Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.6.1.2 (alanine aminotransferase)
26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PD 132301-2 is a substituted urea hypolipidemic and antiatherosclerotic agent that is a potent inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT). To determine its subacute toxicity, PD 132301-2 was administered orally to beagle dogs at 0, 6, 12, 25, 50, 200, 400, or 800 mg/kg/day for 2 weeks. Clinico-pathologic evaluations were completed on all dogs. Liver and adrenal total and esterified cholesterol concentrations, adrenocorticotrophic hormone (ACTH) responsiveness, and adrenal ultrastructure were determined at 0, 6, 12, and 25 mg/kg. At 12 mg/kg or greater, salivation, epiphora, conjunctivitis, emesis, anorexia or decreased food consumption, and soft to mucoid feces and/or diarrhea were noted. Suppression of ACTH response occurred by Day 6 at all doses. Adrenocortical degeneration and/or necrosis in zona fasciculata and reticularis was seen at all doses; adrenal free and esterified cholesterol were normal at 6 mg/kg and decreased at 12 and 25 mg/kg. Increases in serum alanine aminotransferase (2- to 15-fold), aspartate aminotransferase (2- to 12-fold), and alkaline phosphatase (2- to 7-fold) were noted at 50 mg/kg or greater. Periportal hepatocellular hypertrophy and hypereosinophilia occurred at 50 mg/kg or greater; hepatic cholesterol values were not significantly affected by treatment. Dose-dependent ultrastructural alterations in adrenocortical cells included decreased numbers of mitochondria and smooth endoplasmic reticulum profiles, qualitative and quantitative changes in lipid globules, and increased numbers of autolysosomes. PD 132301-2 or one of its metabolites has potent adrenocorticolytic properties and limited hepatotoxic properties by mechanism(s) that are likely independent of systemic ACAT inhibition.
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PMID:Subacute toxicity of a novel inhibitor of acyl-CoA: cholesterol acyltransferase in beagle dogs. 838 21

In order to determine the usual dose in the first line therapy and a high dose in the second or third line therapy, a dose finding study of a novel antiestrogen NK 622 (toremifene citrate) was performed in patients (pts) with advanced or recurrent breast cancer. NK 622 was orally administered daily once for more than 8 weeks. In pts without previous drug therapy or in pts with cancer relapse after adjuvant therapy, the response rates [(CR + PR)/total] were 24.1% (7/29), 13.8% (4/29), 20.0% (1/5) and 40.0% (2/5) at doses of 40, 60, 120 and 240 mg/day, respectively. A 40 mg/day dose showed an objective response only in postmenopausal pts with estrogen receptor (ER) positive or unknown cancer. At a dose of 60 mg/day, some of the responding cases were premenopausal pts or pts with ER(-) cancer. In pts with cancer relapse during adjuvant therapy or in those with previous therapy and/or radiation, response rates were 25.0% (2/8), 0% (0/4), 13.5% (5/37) and 10.3% (4/39) at doses of 40, 60, 120 and 240 mg/day, respectively. Response was more frequent in pts with ER (+) cancer than with ER (-) cancer. The response rates in pts with previous therapy including tamoxifen (TAM) except medroxyprogesterone (MPA) were 14.3% (4/28) at a 120 mg/day dose and 6.1% (2/33) at a 240 mg/day dose. In pts with previous therapy including TAM, MPA and other antitumor agents, the rate was 18.2% (2/11) at a 120 mg/day dose. Side effects such as elevation of GOT, GPT and serum Ca level, decrease of hemoglobin, anorexia, nausea/vomiting, fatigue, dizziness and hot flush were observed. These side effects were moderate in grade and reversible. Dose dependency of side effects was not clearly observed in grade and incidence. From these results, NK 622 is expected to be a safe drug with efficacy in first line therapy at a dose of 40 mg/day and in second or third line therapy at a dose of 120 mg/day.
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PMID:[Phase II study of NK 622 (toremifene citrate) in advanced breast cancer, a multicentral cooperative dose finding study]. 842 89

TT-62 is a new derivative of FdUMP, which is the active metabolite of 5-FU. A phase I clinical study of TT-62 was conducted by a cooperative study. The same patients received single and 2-week oral administration of TT-62. Starting from 60 mg/m2 (1n), the dose was escalated to 420 mg/m2 (7n). In the single administration, the maximum tolerated dose (MTD) could not be determined. In the 2-week administration, MTD was 420 mg/m2, and the dose limiting factor was gastro-intestinal disturbances such as anorexia, nausea, vomiting and diarrhea. Increases in GOT.GPT and a decrease in hemoglobin content were observed. After administration was stopped all side effects disappeared. TT-62 was detected mainly in the plasma, while trace amounts of 5-FU and FUdR were also detected. TT-62 was excreted mostly in the urine, as alpha-fluoro-beta-alanine (FBAL). The cumulative urinary excretion of FBAL was about 80% of the total dose, and the oral absorption of TT-62 was thus thought to be good.
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PMID:[Phase I clinical study of TT-62. Research group of TT-62]. 843 62

Plasma lonidamine concentration and toxicity were investigated in dogs receiving 100, 200, 400, 800, 1200 mg/m2 orally twice daily for 30 days and in dogs receiving single intravenous doses of 200, 400, 800, 1200 mg/m2. Physical or laboratory signs of toxicity were not observed in dogs receiving oral lonidamine, but severe vomiting and signs of acute hepatic and pancreatic toxicity were observed in dogs receiving intravenous doses that exceeded 400 mg/m2. The area under the lonidamine concentration versus time curve (AUC) in dogs receiving 200, 400, and 800 mg/m2 of lonidamine intravenously was a 1.8-, 3.3-, and 8.7-fold higher than in dogs receiving oral lonidamine. This suggests that the bioavailability of oral lonidamine may be limited. However, centrilobular hepatocellular swelling and vacuolation were observed in dogs receiving oral lonidamine. Serum alanine aminotransferase (ALT) activity was increased in dogs receiving intra-venous lonidamine. These findings suggest that lonidamine is hepatotoxic in dogs. However, serum ALT was increased in only 1/4 dogs receiving 400 mg/m2 of lonidamine intravenously and plasma concentration were within the range capable of sensitizing hyperthermia and chemotherapy. Therefore, this dose and route appears to be a viable and controllable method for prospective quantification of lonidamine interaction with systemic chemotherapy and/or hyperthermia.
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PMID:Pharmacokinetics and toxicity of oral and intravenous lonidamine in dogs. 861 2

We report the case of a 28-year-old-prostitute from Thailand with HIV infection stage B2 associated with retroperitoneal lymph node tuberculosis. 6 days after the beginning of anti-tuberculous therapy (isoniazid, rifampicin, pyrazinamid and ethambutol) the temperature rose to 40.5 degrees C, diarrhea, vomiting, and tachycardia developed and systolic blood pressure fell to 80 mm Hg. Liver function tests revealed acute hepatic failure (ALT 800 IU/l rising to 1500; serum bilirubin 89 mumol/l rising to 238.0; alkaline phosphatase 199 IU/l; glucose 1.8 mmol/l; prothrombin time 20%). Isoniazid, rifampicin, and pyrazinamid were replaced by streptomycin and PAS. A few days after withdrawal the liver profile returned to normal. Hours after the reintroduction of rifampicin total body erythema, pruritus, vomiting and severe hypotension developed, requiring saline methylprednisolone and epinephrine administration. The next reexposure to intravenous rifampicin produced a rash and was rapidly discontinued. Liver function tests remained normal. Later mild adverse reactions to streptomycin and pyrazinamid occurred, two drugs which had been well tolerated before. Subsequently the diagnosis of adrenal insufficiency was established. After initiation of steroid replacement (50 mg prednisolone) the antituberculous therapy with isoniazid, pyrazinamid and ethambutol was well tolerated. We conclude that the shock in this HIV-infected patient was either due to severe anaphylaxis to rifampicin or acute adrenal insufficiency ensuing on this drug. The reversible fulminant acute hepatic failure represents either an adverse effect of antituberculous drugs, especially hepatotoxic interactions of drug combinations, or an ischemic liver injury during hypotension caused by anaphylaxis. The case illustrates the complex nature of side effects of antituberculous drugs in HIV patients and their aggravation by adrenal insufficiency.
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PMID:[Fulminant, rapidly reversible hepatitis and life-threatening anaphylaxis following rifampicin in an HIV-positive female patient with latent adrenal cortex insufficiency]. 864 39

To evaluate the frequency, pattern, and severity of liver function test abnormalities in patients with Lyme disease associated with erythema migrans (EM), 115 individuals with no other identifiable cause for liver function test abnormalities who presented with EM between July 1990 and September 1993 were prospectively evaluated. For individuals with abnormal liver function tests, common causes of hepatitis, including hepatitis A, B, and C, were excluded. A local control group was used for comparison. Forty-six (40%) patients had at least one liver test abnormality, and 31 (27%) had more than 1 abnormality compared with 19 (19%) and 4 (4%) of controls, respectively (P < .01 for each comparison). gamma-Glutamyl transpeptidase (28%) and alanine transaminase (ALT) (27%) were the most frequently elevated liver function tests among Lyme disease patients. Anorexia, nausea, or vomiting was reported by 30% of patients, but did not occur more frequently in patients with elevated liver function tests compared with those with normal values. Patients with early disseminated Lyme disease were more likely to have elevated liver function studies (66%) compared with patients with localized disease (34%) (P = .002). After antibiotic treatment, elevated liver function tests improved or resolved in most patients. Liver function test abnormalities are common in patients with EM but were mild, most often not associated with symptoms, and improved or resolved by 3 weeks after the onset of antibiotic therapy in most patients.
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PMID:Liver function in early Lyme disease. 867 58

LY188011 (Gemcitabine hydrochloride) is a new derivative of deoxycytidine. Phase I study was carried out by a cooperative study group. LY188011 was administered weekly for 3 consecutive weeks starting with an initial dose of 60 mg/m2 (1n) and then increasing the dosage to 1,000 mg/m2 (16.7n). Dose limiting factor was found to be myelosuppression (decreases of WBC, neutrophils and platelet), and MTD was considered to be 1,000 mg/m2. The nadir of WBC and platelet were observed after about 1-3 weeks. It took 1-2 weeks for their recovery. Other adverse reactions included fever, fatigue, anorexia, nausea/vomiting, anemia and transient elevations of GOT and GPT. However, those adverse reactions were mild. T1/2 rho of plasma concentration was about 19 min and the C5min was dependent on the dose. Anti-cancer effects were observed in one gastric cancer and two colon cancer patients. It is recommended that the dosing schedule for an early phase II study is 800 mg/m2 weekly for 3 weeks with 1 week of rest as one cycle, in multiple cycles.
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PMID:[LY188011 phase I study. Research Group of Gemcitabine (LY188011)]. 868 15

A repeated dose toxicity study of prulifloxacin, a new antibacterial agent, was conducted in beagle dogs. Male and female dogs were given the test material orally for 13 weeks at doses of 0 (control), 20, 100 and 500 mg/kg. After discontinuation of the treatment, a 5-week recovery test was also conducted. Vomiting, salivation and decreased body weight gain or reduced body weight were seen in the 100 and 500 mg/kg groups. In the 500 mg/kg group, tremor, paresis of posterior limb associated with prone or sitting position and decreased food consumption were also observed. There were no treatment-related effects on survival and water consumption. Ophthalmoscopic, electrocardiographic and hematologic examinations, and urinalysis failed to show any abnormalities attributable to the treatment. Blood chemical examination showed increased GPT and decreased beta- and gamma-globulins in the 100 and 500 mg/kg groups, and increased GOT in the 500 mg/kg group. In pathological examination, cavitations and erosions were seen in the humeral and femoral articular cartilages in the 100 and 500 mg/kg groups. The above-mentioned changes were satisfactorily reversible except for erosions in the humeral and femoral articular cartilages in the 100 and 500 mg/kg groups. No toxicological findings were seen in the 20 mg/kg group. The results show that the NOAEL of prulifloxacin is 20 mg/kg for 13-week repeated dose toxicity in dogs.
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PMID:[A 13-week oral toxicity study of prulifloxacin (NM441) in dogs followed by a 5-week recovery test]. 870 56

Single-dose and repeated dose toxicity studies of prulifloxacin, a new antibacterial agent, were conducted in aged beagle dogs. I. A single-dose toxicity study Prulifloxacin was administered orally to aged female dogs at a single dose of 2500 and 5000 mg/kg. No death occurred in any group. Vomiting was observed in one of two animals at 2500 mg/kg and in both animals at 5000 mg/kg 3-4 hr after dosing. At 5000 mg/kg, vomiting was observed in both animals after feeding on the day after dosing. One animal also showed soft stool. Thereafter, no abnormalities were observed in any animal. No test article related changes were noted in food consumption, water consumption, body weight or pathological examination in any group. The results show that the lethal dose of prulifloxacin is judged to be greater than 5000 mg/kg in aged female dogs. II. A repeated dose toxicity study Aged male and female dogs were given the test article orally for 4 weeks at doses of 0 (control), 20, 100 and 500 mg/kg. No death occurred in any group. At 500 mg/kg, vomiting was observed every day or intermittently throughout the dosing period and salivation was observed almost every day from day 6 to the end of the dosing onward. Decreases or lack of food and water consumption, and decrease of body weight were noted at 500 mg/kg. At 100 mg/kg, slight decreases in food consumption and body weight were noted in the females. No abnormalities were noted in ophthalmoscopic or electrocardio-graphic examination. In urinalysis, decreases in Na+, K+ and Cl- concentrations and the total excretion amount were noted mostly at 500 mg/kg. A low specific gravity was noted in males at 500 mg/kg. In hematology and serum biochemistry, high GPT, BUN and creatinine, and decreases in WBC were noted in both sexes at 500 mg/kg. A high GOT was noted in males, and low Cl- in females at 500 mg/kg. At 100 mg/kg, a high GPT was noted. Rough surface in the kidney and chronic interstitial nephritis (basophilic change of tubule, atrophy of tubule, thickening of tubular basement membrane, interstitial mononuclear cell infiltration, interstitial focal fibrosis) were increased at 500 mg/kg. No toxicological findings were seen in the 20 mg/kg group. The results show that the NOAEL of prulifloxacin is 20 mg/kg for 4-week repeated dose toxicity in aged dogs.
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PMID:[Single and 4-week oral toxicity studies of prulifloxacin (NM441) in aged dogs]. 870 58

Fifty-one patients with histologically confirmed epithelial stage III or IV ovarian cancer were entered into a study in which gemcitabine 800 mg/m2 was given as a 30 min intravenous infusion in a cycle once a week for 3 weeks followed by a week of rest. Patients were aged 58 years (range 23-70 years) with WHO performance status 0-2, and had received up to two different chemotherapy regimens. Thirty-eight patients had received only one prior platinum-containing chemotherapy regimen whereas 9 had received a first-line regimen on more than one occasion. A further 3 patients had received two different regimens. Of 42 patients evaluable for response, 8 (19%; 95% CI: 9%-34%) were partial responders. Seven of the 8 responders were resistant to first-line platinum-based therapy. Median duration of response was 8.1 months (range 4.4-12.5 months). Median progression-free survival was 2.8 months (range 0.2-12.5 months). Haematological toxicity with gemcitabine was modest, with grade 3 leukopenia (11 patients) and grades 3 and 4 thrombocytopenia (6 patients). Grade 3 non-haematological toxicity included nausea/vomiting (6 patients) and elevated AST/ALT (1 patient), while dose-limiting non-haematologic toxicity consisted of flu-like symptoms (2 patients), peripheral oedema (1 patient) and lethargy (1 patient). The activity and modest haematological and non-haematological toxicity seen with gemcitabine suggest that this agent should be further evaluated in the treatment of patients with ovarian cancer and in combination chemotherapy regimens, primarily in combination with platinum.
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PMID:Phase II study of gemcitabine in previously platinum-treated ovarian cancer patients. 871 27


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