Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.2 (alanine aminotransferase)
 26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Late Phase II clinical study with bropirimine (U-54461S), a novel oral antitumor agent that has interferon inducing and anti-proliferative activities, was conducted in patients with bladder CIS at 38 institutions nationwide. To investigate the efficacy and safety of the treatment, bropirimine was administered to the patients at the dose of 750 mg every two hours, three times a day, for three consecutive days with four-day drug withdrawal, based on the results of the preceding clinical studies up to early phase II. Among the 48 patients registered, 41 patients were evaluable for antitumor efficacy. Complete response (CR) was observed in 17 of them, no change (NC) in 18 patients, and progressive disease (PD) in 6 patients; so the efficacy rate was 41.5%. Classified by patient background, the efficacy rates were 58.3% (7/12) in patients with primary bladder CIS, 34.5% (10/29) in those with secondary bladder CIS, 45.5% (10/22) in those with Grade 3, and 23.8% (5/21) in those previously given chemotherapeutic agents or BCG by intravesical or other routes. Adverse drug reactions frequently observed were influenza-like symptoms such as fever and generalized malaise and gastrointestinal symptoms like anorexia and nausea/vomiting; these symptoms were all Grade 2 or milder. Abnormalities in laboratory tests, such as an elevation in GOT/GPT, neutropenia, and leukopenia were observed. These adverse effects were all tolerated by the patients. From the above results, bropirimine was considered to be a useful oral agent for the treatment of bladder CIS.
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PMID:[Bropirimine (U-54461S) late phase II clinical study for carcinoma in situ of the bladder. Japan Bropirimine Study Group]. 902 Sep 49

The inhibitory effects of GG032X tablets, a new dosage form (fast dispersing tablet) of ondansetron, 5-HT2 receptor antagonist, on nausea and emesis induced by cisplatin (CDDP), were investigated along with safety and usefulness. Subjects were chemotherapy patients starting CDDP administration for the first time, who were receiving a high single dose of CDDP (50 mg/m2 or more and intravenous drip infusion of less than 4 hours), or lower multiple doses of CDDP (a single dose of 10 mg/m2 or more, administered intravenously for 3-5 consecutive days). GG032X tablets were administered orally 1-2 hours before CDDP administration. In lower multiple doses of CDDP, GG032X tablets and CDDP were administered, as much as possible, at the same respective time when they were administered on the first day. Efficacy of GG032X tablets was evaluated in terms of inhibitory effect on nausea and emesis 24 hours after administration of a high single dose of CDDP, and of the inhibitory effect on nausea and emesis during the study period (3-5 days) in lower multiple doses of CDDP. Efficacy, safety and usefulness were evaluated in accordance with the evaluation criteria used in the clinical study of already-approved ondanstron tablets. In a high single dose of CDDP, the cases judged "effective" or better in the investigation of the inhibitory effect of the drug on nausea and emesis, accounted for 52.9% (63/119 cases). As for the overall safety rating, the cases judged as "safe" accounted for 87.0% (107/123 cases), and as a "minor safety problem" accounted for 13.0% (16/123 cases). As for the usefulness rating, the cases judged "useful" or better accounted for 52.1% (62/119 cases). Major adverse effects included headache, fever, atrial fibrillation and increases in total bilirubin, GOT and GPT values. None of these was serious, and the patients recovered without any treatment or by nosotropic therapy. Meanwhile, in lower multiple doses of CDDP, the inhibitory effect judged "effective" or better accounted for 70.6% (12/17 cases). As for the overall safety rating, all cases were judged "safe". In terms of usefulness, those cases judged "useful" or better accounted for 70.6% (12/17 cases). No adverse effect was observed. Study results of these two groups were almost the same as those for already-approved ondansetron tablets. According to the results of questionnaires for the patients who participated in the study and took GG032X tablets, the drug was found to be easy to take and had favorable results. Based on the above results, GG032X tablets were evaluated as having the same inhibitory effect as the already-approved ondansetron tablets against CDDP-induced nausea and emesis, and were considered safe and clinically useful.
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PMID:[Clinical efficacy of GG032X tablets, a new dosage form of ondansetron (fast dispersing tablet), on cisplatin-induced nausea and emesis]. 921 10

To evaluate the feasibility of adjuvant chemotherapy, we analyzed the toxicities of chemotherapy for primary breast cancer in Japanese women. Since the opening of the National Cancer Center Hospital East, 180 female breast cancer patients have received adjuvant chemotherapy or chemo-hormonal therapy following surgical treatment between June 1992 and December 1995. On the basis of informed consent about prognosis and adjuvant therapy, most patients decided to choose the type of cytotoxic chemotherapy themselves. Adjuvant chemotherapy consisted of oral fluoropyrimidine compounds (OFP), cyclophosphamide + adriamycin +/- 5-fluorouracil [CA(F)] or cyclophosphamide + methotrexate + 5-fluorouracil (CMF). Toxicity was determined using the Toxicity Grading Criteria of the Japan Clinical Oncology Group (JCOG). Sixty-six patients received OFP, 59 CA(F) and the rest 55 CMF. The toxicity grading of leukocytes and neutrophils was significantly higher in patients treated with CA(F) or CMF than in those treated with OFP. Similar results were also seen relating to the toxicity of nausea/vomiting and alopecia. There was no statistical difference in the toxicity grading of hemoglobin, glutamic oxaloacetic transaminase/glutamic pyruvic transaminase (GOT/GPT) and stomatitis/ gastritis between the three groups of patients. Interestingly, the number of patients that were forced to discontinue chemotherapy was higher in those receiving OFP than in those receiving CA(F) or CMF. Cytotoxic chemotherapy of CA(F) or CMF results in greater toxicity than OFP, but is tolerated and feasible in the adjuvant setting used in Japanese breast cancer patients from the viewpoint of toxicities by anticancer chemotherapy.
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PMID:Feasibility of adjuvant chemotherapy for breast cancer patients. 939 Feb 7

The safety of tacrine (Cognex), a centrally active, reversible acetylcholinesterase inhibitor approved in 1993 for the treatment of mild to moderate dementia of the Alzheimer type, was evaluated in 2,706 patients with Alzheimer disease (AD) in clinical trials and in 9861 patients with AD in a treatment investigational new drug (TIND) program. More than 190,000 patients in the United States received tacrine during the first 2 years following marketing approval. The most common tacrine-associated adverse events were elevated liver transaminase levels [alanine aminotransferase (ALT) and, to a lesser degree, aspartate aminotransferase] and peripheral cholinergic events involving primarily the digestive system (nausea, vomiting, diarrhea, dyspepsia, anorexia, and weight loss). Based on clinical trial experience, potentially clinically significant (>3 x upper limit of normal) ALT elevations occurred in 25% of patients, requiring routine monitoring early in treatment. The elevations were almost always asymptomatic, rarely accompanied by significant increases in bilirubin, and related to time on drug rather than to dose (90% occurred within the first 12 weeks of treatment). Gastrointestinal events were related to dose and generally of mild to moderate intensity. Tacrine-associated events, including ALT elevations, were reversible. Cholinergic events were manageable with dosage adjustment. Tacrine was not associated with permanent liver injury in clinical trials or a TIND setting.
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PMID:Safety of tacrine: clinical trials, treatment IND, and postmarketing experience. 965 Nov 38

Deferiprone, also known as L1, is an orally active iron chelator that has been studied extensively in clinical trials. The sporadic occurrence of agranulocytosis in association with deferiprone and the highly variable frequency of other possible side effects such as arthralgia have created uncertainty about the true incidence of deferiprone-related complications. A multi-center, 1-year trial was initiated to determine the safety profile of deferiprone. Using the Apotex formulation of deferiprone, 187 patients with thalassemia who were unable or unwilling to use deferoxamine were enrolled in four centers; 162 patients completed one year of therapy. Agranulocytosis (ANC < 500/mm3) occurred in one patient after 15 weeks of treatment, was not accompanied by infection and resolved following treatment with G-CSF. Nine other subjects developed less severe neutropenia (ANC 500-1500/mm3) with the lowest absolute neutrophil count reaching 500-1250/mm3. The neutropenia in these patients developed after 1-50 weeks of therapy, frequently accompanied febrile illnesses, and occurred predominantly in non-splenectomized patients. Reasons other than neutropenia for discontinuing use of deferiprone included nausea (4), voluntary withdrawal (3), high ALT (2), platelet count < 100,000/mm3 (2), low but unconfirmed ANC (1), protocol violation (1) fatigue (1), and depression (1). Mean ALT levels rose within three months of therapy and stabilized thereafter. Arthralgia and nausea and/or vomiting occurred in 6% and 24% of subjects, respectively. In this multi-center trial with weekly monitoring of blood counts, the incidence of agranulocytosis was 0.58 per 100 patient-years, and the frequency of agranulocytosis after one year was 0.5%. These findings support the safety of this formulation of deferiprone, using the careful monitoring system employed in this trial.
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PMID:A multi-center safety trial of the oral iron chelator deferiprone. 966 43

AG331 (N6-[4-(morpholinosulfonyl)benzyl]-N6-methyl-2, 6-diaminobenz-[c,d]-indole glucuronate) is a lipophilic thymidylate synthase inhibitor with activity in solid tumor models. On the basis of preclinical data supporting regimens of frequent drug administration, we performed a Phase I trial of AG331 as a 5-day continuous infusion repeated every 3 weeks. Twenty-nine patients were entered at doses ranging from 25 to 1000 mg/m2/day. The major side effects were mild to moderate fatigue, nausea, vomiting, diarrhea, and fever. At doses >/=400 mg/m2, acute reversible elevation of bilirubin, aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyltranspeptidase was observed. All patients who received >/=600 mg/m2/day experienced elevated alanine aminotransferase. Elevated liver function tests were evident by day 3 of the infusion and had resolved by day 8 in the majority. This toxicity was dose limiting at 1000 mg/m2/day, at which dose two of two patients developed grade 4 reversible hyperbilirubinemia in addition to the enzyme elevations. Serum and urine samples were analyzed by a novel high-pressure liquid chromatography method for the determination of the pharmacokinetics of AG331. Over the 50-1000 mg/m2/day dose range, mean total clearance ranged from 11.6 to 30.0 liters/h/m2, and volume of distribution at steady state ranged from 279.5 to 758.7 liters/m2. These parameters were dose independent over the dose range tested. The harmonic mean terminal half-life of AG331 was 20.2 h. Less than 5% of an AG331 dose is eliminated unchanged in the urine. Both the administered dose and exposure to the drug were related to the changes in bilirubin and aminotransferase blood levels. Evidence for inhibition of thymidylate synthase was obtained at doses ranging from 100 to 1000 mg/m2 in seven patients; plasma deoxyuridine concentrations at end-infusion were 1.8-3.8-fold higher than pretreatment values. Because of the nature of toxicity on this schedule, more extensive Phase II evaluation is not recommended, although an AG331 dose of 800 mg/m2/day for 5 days is tolerable. Exploration of less frequent dose administration is under way.
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PMID:Phase I trial of the thymidylate synthase inhibitor AG331 as a 5-day continuous infusion. 981 17

A multicenter cooperative phase I study of ZD-1694 (raltitrexed), a novel, folate-based thymidylate synthase (TS) inhibitor, was conducted with single and repeated doses in 30 patients with various malignant tumors. ZD-1694 was intravenously infused over 15 minutes. In the single-dose study, the initial dose was fixed at 1.0 mg/m2 (1n), and the dose was escalated stepwise up to 3.5 mg/m2 (3.5 n). Based on the results of the single-dose study, in the repeated-dose study, doses of 2.5 n and 3 n were infused every three weeks (3 weeks/one course). In principle, patients received 2 courses or more. Of the 29 eligible patients, 16 were in the single-dose study and 13 in the repeated-dose study. Adverse reactions were evaluated in all eligible patients. In the single-dose study, neutropenia, nausea/vomiting, diarrhea, and transaminase (GOT, GPT) increases, of grade 3 or higher, occurred at high doses of 3 n and 3.5 n. These were regarded as dose-limiting toxicities (DLT). DLT of grade 3 or higher were observed in 1 of 4 patients given 3 n and 2 of 4 patients given 3.5 n. These results suggested that the maximum tolerated dose (MTD) of ZD-1694 was 3.5 n (3.5 mg/m2). In the repeated-dose study, DLT of grade 3 or higher was observed in no more than one third of each dose group, 2 of the 6 patients given 2.5 n and 2 of the 7 patients given 3 n. These results suggested that 3 n (3.0 mg/m2), a dose nearer to MTD, was the recommended dose for the phase II study. Although transaminase increases were observed in all patients, in 12 of them the increase was grade 2 or lower and reversible. A pharmacokinetic investigation showed the mean elimination half life of ZD-1694 plasma concentration was 91.5 hours in the single-dose group and 119.1 hours in the repeated dose group. It was suggested that ZD-1694 is metabolized to polyglutamates after uptake and retained in the cells for a long duration. However, no accumulation was seen in plasma concentration of ZD-1694 following repeated doses at 3-weekly intervals. One PR was observed in a patient with colorectal cancer receiving 2.5 n in the repeated-dose study. Based on these results, the recommended dosage and administration for the phase II study of ZD-1694 was 3 n (3.0 mg/m2) intravenously infused over 15 minutes every 3 weeks.
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PMID:[Phase I study of raltitrexed (ZD-1694)]. 983 10

To evaluate the toxicity of zidovudine (ZDV) prophylaxis in human immunodeficiency virus (HIV)-exposed healthcare workers (HCWs) in Italy, a national protocol for postexposure prophylaxis has been implemented and a national registry has been established. All Italian clinical centers licensed to dispense ZDV participate. As of December 1995, data from 674 individuals who received ZDV prophylaxis have been collected. In three cases ZDV was used in combination with either didanosine (DDI) or dideoxycytidine (DDC). In 556 cases (82%), the daily dose of ZDV was 1,000 mg/day; 21 HCWs (3%) were treated with 300-800 mg/day, and in 72 persons (11%) the dose was 1,200-3,000 mg/day. A total of 332 (49%) HCWs reported at least one adverse effect; 132 (20%) discontinued prophylaxis because of side effects (40% of those reporting side effects). Nausea was reported in 243 cases; other side effects included vomiting, gastric pain, diarrhea, asthenia, and headache. Most constitutional adverse effects were reported during the first week of prophylaxis. Grade 1 anemia (hemoglobin 9.5-11 g/dL) occurred in 10 cases (3%); in 2 cases, the neutrophil count decreased to <1,000 cells/mm3. A transient increase of serum alanine aminotransferase to three times the upper limit of normal was observed in 7 persons. All side effects were reversible after the prophylaxis was stopped. Among those reporting at least one side effect the mean duration of treatment was 22 days; for HCWs reporting hematologic or liver adverse effects the mean length of treatment was 34 days. A total of 351 HCWs (54.6%) ceased the treatment before the scheduled 1-month period. In the 132 persons who discontinued treatment because of side effects, the mean length of prophylaxis was 8 days. One HCW seroconverted after conjunctival exposure to blood. The short-term toxicity of ZDV prophylaxis is frequent, mild, dose related, and reversible. Further studies are needed to assess the risk of long-term sequelae of this treatment as well as of prophylaxis with combinations of antiretroviral drugs.
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PMID:Zidovudine toxicity in uninfected healthcare workers. Italian Registry of Antiretroviral Prophylaxis. 984 98

Flutamide is a nonsteroidal antiandrogen agent. Since it was marketed in February of 1989 in the USA for treatment of prostate cancer, its potential for hepatotoxicity has been reported in Western countries. Here we report the case of a 72-year-old patient who suffered from general malaise, poor appetite, nausea and jaundice after six months of flutamide therapy for the treatment of prostate cancer. He had no past history of liver disease and was not receiving other medications. Liver biochemistries revealed elevated serum alanine aminotransferase and aspartate aminotransferase concentrations of up to 1,035 U/l and 745 U/l, respectively. Serum total bilirubin concentration was elevated to 7.0 mg/dl. Serologic markers for acute viral hepatitis were all negative. Serum antinuclear antibody, antimitochondrial antibody and antismooth-muscle antibody were also negative. Percutaneous liver biopsy revealed pericentral zonal necrosis with bridging hepatic necrosis. The patient's clinical symptoms and signs began to improve after discontinuation of flutamide, and his liver function had returned to normal three months later. Roussel Uclaf causality assessment for adverse drug reaction confirmed the diagnosis of drug-induced liver injury. This case reminds us that patients who are receiving flutamide should be regularly monitored for liver function. If drug-induced liver injury is suspected, flutamide must be discontinued promptly to avoid progression of liver injury.
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PMID:Flutamide-induced liver injury: a case report. 987 26

2-Amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)-quinazoline dihydrochloride (nolatrexed dihydrochloride, Thymitaq, AG337), a specific inhibitor of thymidylate synthase, was developed using protein structure-based drug design. Intravenously administered nolatrexed is active clinically. As oral bioavailability is high (70-100%), nolatrexed was administered orally, 6 hourly for 10 days, at 3-week intervals, and dose escalated from 80 to 572 mg m(-2) day(-1) in 23 patients. Common toxicity criteria (CTC) grade 3 toxicities included nausea, vomiting, stomatitis and liver function test (LFT) abnormalities. Thrombocytopenia (grade 1 or 2) occurred at doses > or = 318 mg m(-2) day(-1) and neutropenia (grade 2) at 429 and 572 mg m(-2) day(-1). An erythematous maculopapular rash occurred at dosages > or = 318 mg m(-2) day(-1) (7 out of 19 patients). LFT abnormalities occurred in two out of six patients (grade 3 or 4 bilirubin and grade 3 alanine transaminase) at 572 mg m(-2) day(-1). Nolatrexed plasma concentrations 1 h after dosing were 6-16 microg ml(-1), and trough 3-8 microg ml(-1), at 572 mg m(-2) day(-1). Inhibition of thymidylate synthase was demonstrated by elevation of plasma deoxyuridine. Six-hourly oral nolatrexed for 10 days was associated with antiproliferative effects, but nausea and vomiting was dose limiting at 572 mg m(-2) day(-1). Nine patients were treated at 429 mg m(-2) day(-1); three out of nine experienced grade 3 nausea, but 17 out of 22 treatment courses were completed (with the co-administration of prophylactic antiemetics) and this dose level could be considered for phase II testing.
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PMID:A phase I study of the lipophilic thymidylate synthase inhibitor Thymitaq (nolatrexed dihydrochloride) given by 10-day oral administration. 1007 Aug 90


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