients were entered; 79% experienced mild sedation. At the 0.04-mg/kg dose level, sedation began a median of 18 min following administration and continued for a median of 170 min. Midazolam can be given safely to patients receiving chemotherapy with and without concomitant antiemetics. The predictability and duration of its sedative effects suggest it can be used in outpatients.

Adult↗
PubMed1993

Quality of life assessment in individuals with lung cancer: testing the Lung Cancer Symptom Scale (LCSS).

This paper presents the continued development and multi-institutional testing of an instrument focusing on measuring the physical and functional dimensions of quality of life. It emphasises evaluation of symptoms associated with lung cancer and their effect on activity status. The Lung Cancer Symptom Scale (LCSS) is a disease- and site-specific instrument which has both a patient and an observer (health care professional) form. The patient scale required 8 min to administer and the observer scale 2 min. The readability index was second-grade level for the patient scale and ninth-grade level for the observer scale. Content validity revealed a mean of 96% agreement for all major symptoms among 52 experts surveyed (confidence interval = 86-99%, P = 0.05). 69 patients with non-small cell and 52 patients with small cell lung cancer confirmed that the symptoms matched their experiences. Interrater reliability showed consistency for all items but one among 21 raters at eight institutions; that one item was consistent for 20 of the 21 raters. Similar results were found on a 9-month interval replication. Using the Kappa statistic to estimate extent of agreement for repeated interrater reliability, almost perfect agreement was obtained (mean coefficients, 0.95-0.98). Using the same rule of agreement as for Kappa (+/- one category) intrarater agreement was 95-100% for all 21 raters. Past test re-test reliability indicated high patient reproducibility for 52 patients (r > 0.75, P < 0.01 for all items). We conclude that (1) the LCSS demonstrates good feasibility, reliability, and content validity, (2) high interrater reliability indicates utility in multicentre trials, and (3) continued testing for internal consistency, construct validity and criterion-related validity is warranted.

Adult↗
PubMed1993

Phase II trial of a single intravenous dose of ondansetron in patients receiving cisplatin > or = 100 mg/m2.

Ondansteron, a serotonin antagonist antiemetic, controls emesis caused by cisplatin when given as multiple 0.15 mg/kg dosages in a variety of administration schedules. This trial evaluated a single 0.45 mg/kg i.v. dose of ondansetron in 21 cancer patients receiving cisplatin at doses > or = 100 mg/m2 as initial chemotherapy. Twenty-five percent of patients had no emetic episodes (95% confidence interval: 9-49%), and 45% had two or fewer emetic episodes (95% confidence interval: 23-69%). No significant adverse effects were seen. In prior trials at this institution in similarly treated patients, ondansetron given in three divided doses yielded a 42% no emesis rate. In this trial a single i.v. 0.45 mg/kg dose of ondansetron prevented emesis in 25% of patients receiving initial cisplatin > or = 100 mg/m2. For this dose of cisplatin and ondansetron, the observed emesis complete control rate was lower than that previously seen using multiple dose schedules.

Adult↗
PubMed1993

Pathologic complete response in advanced non-small-cell lung cancer following preoperative chemotherapy: implications for the design of future non-small-cell lung cancer combined modality trials.

PURPOSE: This report determines the incidence of pathologic complete response in patients with locally advanced non-small-cell lung cancer (NSCLC) treated with mitomycin, vinca alkaloid, and high-dose cisplatin (MVP) chemotherapy, and estimates the effect of MVP on survival. PATIENTS AND METHODS: We have identified and reviewed the course of 21 patients with advanced NSCLC who achieved a pathologic complete response following a median of three preoperative MVP combination chemotherapy courses including vinblastine or vindesine, cisplatin (120 mg/m2), and mitomycin (n = 19). RESULTS: All patients had a major objective response following preoperative chemotherapy and nine (43%) had a clinical complete response. Nine patients with pathologic complete responses were among 73 entered on a preoperative chemotherapy program, yielding an incidence estimate of 12% (95% confidence interval, 6% to 22%). The median survival duration for all 21 patients has not been reached. The median follow-up duration is now 68 months (range, 17 to 109). Survival estimates are 90% at 1 year, 62% at 3 years, and 54% at 5 years. Nine patients have relapsed with initial sites of recurrence as follows: brain (n = 5), other systemic sites (n = 3), and locoregional (n = 1). One patient died in the postoperative period. Eleven patients remain disease-free and all have excellent functional status. CONCLUSION: We have observed pathologic complete responses in approximately 12% of advanced NSCLC patients treated with preoperative MVP chemotherapy. These pathologically determined responses were seen only in patients with major objective responses clinically. Pathologic complete response predicts excellent survival and functional level and should be considered a major end point in the evaluation of preoperative chemotherapy programs.

Adult↗
PubMed1993

Edatrexate, an antifolate with antitumor activity: a review.

Edatrexate (10-ethyl, 10-deaza-aminopterin; 10-EdAM) is one of a group of compounds developed by substitutions at the N10-position of 4-aminofolate. In phase I and II trials, activity has been seen against non-small-cell lung cancer, breast cancer, non-Hodgkin's lymphoma, and cancer of the head and neck. In preclinical studies, a synergistic effect has been reported when edatrexate is combined with other antineoplastic drugs, and enhanced activity has been seen in two combination-chemotherapy phase II studies in patients with non-small-cell lung cancer. In in vivo preclinical studies, edatrexate has demonstrated antitumor activity against mouse solid and ascites tumors as well as human tumor xenografts. The activity is superior to that of methotrexate and the other antifolates tested. The improved therapeutic index of edatrexate appears to be related to its increased entry into, and polyglutamylation within, tumor cells, and its relative exclusion and rapid elimination from sensitive host tissues, compared to methotrexate. Edatrexate is metabolized in the liver and then excreted mainly in the bile. In clinical trials in cancer patients, the dose-limiting and most frequent toxicity is mucositis. Other side effects are generally mild and include myelosuppression, nausea, vomiting, elevations in SGOT, and macular rash. The responses seen in clinical trials along with preclinical data suggest that edatrexate may be a valuable agent in the treatment of cancer. Studies currently underway include the evaluation of edatrexate in small-cell lung cancer and edatrexate in combination with leucovorin, new vinca alkaloids, and cisplatin.

Aminopterin↗
PubMed1992

Phase I clinical and pharmacological study of chloroquinoxaline sulfonamide.

Chloroquinoxaline sulfonamide (CQS) is a halogenated heterocyclic sulfanilamide identified by the in vitro human tumor colony-forming assay as an active agent in a variety of human solid tumors. In this phase I study, 182 courses of CQS were administered intravenously every 28 days to 88 patients at doses ranging from 18 to 4870 mg/m2. Hypoglycemia associated with hyperinsulinemia was the dose-limiting adverse effect at 4870 mg/m2. Supraventricular tachyarrhythmias were observed at doses > 4000 mg/m2. Less common reactions included infusion site phlebitis, nausea, anemia, alopecia, perioral numbness, and diarrhea. Cumulative toxicity was not observed. Minor objective antitumor responses were noted in 7 patients; 6 of the 7 responses occurred in patients with non-small cell lung cancer. Results of pharmacokinetic studies were consistent with the preclinical observations that CQS is highly bound to plasma protein. Plasma elimination followed a two-compartment model; the mean t 1/2 alpha was 2.7 +/- 0.3 h and the t 1/2 beta was 52 +/- 6 h (+/- SE). The total body clearance and the volume of distribution at steady state of CQS both increased with the dose (distribution at steady state, 3.7-10.5 liter/m2; total body clearance, 53-264 ml/h/m2 for doses of 18-4060 mg/m2) and may reflect saturation of the protein binding and "free" drug clearance. Although inactive against common animal tumors in preclinical screening systems both in vitro and in vivo, CQS has demonstrated definite activity in the human tumor stem cell colony-forming assays, as well as modest anticancer activity in this phase I study in patients with advanced solid tumors. The pharmacokinetic results and the limiting effect of transient hypoglycemia suggest that considerably higher cumulative doses of CQS could be administered using a more frequent dosing schedule.

Adult↗
PubMed1992

Oral ondansetron for the control of delayed emesis after cisplatin. Report of a phase II study and a review of completed trials to manage delayed emesis.

BACKGROUND: Despite excellent control of vomiting during the initial 24 hours after chemotherapy with combination antiemetics, most patients who receive cisplatin at doses of 120 mg/m2 experience delayed emesis 24-120 hours after chemotherapy. METHODS: Twenty patients receiving cisplatin (greater than or equal to 100 mg/m2) as initial chemotherapy were entered into this Phase II trial to test the effectiveness of oral ondansetron, a specific serotonin receptor (5-HT3) antagonist, in controlling delayed emesis. All patients received intravenous metoclopramide, dexamethasone, and lorazepam for the control of acute emesis 0-24 hours after receiving cisplatin. They then received ondansetron 16 mg orally three times a day for 4 days. RESULTS: Fifteen percent of those who were treated with oral ondansetron had complete control of delayed emesis during the entire 4-day period (95% confidence interval, 3-38%). No serious adverse events occurred. CONCLUSIONS: At the dose and schedule tested, oral ondansetron did not appear to control delayed emesis. Previous trials of programs to lessen this complication suggest that both metoclopramide and dexamethasone are effective in lessening delayed vomiting and that the combination of these drugs is more effective than placebo. Although in one trial ondansetron appeared to control delayed emesis in patients who received cisplatin at doses of 50-120 mg/m2, it was not superior to either placebo or metoclopramide in two randomized studies. Additional testing of the 5-HT3 antagonists, both alone and in combination, will be needed to establish their role in the management of this condition.

Administration, Oral↗
PubMed1992

Induction chemotherapy for non-small cell lung cancer with clinically evident mediastinal node metastases: the role of postoperative radiotherapy.

Survival for clinical Stage IIIa (T1-3, N2) non-small cell lung cancer is very poor because of poor local disease control and systemic spread. To address these shortcomings, we initiated a treatment program with induction chemotherapy, surgery, and postoperative radiation reserved for patients with residual disease at thoracotomy. Between 1984 and 1986, 41 patients with clinically evident N2 disease were treated with induction chemotherapy followed by resection and the selective use of intraoperative brachytherapy. All patients with tumor in the resection specimen received two cycles of chemotherapy and 15 patients received radiation therapy. With a median follow-up of 5.4 years, overall survival is 27% at 3 years, and 12% at 5 years. Despite the adverse selection process median survival is 19 months for patients receiving postoperative radiation therapy, and 22 months for the more favorable patients not requiring radiation therapy, supporting the selective use of postoperative radiation in this setting. In summary, this treatment has yielded good median survival and long-term survival for some of the patients. However, the ultimate value of this approach can only be determined by prospective trials which compare it to standard therapy.

Adult↗