Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0854467 (myelosuppression)
 5,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The therapeutic effects of interferon alpha-2b (Intron A; Scherag) in patients with chronic active hepatitis caused by hepatitis B virus (HBV) were assessed in a randomised, case-controlled clinical trial conducted between January 1988 and June 1990. Treatment involved a short course of prednisone followed by interferon alpha-2b, initially 10 million U by subcutaneous injection, 3 times a week for 16 weeks. All patients were symptomatic, were known to have had hepatitis B surface antigen and hepatitis B e antigen (HBeAg) in their blood for at least 6 months, and had elevated serum aminotransferase activities with histological evidence of chronic active hepatitis. Patients with carcinoma, renal or haematological abnormalities or decompensated cirrhosis were excluded. In 6 of 10 patients randomised to receive interferon and 1 of 10 controls, HBeAg and HBV DNA were cleared from the blood during the 12-month study period (P < 0.05). An indeterminate response with clearance of HBV DNA but persistence of HBeAg was noted in 1 patient receiving interferon. Serum aminotransferase levels decreased only in those patients who had responded to treatment, but this did not reach statistical significance for the group as a whole. Histological studies, where available, showed decreased hepatic periportal necrosis in patients who underwent treatment. Two patients relapsed to HBeAg-positive status 2 months after their initial seroconversion; 1 became clear again during a repeat course of interferon. Side-effects of treatment were common and included fever, malaise, myalgias and myelosuppression. One patient developed hypothyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Safety and efficacy of interferon alpha-2b following prednisone withdrawal in the treatment of chronic viral hepatitis B. A case-controlled, randomised study. 144 11

cis-Bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum++ +(II) (NDDP) is a liposome dependent cisplatin analogue since the liposome carrier is required for its i.v. administration and for its biological activity. A Phase I study of liposome entrapped NDDP (L-NDDP) was performed using a single i.v. injection every 4 weeks. L-NDDP was prepared and characterized at M. D. Anderson Cancer Center. The maximum tolerated dose of L-NDDP was 312.5 mg/m2. The dose-limiting toxicity was myelosuppression, affecting all three blood cell lineages. The granulocyte nadir occurred on days 14-18, and the platelet nadir consistently earlier (days 11-12). The median day of recovery of blood cell counts was day 21 (range, 18-32). Other toxicities included grade 2 nausea and vomiting, fever consisting of a single temperature spike in most patients, grade 1 diarrhea after 60% of courses, and grade 1-2 malaise lasting for 5-10 days after the infusion in 73% of courses. Transient alanine aminotransferase elevations without clinical relevance were common. No signs of renal dysfunction or ototoxicity were observed. One patient with a preexisting peripheral neuropathy showed some progression of the neuropathy after a cumulative dose of 1605 mg/m2. Except for fever and transient liver dysfunction, no liposome related side effects were observed in spite of the high doses of lipid administered. The blood clearance of L-NDDP fits a two-compartment model at lower doses and a single-compartment model at the maximum tolerated dose, suggesting that saturation of the reticuloendothelial organs occurs at the maximum tolerated dose. Two minimal responses were observed. L-NDDP has a toxicity profile similar to that of carboplatin. Phase II studies to address the issue of how the therapeutic index of platinum compounds is affected by liposome entrapment are being planned.
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PMID:Phase I clinical and pharmacological study of liposome-entrapped cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II). 236 84

Brequinar sodium is a quinoline carboxylic acid derivative that has shown antitumor activity in a number of in vivo murine and human tumor xenograft models. Its mechanism of action is blockade of de novo pyrimidine biosynthesis by inhibition of dihydroorotic acid dehydrogenase. In vitro and in vivo studies demonstrate the superiority of prolonged drug exposure in achieving tumor growth inhibition. This phase I study evaluated the administration of brequinar sodium by short, daily i.v. infusion for 5 days repeated every 4 weeks. Fifty-four subjects were enrolled in the study and received drug in doses ranging from 36-300 mg/m2. The dose-limiting toxicities were mucositis and diffuse skin rash. Other toxicities included myelosuppression, nausea, vomiting, malaise, and burning at the infusion site. The maximum tolerated dose on the "daily times 5" schedule was 300 mg/m2. The recommended phase II dose is 250 mg/m2. Pharmacokinetic analysis of the day 1 drug clearance curves in 51 subjects showed slight nonlinearity in the relationship between dose and area under the clearance curve (AUC). The dose versus AUC relationship was well described using a Michaelis-Menten model of brequinar elimination kinetics with Vmax = 45 (micrograms/ml)/h and Km = 123 micrograms. Analysis of the day 5 drug clearance curves revealed a diminution in Vmax to 30 (micrograms/ml)/h. As a consequence of the reduction in Vmax brequinar plasma concentrations on day 5 were higher than predicted from day 1 drug kinetics. Pharmacodynamic analysis of the day 1 kinetic parameters and the toxicities occurring during the first cycle of drug therapy revealed significant correlations between mucositis and dose, AUC, and peak brequinar concentration; between leukopenia and AUC and peak drug concentration; and between thrombocytopenia and beta elimination rate.
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PMID:Phase I and pharmacokinetic study of brequinar sodium (NSC 368390). 236 34

The effects and toxicities of interferon alfa are described, and the role of the pharmacist in making decisions and providing education about biologic response modifiers (BRMs) is discussed. Interferons have both direct antitumor activity and extensive effects on the immune system. Two recombinant interferon alfa products--interferon alfa-2a and interferon alfa-2b are available commercially. Indications in FDA-approved labeling for interferon alfa include the treatment of hairy-cell leukemia, acquired immunodeficiency syndrome-related Kaposi's sarcoma, and genital warts; however, it also is being used successfully against early chronic myelogenous leukemia, low-grade non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, and previously untreated multiple myeloma. Other malignancies that respond to treatment with interferon alfa are malignant melanoma, ovarian carcinoma, and renal cell carcinoma. The toxic pattern of interferon alfa consists of flu-like symptoms, which are seen at all doses, on all schedules, and in virtually all patients. After repeated dosing, the chronic toxicities of anorexia, weight loss, and malaise and fatigue may develop. Myelosuppression, central nervous system toxicity, increased hepatic enzyme concentrations, nausea and vomiting, and cardiovascular toxicity also are possible. Serum neutralizing antibodies may be formed during therapy; this phenomenon may affect the clinical outcome. Numerous BRMs are being investigated for clinical use, and pharmacists must become conversant in the issues that surround these agents. Areas in which pharmacist involvement and knowledge are important include overall cost, product similarities and differences, dosing and scheduling, drug delivery systems, ways to minimize waste, adverse effects and their management, drug interactions, storage requirements, differences in production and purification techniques among manufacturers, and education of patients and staff.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Biologic response modifiers: the interferon alfa experience. 248 96

Based on the in vitro and in vivo data suggesting synergistic cytolysis by the combination of 5-fluorouracil and interferon-gamma against a variety of malignant cell lines including a human colon carcinoma cell line (HT-29), we initiated studies in patients with advanced colon or rectal carcinoma. Forty-six patients received 5-fluorouracil as an intravenous injection on days 1-5 and recombinant human interferon-gamma as an intramuscular injection on days 1-14, followed by a rest period of 14 days; courses were repeated every 28 days. In the phase I study, cohorts of two patients received a stepwise dose level increase to achieve the maximum tolerated dose (MTD), at which a total of six patients were studied. The dose levels constituting the MTD were as follows: 5-fluorouracil (500 g/m2/day) and recombinant gamma-interferon (0.5 mg/m2/day). Four patients achieved a partial response in the phase I study. In the phase II study, 30 patients received therapy at the MTD. Among 29 evaluable patients in the phase II study, two patients achieved a partial response. Common toxicities included malaise, fever, anorexia, nausea and vomiting, and diarrhea. Transient severe myelosuppression was common but did not result in significant morbidity. Our data suggest that the combination of 5-fluorouracil and recombinant gamma-interferon did not have the same antitumor effect in patients as it had in the preclinical experiments.
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PMID:Phase I and II studies of the combination of recombinant human interferon-gamma and 5-fluorouracil in patients with advanced colorectal carcinoma. 249 63

This phase I study was conducted to reevaluate the dose-limiting toxicities, maximum tolerated (MTD) and recommended phase II doses of oral NMF administered on a three times weekly schedule for 4 out of every 6 weeks. This schedule was based on the observation that prolonged administration of NMF was associated with the most efficacious antitumor activity in preclinical studies. Phase II trials that employed a starting dose of 800 mg/m2, determined in a previous phase I trial, were suspended because of frequent and severe toxicities. In the current study, a symptom complex characterized by nausea, vomiting, and malaise was the dose-limiting toxicity of oral NMF administered on this schedule. Other toxicities included hepatic enzyme elevations, mild myelosuppression, and worsening of preexistent toxic peripheral neuropathies. Of interest, three patients who were asymptomatic prior to treatment, rapidly developed symptoms of increased intracranial pressure after starting NMF; and, computerized tomographic brain scans revealed metastatic tumors with significant peritumoral edema. NMF was well tolerated at 600 mg/m2, however, an abrupt increase in toxicity resulted when the dose was increased to 700 mg/m2. Although NMF peak plasma concentrations (Cmax) and areas under the plasma disappearance curves (AUC) differed between the 600 and 700 mg/m2 dose levels, these differences were not striking, and similar NMF plasma concentrations and exposures were well tolerated during intravenous trials. Based on this study, the recommended phase II dose for oral NMF administered three times weekly for 4 of 6 weeks was 600 mg/m2.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Assessment of N-methylformamide (NMF) administered orally on a three times weekly schedule: a phase I study. 259 2

Forty-eight patients with advanced breast cancer were treated in a disease-specific phase I trial of doxorubicin and iproplatin combination chemotherapy. The doses of doxorubicin ranged between 30 and 50 mg/m2, and the doses of iproplatin ranged between 150 and 250 mg/m2. Myelosuppression was observed at all levels, but was dose-limiting at the highest level. In addition, nausea, diarrhea and malaise were prominent toxicities. Neither cardiac nor renal toxicity was encountered. Nine of 26 (35%) of previously untreated patients, and 5 of 22 (23%) previously treated patients demonstrated partial or complete responses. Although this combination possesses therapeutic activity, given its toxicities, further evaluation of doxorubicin in combination with iproplatin is not recommended.
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PMID:Phase I clinical trial of doxorubicin and iproplatin combination chemotherapy in patients with breast cancer. 279 71

Because recombinant interleukin 2 (rIL-2) and recombinant alpha-interferon (rIFN-alpha) exhibit synergistic antitumor activity in C3HMT1820 T-cell lymphoma and B16 melanoma tumor systems, we have performed a Phase I study of this combination in 55 patients with advanced malignancies for whom no standard therapy exists. Successive groups of greater than or equal to 4 patients have been entered into 12 dose levels (1A-3D), with dose levels 1-3 referring to doses of rIL-2 of 0.1, 0.5, and 2.0 x 10(6) units/m2, respectively, and dose levels A-D referring to doses of recombinant human alpha 2a-interferon (rHuIFN-alpha 2a) of 0, 0.1, 1.0, and 10.0 x 10(6) units/m2. Both agents were given on Mondays, Wednesdays, and Fridays, with rIL-2 being given as i.v. bolus injections and rHuIFN-alpha 2a being given intramuscularly. Myelosuppression was dose-limiting and was related primarily to the dose of rHuIFN-alpha 2a. The maximum-tolerated dose level was reached at a dose of rIL-2 of 2.0 x 10(6) units/m2 and of rHuIFN-alpha 2a of 10.0 x 10(6) units/m2 (dose level 3D). At this dose level, 3/6 patients developed grade 3 neutropenia (absolute granulocyte count less than 1 x 10(9)/liter). Myelosuppression was transient, with no documented infections being associated with neutropenia. Hypotension was mild; a single patient was treated with a vasopressor, but all other cases of hypotension responded to fluid administration. No significant pulmonary toxicity was produced. Fever, chills, and malaise were universal but not dose-limiting. Three partial responses and one minor response were observed in patients with malignant melanoma, renal cell carcinoma, and breast cancer. Immunological studies suggested that natural killer activity was related to both the dose of rIL-2 and the dose of rHuIFN-alpha 2a, with natural killer activity being positively related to the dose of rIL-2 and maximal at the lowest dose of rHuIFN-alpha 2a of 0.1 x 10(6) units/m2.
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PMID:Phase I clinical trial of interleukin 2 and alpha-interferon: toxicity and immunologic effects. 280 86

Twenty-five women with advanced breast cancer were treated in a phase II trial of iproplatin 275 mg/m2 administered intravenously every 4 weeks. All patients had measurable or evaluable indicator lesions, and had undergone treatment with no more than one previous chemotherapy regimen, including adjuvant chemotherapy. Two of the twenty-four evaluable patients (8%) experienced major therapeutic responses. One patient had a complete regression of pulmonary nodules lasting 18+ months; another had a partial regression of metastatic disease in the liver (4 months). The inevaluable patient was ineligible for the study because of previous radiation to the indicator lesions on her chest wall; nonetheless, she experienced a 10 month partial regression of those nodules. Myelosuppression was generally dose limiting; thrombocytopenia was more profound, but leukopenia was more prolonged. Nausea, vomiting, diarrhea, and general malaise were prominent toxicities, and led to discontinuation of therapy in 4 patients. Iproplatin has limited activity in previously treated women with advanced breast cancer.
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PMID:Clinical trial of iproplatin (cis-dichloro-trans-dihydroxy-bis-isopropylamine platinum IV, CHIP) in patients with advanced breast cancer. 304 33

Dichloromethotrexate (DCMTX) has been the subject of sporadic clinical development for the last 30 years. Although DCMTX was developed in hopes of discovering a more potent antifolate, the potential pharmacologic and toxicologic advantages of the analog have become of greater interest. This phase I and pharmacokinetic trial of DCMTX given on days 1, 8, and 15 every 28 days was undertaken to test these potential advantages. The maximally tolerated dose on this schedule was 980 mg/m2. Hepatic toxicity was dose limiting. Malaise, myelosuppression, and mucositis were also major toxic effects. The recommended dose for subsequent phase II studies of DCMTX administered on this schedule is 785 mg/m2 with a reduction to 625 mg/m2 for patients with a poor performance status or extensive prior therapy. Plasma disappearance curves for most patients were biphasic or triphasic, although several demonstrated more complex kinetic patterns that suggested significant enterohepatic circulation. The magnitude of the area under the plasma disappearance curve was related to the severity of DCMTX-induced hepatotoxicity. The elimination kinetics were linear, with a mean plasma clearance of 294 mL/min (range, 128-715). The pharmacokinetic behavior of DCMTX does not support its use over methotrexate in regional perfusion. DCMTX's primarily nonrenal elimination suggests that it may have an advantage over methotrexate when combined with nephrotoxic drugs such as cisplatin. However, there is little reason to commit major resources to further evaluation of DCMTX unless significant advantages in antineoplastic activity are identified.
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PMID:Clinical and pharmacologic reappraisal of dichloromethotrexate. 271 75


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