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:3.1.3.1 (alkaline phosphatase)
47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The safety of amphotericin B colloidal dispersion (ABCD) was tested in five open-label Phase I/II clinical trials in 572 selected patients who had a fungal infection secondary to a severe underlying disease. In 442 cases ABCD was administered after therapy with amphotericin B, which had been withdrawn in 192 of them because of toxicity. One hundred and forty patients had pre-existing nephrotoxicity. ABCD doses of up to 6 mg/kg/day resulted in no differences in serum creatinine levels, even in patients with pre-existing renal failure. ABCD therapy resulted in no difference in liver function as measured by SGOT, alkaline phosphatase and total bilirubin levels in serum. Apart from thrombocytopenia, there was no significant alteration in hematological or other biochemical parameters in the blood. Adverse events attributable to ABCD requiring discontinuation of therapy occurred in 70 patients (12.2%). The most frequent of these were infusion-related adverse events, which occurred in 5.4% of patients. As a consequence, the maximum tolerated dose was set at 7.5 mg/kg/day. These studies show clearly that ABCD can be administered safely to patients without the risk of renal toxicity, even when renal impairment has already developed following therapy with conventional amphotericin B deoxycholate.
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PMID:Safety of amphotericin B colloidal dispersion. 906 77

The subchronic toxicity of ISIS 2302 and ISIS 3082, phosphorothioate oligonucleotides with antisense activity against human and murine ICAM-1 mRNA, respectively, was investigated in CD-1 mice. ISIS 2302 is currently in clinical trials as an anti-inflammatory agent. Because of the differences in mRNA sequence targets between humans and mice, ISIS 2302 has no pharmacologic activity in mice. ISIS 3082 was specifically designed to inhibit murine ICAM-1 and was included in this study to evaluate the effects of prolonged ICAM-1 inhibition. The oligonucleotides were administered by bolus i.v. injection (via tail vein) every other day for 27 days (14 doses) at dose levels of 0, 0.8, 4, 20, and 100 mg/kg per injection ISIS 2302 or 20 mg/kg per injection ISIS 3082. The basic group size consisted of 10 male and 10 female mice, which were sacrificed 2 days after the last dose and an additional 5 mice per sex in vehicle control and 100 mg/kg ISIS 2302 dose groups, which remained on study for a 28-day treatment-free period. No treatment-related deaths occurred during this study, and there were no effects of either oligonucleotide on body weight gain or food consumption. The most common changes observed in this study included a mixed mononuclear cell infiltrate seen in a number of organs or tissues, splenomegaly, and lymphoid hyperplasia at dose levels of > or = 20 mg/kg ISIS 2302. In the group that received the highest dose level of ISIS 2302 (100 mg/kg), there were alterations in serum chemistry parameters that appeared to be related to perturbations in the liver, including 3- to 4-fold increases in aspartate and alanine aminotransferase and smaller changes in bilirubin, alkaline phosphatase, cholesterol, triglycerides, and albumin levels. Treatment-related effects on hematologic parameters were limited to the 100 mg/kg ISIS 2302 dose group and included slight monocytosis and thrombocytopenia. None of the effects observed appeared to be life threatening. Complete or partial reversal of all effects was evident in the remaining high-dose ISIS 2302 animals at the end of the 4-week recovery period. Comparison of the effects produced by the same dose level (20 mg/kg) of ISIS 2302 and ISIS 3082 did not reveal any differences that could be attributed to exaggerated pharmacology. In conclusion, treatment-related alterations were observed primarily at the 100 mg/kg dose level, including immune stimulation and hepatic alterations, which were partially reversed following a 4-week treatment-free period.
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PMID:Evaluation of the toxicity of ISIS 2302, a phosphorothioate oligonucleotide, in a 4-week study in CD-1 mice. 936 6

The aim of the present study is to evaluate the in vivo toxicologic effects of a phosphorothioate oligodeoxynucleotide (PS oligo) and three of its analogs [PS oligo containing four methylphosphonate linkages at the 3' and 5'-ends (MBO 1), PS oligo containing four 2'-O-methylribonucleosides at both the 3'- and 5'-ends (MBO 2), and PS oligo containing an 8 bp loop region at the 3'-end (self-stabilized oligo)]. Oligodeoxynucleotides were administrated intravenously to male and female rats at doses of 3, 10, and 30 mg/kg/day for 14 days. Rats were killed on day 15, blood samples were collected for hematology and clinical chemistry determinations, and tissues, including lymph nodes, spleens, livers, and kidneys, were subjected to pathologic examinations. The toxicity profiles of the four oligodeoxynucleotides were very similar, but differed in magnitude. In terms of the severity of the abnormalities caused by the oligodeoxynucleotides, the order was MBO 2 > PS oligo > self-stabilized oligo > MBO 1. Alterations in hematology parameters included thrombocytopenia, anemia, and neutropenia. Abnormalities in clinical chemistry parameters observed with PS oligo or MBO 2 were dose-dependent elevation of liver transaminases and reduction of the levels of alkaline phosphatase, albumin, and total protein. In addition, MBO 2 caused elevation of the total bilirubin level in male rats at the 30 mg/kg dose. No major alterations in hematology or clinical chemistry were observed in rats receiving MBO 1 or self-stabilized oligo. Dose-dependent enlargements of spleen, liver, and kidney were observed, especially in rats receiving PS oligo and MBO 2. Pathologic studies showed a generalized hyperplasia of the reticuloendothelial (RE) system in the tissues examined. Alterations in the spleen were mainly RE cell hyperplasia and hematopoietic cell proliferation. In addition to RE cell hyperplasia, lymph nodes showed necrosis, hepatocytes showed cytologic alterations and necrosis, and kidneys showed renal tubule regeneration. The severity of pathologic changes observed was oligodeoxynucleotide dependent, in the order of MBO 2 > PS oligo > self-stabilized oligo > MBO 1.
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PMID:Toxicologic effects of an oligodeoxynucleotide phosphorothioate and its analogs following intravenous administration in rats. 945 Sep 15

Pyrazine diazohydroxide (PZDH) is a novel antitumor agent that forms DNA adducts via the reactive pyrazine diazonium ion. In a recent Phase I study of PZDH, we identified a recommended Phase II dose of 100 mg/m2/day x 5, given as a 5-min i.v. bolus with the cycles repeated every 42 days (N. J. Vogelzang, et al, Cancer Res., 54: 114-119, 1994). There was a moderate negative correlation between serum chloride concentration and logarithm platelet nadir, suggesting the hypothesis that PZDH is activated in an acidic environment, leading to more toxicity in acidotic patients. Therefore, the University of Chicago Phase II cooperative network conducted two Phase II studies of PZDH in renal cancer (15 patients, 2 with liver metastases) and in 5-fluorouracil-refractory colorectal cancer (14 patients, 13 with liver metastases) to determine efficacy in each disease and to correlate safety and tolerance of the drug with PZDH pharmacokinetics/pharmacodynamics and with arterial blood gas measurements. There were no responses seen in either tumor type. The primary toxicity of PZDH was myelosuppression with neutropenia (absolute neutrophil count, < 1000/microl) and thrombocytopenia (<50,000 cells/microl), seen in 41 and 24% of all cycles, respectively. Other grade 3 and 4 toxicities were rare. Pharmacodynamic analysis revealed no significant correlation between plasma levels at 5, 60, and 120 min; WBCs; absolute neutrophil and platelet count nadirs; and initial serum chloride or blood pH levels. The colorectal patients experienced significantly more thrombocytopenia than did the renal cancer patients (median platelet nadir after cycle 1 was 151 x 10(3)/microl for renal patients versus 76 x 10(3)/microl for colon patients; P = 0.04), suggesting either that prior 5-fluorouracil and leucovorin reduced bone marrow reserve or that colorectal patients with liver metastases experienced more PZDH toxicity. Regression analyses revealed a possible relationship (P = 0.06) between serum pH and thrombocytopenia (i.e., for each increase of 0.03 in pH, there was a 34% increase in the platelet nadir), but there was no relationship between serum chloride and thrombocytopenia. Curiously, an increase in alkaline phosphatase was associated with an increase in the platelet nadir (P = 0.02). If PZDH continues to be developed as an antineoplastic agent, further studies of these relationships are suggested.
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PMID:Phase II and pharmacodynamic studies of pyrazine diazohydroxide (NSC 361456) in patients with advanced renal and colorectal cancer. 956 86

A 35-year-old Chinese woman initially presented with histologically and bacteriologically confirmed tuberculous lymphadenitis. She was also found to have thrombocytopenia, elevated serum alkaline phosphatase, and bilateral lung infiltrates. After 15 months of antituberculosis treatment, despite resolution of the cervical lymphadenopathy, she started to experience dyspnea. Chest radiograph appearance, thrombocyte count, and liver biochemistry had all deteriorated as well. Histologic findings from tissues obtained via transbronchial biopsy and open lung biopsy were consistent with sarcoidosis but also showed the presence of mycobacterial DNA by the polymerase chain reaction. She subsequently achieved a very good response clinically, radiographically, hematologically, and biochemically with 1-year of corticosteroid treatment for her sarcoidosis, and she remained relapse-free afterwards. The concomitant presence of tuberculosis and sarcoidosis in this patient together with the presence of mycobacterial DNA in the sarcoid lesion reiterate the possibility that mycobacteria or some of its components may be capable of inducing the immune response and the pathologic changes of sarcoidosis.
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PMID:A case of concomitant tuberculosis and sarcoidosis with mycobacterial DNA present in the sarcoid lesion. 1033 81

A 44-year-old man was admitted to our hospital because of purpura, increased serum alkaline phosphatase, and thrombocytopenia. He had undergone subtotal gastrectomy for gastric cancer 11 years earlier. A biopsy specimen of the bone marrow revealed metastatic mucin-forming, moderately differentiated adenocarcinoma. Because the primary tumor was not detected in any other organ, the gastric cancer the patient was treated for 11 years earlier was suspected as the primary tumor. Microangiopathic hemolytic anemia and disseminated intravascular coagulation developed during the clinical course, and the patient deteriorated despite treatment with anticoagulants. Finally, he died of pulmonary carcinomatous lymphangitis. Autopsy revealed a small number of adenocarcinomatous cells in the lymphoduct of the remaining stomach in spite of its mucosa being intact. We concluded that the bone marrow was infiltrated by cancer cells which originated in the stomach 11 years before. It is unclear why adenocarcinoma cells remained dormant for as long as 11 years in the gastric lymphoduct and bone marrow.
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PMID:[Disseminated carcinomatosis of the bone marrow occurring 11 years after subtotal gastrectomy for gastric cancer]. 979 1

A total of 171 workers with occupational exposure to benzene, toluene, xylene and ethylbenzene, and 37 controls were studied. Hematological parameters were measured using the automated hematology analyzer, (System 190). By routine microscopic methods we investigated the differential distribution of leukocytes and alkaline phosphatase in granulocytes. Of the workers, 95 (55.5%) had deviations of the different blood cells. Hypochromic anemia was found in 50 male workers (29.6%), while leukocytosis with lymphocytosis and neutropenia was found in 20%. In 11 workers (6.4%), dyshematopoiesis, was detected, affecting more than one blood population: anemia in combination with thrombocytopenia or leukocytosis with decreased enzyme activity of the granulocyte alkaline phosphatase. No definite relationship between changes in peripheral blood elements and length of service of the workers was found, but workers with over 20 years' exposure to aromatic hydrocarbons suffered from more severe forms of anemia.
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PMID:Changes in the peripheral blood of workers with occupational exposure to aromatic hydrocarbons. 982 88

When peripheral blood stem cell (PBSC) concentrates are used for allogeneic transplants, two or more apheresis procedures must often be performed. To determine how many cells could be collected from healthy people by two back-to-back apheresis procedures and what effect these collections would have on donors, we gave 19 healthy people 5 micrograms kg-1 day-1 and 21 people 10 micrograms kg-1 day-1 of granulocyte colony stimulating factor, filgrastim, for 5 days. We then collected two PBSC concentrates, one on day 5 and one on day 6. A third group of six people was given filgrastim 10 micrograms kg-1 day-1 for 5 days but had no PBSC concentrates collected. PBSC concentrate cell counts and donor cell counts, symptoms, and blood chemistries were assessed for up to 1 year. On day 5, three times more CD34+ cells were collected from donors given 10 micrograms kg-1 day-1 than those given 5 micrograms kg-1 day-1 (P = 0.009) but on day 6 the quantity of cells collected was the same (P = 0.23). The total number of CD34+ cells collected was two times greater in donors given the higher dose of filgrastim (median = 579 x 10(6); range = 174-1639 x 10(6) compared to 237 x 10(6); 103-1670 x 10(6); P = 0.061). Platelet counts fell after each PBSC concentrate collection, but there were no differences between the two groups of donors in platelet counts measured immediately after each collection. The platelet counts also fell in people who did not donate PBSC concentrates. The lowest counts in all three groups of people also occurred on day 10. In PBSC donors given 10 micrograms kg-1 day-1 of filgrastim the absolute neutrophil count (ANC) fell below premobilization counts on day 14. In donors given 5 micrograms kg-1 day-1 the ANC fell below premobilization counts on days 21, 28 and 49, CD34+ cell counts were significantly lower than premobilization counts on days 14 and 28 in donors given 10 micrograms kg-1 day-1 of filgrastim and on day 14 in those given 5 micrograms kg-1 day-1. No decrease in neutrophil or CD34+ cell counts occurred after filgrastim was given in the people who did not donate PBSC concentrates. The incidence of symptoms was similar in both groups of PBSC concentrate donors, except that those given 10 micrograms kg-1 day-1 were more than twice as likely to experience myalgias as those receiving the lower dose (P = 0.029). Several blood chemistries changed. Levels of alkaline phosphatase, LDH, SGPT, SGOT, uric acid and sodium increased. Levels of bilirubin, total protein, potassium, calcium and chloride decreased. In conclusion, twice as many CD34+ cells were collected from donors given 10 micrograms kg-1 day-1 of filgrastim. Platelet, neutrophil and CD34+ cell counts fell after the PBSC concentrate collections. The fall in platelet counts was due to both the collection and the administration of filgrastim. The falls in neutrophil and CD34+ cell counts were due to the loss of haematopoietic progenitor cells in the PBSC concentrates. Allogeneic PBSC concentrate donors should be given 10 micrograms kg-1 day-1 of filgrastim, and if possible only one component should be collected in order to avoid thrombocytopenia.
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PMID:Collection of two peripheral blood stem cell concentrates from healthy donors. 1021 4

Twenty-six serum samples from 24 patients were investigated for the presence of platelet-specific antibodies in a partly retrospective (n = 15) and partly prospective (n = 9) study. The sera contained either alloantibodies to human platelet antigens (HPA) (n = 23) or were from clinically suspected cases of fetomaternal alloimmune thrombocytopenia (FMAITP) in which platelet-specific antibodies had not been detected (n = 3). Three techniques were used to detect platelet antibodies: the platelet immunofluorescence test, the monoclonal antibody immobilization of platelet antigens (MAIPA) assay and a commercially available enzyme-linked immunosorbent assay--GTI PakPlus (GTI kit). Two alkaline phosphatase-conjugated antiglobulin reagents provided by the manufacturer were used in the GTI kit: an antihuman IgG/IgA/IgM (IgGAM) conjugate and an antihuman IgG conjugate. The GTI kit with the anti-IgGAM conjugate failed to detect eight antibody specificities in seven sera (anti-HPA-1a [n = 3], anti-HPA-3a [n = 1], anti-HPA-3b [n = 1] and anti-HPA-5b [n = 3]). Greater signal-to-background ratios were achieved in the GTI kit with the anti-IgG conjugate but five antibody specificities (anti-HPA-1a [n = 1], anti-HPA-3a [n = 1], anti-HPA-3b [n = 1], anti-HPA-5b [n = 2]) remained undetectable. All the sera were detected by MAIPA assay and, furthermore, the MAIPA assay achieved the greatest signal-to-background ratio in the majority of sera tested. These findings re-emphasize the value of the MAIPA assay in reference laboratories and illustrate that the GTI kit may either fail to detect or incorrectly identify clinically significant HPA antibodies.
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PMID:Evaluation of an enzyme-linked immunosorbent assay kit (GTI PakPlus) for the detection of antibodies against human platelet antigens. 1058 92

Docetaxel has been reported to show promising anti-tumour activity in pancreatic ductal cancer (PC). This study was conducted to evaluate the activity and toxicity of moderate-dose (60 mg m(-2)) docetaxel in Japanese chemo-naive patients with measurable metastatic PC. The patients had a performance status of 0-2. They received docetaxel intravenously over a 1- to 2-h period without any premedication for hypersensitivity reactions. This treatment was repeated every 3-4 weeks with dose adjustments based on the toxic effects observed. Twenty-one patients were eligible and treated with docetaxel. The median number of courses was 2 (range, 1-4). None of the patients achieved an objective response; seven showed no change and 13 showed progressive disease. In one patient, the response was not assessable because of early death. The median survival time for all patients was 118 days. The main grade 3-4 toxicities by patient were leucocytopenia (67%) and neutropenia (86%). Other grade 3-4 toxicities included anaemia (10%), thrombocytopenia (5%), nausea/vomiting (29%), anorexia (29%), GOT/GPT increase (10%), alkaline phosphatase increase (14%), malaise/fatigue (33%) and alopecia (24%). In conclusion, docetaxel, administered on this schedule, did not show significant anti-tumour activity in patients with metastatic PC.
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PMID:Phase II study of docetaxel in patients with metastatic pancreatic cancer: a Japanese cooperative study. Cooperative Group of Docetaxel for Pancreatic Cancer in Japan. 1040 50


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