Emeritus Faculty, Acad Council, Pathology
M.S./M.D., Univ. Oregon Medical School, Biochemistry Medicine (1960)
The general problem with which we are concerned is the elucidation of cellular mechanisms of gene regulation which are related to the neoplastic process in humans. The phenomenon of ectopic protein synthesis in human cancer offers a good experimental model for investigating this problem. The ectopic synthesis of placental proteins by non-trophoblastic neoplasms is of special interest because of the frequent association of similar characteristics in neoplastic cells and embryonic cells. We are investigating the mechanisms associated with the derepression of the genes synthesizing embryonic proteins and those involved in neoplastic transformation:
1. Studies on the regulation of ectopic gene expression in neoplastic breast cells. In these studies we examine the effects of steroid hormones and cholcalciferol analogs on the expression of ectopically produced placental alkaline phosphatase and the eutopic breast-class isoenzyme in human breast cancer cell lines in which embryonic genes are ectopically (non-phenotype) expressed.
2. Studies on a set of nuclear proteins which bind to the regulating sequences controlling the transcription of the placental alkaline phosphatase in response to 1,25,(OH)2D3, which down-regulates the gene and down-regulates cell division.
The rationale for the potential role of antioxidants in the prevention of cardiovascular diseases (CVD) remains strong despite the disappointing results of recent trials with a few select antioxidant vitamins. Glutathione (GSH) is one of the body's most powerful antioxidant agents but there is a surprising paucity of data on its use as an interventional therapy. Glutathione, when taken orally, is immediately broken down into its constituent amino acids, of which cysteine is the only one to be essential. Available cysteine is the critical determinant of intracellular GSH concentrations. N-acetyl cysteine (NAC) is an antioxidant supplement that has been used to provide a source of cysteine to replete GSH levels. By replenishing endogenous glutathione, it is possible that NAC would exert the same effect(s) as exogenous GSH. However, there is a new delivery system, liposomal GSH, which keeps glutathione intact. In this study, the investigators propose to match the cysteine content of NAC and GSH and compare the effects of these two supplements, at two different doses, on markers of inflammation and oxidative stress.
Stanford is currently not accepting patients for this trial. For more information, please contact Antonella Dewell, (650) 736 - 8577.
The Pap smear is currently the most widely used method of screening for squamous cell carcinoma of the cervix (SCCC). Because it is based on cell morphology, it is subject to variability in interpretation. Sensitive molecular markers capable of differentiating cancerous samples from noncancerous ones would be beneficial in this regard.We performed representational difference analysis (RDA) using paired, noncancerous (normal) and cancerous (disease) tissues taken from the same specimen obtained from a single patient with a confirmed diagnosis of SCCC. Linearly amplified cDNA from normal and diseased tissues of the original patient and seven others were hybridized to DNA macroarrays containing the candidate gene transcript fragments. Real-time quantitative reverse transcription-PCR was used to validate the macroarray results.RDA identified a candidate pool of 65 transcript fragments up-regulated in diseased tissue compared with normal tissue. Forty-one transcripts were found to be up-regulated in diseased compared with normal tissue in at least one half the patients by macroarray hybridization. Eleven of those genes were selected for real-time quantitative reverse transcription-PCR analysis, and all were confirmed as transcriptionally up-regulated in cancer compared with normal tissue in at least one half the patients.RDA using tissues from a single patient identified gene fragments confirmed to be transcriptionally up-regulated in SCCC both in the original patient and in seven others. The confirmed genes have a variety of functions and also have the potential to serve as diagnostic or prognostic markers.
View details for DOI 10.1373/clinchem.2004.038620
View details for Web of Science ID 000225991100010
View details for PubMedID 15514096
Effects of lisofylline (1-(5-R-hydroxyhexyl)-3,7-dimethylxanthine), a functional inhibitor of phosphatidic acid (PA) generation derived from de novo synthesis, on neutrophil function were examined in a porcine sepsis model. Hanford minipigs (18-25 kg) were randomly separated into six groups of six animals each: (1) saline control group; (2) sepsis control group, infused with Pseudomonas aeruginosa (1 x 10(6) colony-forming units/kg/min) for 2 h; (3) lisofylline control group, given a 25 mg/kg bolus of lisofylline 30 min prior to time zero, followed by a continuous infusion of 10 mg/kg/h throughout the study; (4) lisofylline pretreatment sepsis group, given lisofylline 30 min prior to sepsis, (5) lisofylline 1-h post-treatment sepsis group, and (6) lisofylline 2-h post-treatment sepsis group. All animals were studied for 6 h. Neutrophils were isolated at -0.5, 2, and 6 h. In the pretreatment and 1-h post-treatment groups, sepsis-induced neutrophil attachment to fibronectin was significantly attenuated. Sepsis-enhanced phagocytic activity was significantly reduced in the lisofylline pretreatment sepsis group, but not in the post-treatment groups. No treatment affected phorbol 12-myristate 13-acetate-induced chemiluminescence and basal filamentous actin content, which increased in sepsis, and cap formation, which declined in sepsis. Sepsis caused neutropenia, pretreatment produced neutrophilia, and 1-h post-treatment caused the neutropenia to recover to control levels. Interestingly, toward the end of the 6-h period, the neutrophil count was higher in the lisofylline control group than in the saline control groups. Thus, the inhibition of PA generation from de novo synthesis during sepsis not only can selectively downregulate some neutrophil functions but can also reverse neutropenia.
View details for Web of Science ID 000078582700005
View details for PubMedID 9927533
A significant number of squamous cell carcinomas of the head and neck (SCCHN) resist radiation treatment, the most common form of adjuvant therapy for this disease. The presence of a mutant form of the tumor suppressor gene p53 has been correlated with disruption of programmed cell death (apoptosis) and reduced cell cycle arrest, resulting in increased radiation resistance and survival.We introduced by means of an adenoviral vector a functional p53 gene into a radiation-resistant SCCHN cell line that harbors mutant p53. Replacement of wild-type p53 restored the G1 block and apoptosis in these cells in vitro. Moreover, introduction of wild-type p53 sensitized SCCHN-induced mouse xenografts to radiotherapy in vivo.The combination of p53 replacement gene therapy with conventional radiotherapy may treat SCCHN more effectively.
View details for Web of Science ID A1997WZ21100007
View details for PubMedID 9158398
Microtubules play an essential role in cell division. Little is known about possible variations of total tubulin and tubulin isotype expression during the cell cycle. We analyzed the total tubulin content, tubulin polymerization status and tubulin isotype content in resting and dividing human K562 leukemic cells and human MES-SA sarcoma cells. Although the total cellular tubulin content increases as the cells progress toward mitosis, the total tubulin/total protein ratio is stable during the cell cycle. Reverse transcriptase-polymerase chain reaction was applied to analyze the levels of expression of alpha, beta, and gamma-tubulin isotypes. Whereas alpha-tubulin isotype and gamma-tubulin transcripts were found to be expressed at constant levels throughout the cell cycle, some of the beta-tubulin isotype transcripts were found to be more highly expressed in dividing then in resting cells. Both of the class IV beta-tubulin isotype transcripts (human 5 beta and beta 2, Class IVa and IVb, respectively) were expressed in dividing K562 and MES-SA cells at twice the levels found in resting cells. Increased expression of the class IV isotype proteins in dividing cells was confirmed by immunoblotting, both in K562 and in MES-SA cells. A larger fraction of total cell tubulin was found to be polymerized in dividing cells (36-40%) than in resting cells (27-30%). The degree of polymerization of class IV tubulin in dividing and resting cells was similar to that of total tubulin. These results show that total tubulin is expressed as constant levels throughout the cell cycle but that the degree of polymerization is increased as cells are committed to division. The relative overexpression of the two class IV beta-tubulin isotypes in dividing cells suggests functional specificity for these isotypes and a regulatory role of these isotypes on the microtubule network during mitosis.
View details for Web of Science ID A1996VE88700004
View details for PubMedID 8874965
Neutrophil adherence to vascular endothelium is partially mediated by adhesion molecules, including intracellular adhesion molecule 1 (ICAM-1), on endothelial cells. We examined the effect of transforming growth factor-beta 1 (TGF-beta 1) on the expression of ICAM-1 in human umbilical vein endothelial cells (HUVEC). TGF-beta 1 (1 ng/ml) increased ICAM-1 and ICAM-1 mRNA expression in HUVEC, as assessed by flow cytometry and Northern blot analysis, respectively. In addition, we investigated whether exogenous recombinant TGF-beta 1 can cause neutrophil-mediated lung injury in guinea pigs. The plasma half-life of 125I-labeled TGF-beta 1 in guinea pigs was 4.6 +/- 0.1 min, and the 125I activity was 2.8 +/- 0.2% 8 h after injection. The ratio of 125I-labeled albumin concentration in lung tissue and bronchoalveolar lavage (BAL) fluid to that in plasma, lung wet-to-dry weight ratio, numbers of neutrophils in BAL fluid, and numbers of neutrophils per alveolus in fixed lung sections increased in guinea pigs that received a high dose of TGF-beta 1 (25 micrograms i.v. followed by 2 micrograms/h for 8 h) compared with the control group. These results suggest that TGF-beta 1 causes neutrophil-mediated lung injury, possibly through upregulation of ICAM-1 on endothelial cells, and might be important in the pathogenesis of lung injury.
View details for Web of Science ID A1994PG91600032
View details for PubMedID 7836132
To determine if the protein kinase C inhibitor, H-7, alone can cause acute lung injury. In cell studies, H-7 inhibited phorbol myristate acetate-induced neutrophil oxygen radical release. Additionally, one animal study demonstrated that H-7 inhibited phorbol myristate acetate-induced lung injury. There have been no studies on the effect of H-7 alone on lung function or on neutrophil release of oxygen radicals.Prospective, randomized, laboratory study along with in vitro studies using flow cytometry and lucigenin-dependent chemiluminescence.Experimental laboratory.Specific, pathogen-free guinea pigs and isolated human peripheral neutrophils.Guinea pigs were randomized into three experimental groups: saline control, H-7 low dose (2 mg/kg bolus + 0.2 mg/kg/hr), and H-7 high dose (6 mg/kg bolus + 0.5 mg/kg/hr). Human neutrophils were randomized into control and experimental groups. The effects of H-7 on pulmonary permeability in guinea pigs were examined over an 8-hr period.We measured the wet/dry weight ratio as an index of pulmonary edema and we measured the concentration ratios of 125I-labeled albumin in lung tissue and in bronchoalveolar lavage fluid and compared the ratios with those values in plasma as indices of pulmonary permeability. We also studied the in vitro effect of H-7 on human neutrophil oxygen radical production, using flow cytometry and lucigenin-dependent chemiluminescence. By flow cytometry, we measured oxygen radical production using the 2',7'-dichlorofluorescin and hydroethidine assays. The 2',7'-dichlorofluorescin assay mainly measures hydrogen peroxide, while the hydroethidine assay measures either superoxide anion alone or in combination with other oxygen intermediaries like hydrogen peroxide. Neutrophils (5 x 10(5)) were obtained by Ficoll-Hypaque gradient centrifugation and were incubated with H-7 (5, 25, 100 microM). In the H-7 high-dose group, wet/dry weight ratio, and 125I-labeled albumin ratios in lung/plasma, and bronchoalveolar lavage/plasma were significantly increased (p < .05 for each ratio). Pulmonary endothelial gap and subendothelial bleb formation were demonstrated in the high-dose group by electron microscopy. One hundred micromols of H-7 caused a small, significant decrease (23.3%, p < .05) in neutrophil oxygen radical production assessed by 2',7'-dichlorofluorescin. H-7 had no other effects on neutrophil oxygen radical production. H-7 did not stimulate neutrophil chemiluminescence; it decreased chemiluminescence.a) Protein kinase C inhibition with high-dose H-7 increased wet/dry weight and albumin in lung/plasma and bronchoalveolar lavage/plasma ratios in guinea pigs; b) the H-7 high-dose group demonstrated damaged pulmonary endothelium by electron microscopy; and c) since neutrophil oxygen radical production was not increased by H-7 as assessed by flow cytometry and chemiluminescence, it appears that H-7-induced acute lung injury and endothelial damage are not mediated by increased neutrophil oxygen radical production.
View details for Web of Science ID A1994PA69600024
View details for PubMedID 8026208
Unlike the related drug carboplatin, cisplatin is highly nephrotoxic and must be given with vigorous intravenous hydration at a much lower dose. As the result of an accidental substitution of cisplatin for carboplatin, a 68-year-old woman received a massive overdose of cisplatin without intravenous hydration.Laboratory documentation included measurements of platinum concentrations by atomic absorption spectroscopy and of xeroderma pigmentosum group E (XPE) binding factor, a protein that is involved in the recognition step of DNA repair.Toxicities included severe emesis, myelosuppression, renal failure, and deafness, which are well known. Other toxicities were seizures, hallucinations, loss of vision, and hepatic toxicity, which were unusual and may have been caused by the magnitude of the overdose. As late as day 19, there was a continued cellular response from cisplatin, as evidenced by decreased levels of XPE binding factor in extracts from the patient's peripheral blood lymphocytes. Plasmapheresis was effective in lowering the platinum concentration from greater than 2900 ng/ml to 200 ng/ml and appeared to be of clinical benefit. Even after the onset of renal failure, hydration to increase urine volume resulted in increased urinary excretion of platinum. Granulocyte-macrophage colony-stimulating factor (GM-CSF) was used to ameliorate myelosuppression. The patient received a transplanted kidney from her monozygotic twin sister and survived with no clinically significant deficit except for deafness.No previous reports exist of survival after such a high dose of cisplatin without intravenous hydration. In the future, patients may benefit from similar management and heightened awareness of the possibility of accidental substitution.
View details for Web of Science ID A1993ML34100023
View details for PubMedID 8252487
Oxygen radicals play an important role in the mechanism of acute lung injury. The 21-aminosteroid lazaroid, U-78518F, is a potent antioxidant. We examined the effect of intravenous U-78518F on acute lung injury in septic guinea pigs over 8 h. The experimental groups (n = 6) were 1) saline control, 2) Escherichia coli (2 x 10(9)/kg i.v.), 3) pretreatment (U-78518F 5 mg/kg bolus + 1 mg.kg-1 x h-1, 15 min before E. coli injection), and 4) posttreatment (U-78518F 30 min after E. coli injection). We measured wet-to-dry weight ratio (W/D) as an index of pulmonary edema and concentration ratios of 125I-labeled albumin in lung tissue and bronchoalveolar lavage fluid compared with plasma (L/P and BAL/P, respectively) as indexes of lung protein fluxes. In septic guinea pigs, pretreatment with U-78518F attenuated W/D, L/P, and BAL/P and posttreatment attenuated W/D and BAL/P (P < 0.05 for each). Furthermore, we studied the effect of U-78518F on human neutrophil oxygen radical production (ORP) by using flow cytometry to assess intracellular ORP and lucigenin-dependent chemiluminescence to assess extracellular ORP. Neutrophils (5 x 10(5) were stimulated with 0.5 micrograms/ml of phorbol myristate acetate. With flow cytometry, we measured intracellular ORP, cross-sectional cell area, and degranulation in neutrophils. U-78518F (minimum concn 1.0 microM) decreased intracellular ORP (n = 4; P < 0.05) when the dihydrorhodamine 123 assay was used. U-78518F (minimum concn 1.0 microM) inhibited phorbol myristate acetate-induced neutrophil chemiluminescence (n = 4; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1993LD69900016
View details for PubMedID 8335543
An Hinf1 associated restriction length polymorphism pattern is reported for the catalase gene of Hungarian normocatalasemic individuals and acatalasemic patients. The 2.4-kb pCAT 10 probe revealed 9 bands (2.1, 1.5, 1.2, 1.1, 0.9, 0.8, 0.6, 0.5 and 0.4 kb) with 9 distinct patterns for the controls. The same patterns were detected for the Hungarian acatalasemic patients. The examination of the A to T mutation of the Hungarian acatalasemic patients and their relatives at position -21 in the flanking region with Hinf1 polymorphism could not reveal any difference between the acatalasemic and the normocatalasemic catalase gene.
View details for Web of Science ID A1993NV38800006
View details for PubMedID 7916241
The authors have shown previously that intracellular glutathione (GSH) plays an important role in the regulation of human immunodeficiency virus (HIV) transcription and replication in vitro, through modulation of signal transduction by inflammatory cytokines. Moreover, intracellular GSH levels are known to regulate T-lymphocyte function. In multiparameter FACS studies presented here, we show that relative GSH levels in CD4+ and CD8+ T cells from HIV+ individuals are significantly lower than in corresponding subsets from uninfected controls. These studies define the relative intracellular glutathione (GSH) levels in CD4+ T cells, CD8+ T cells, B cells, and monocytes from 134 HIV-infected individuals and 31 uninfected controls. The greatest decreases in intracellular GSH occur in subsets of T cells in individuals in the later stages of the HIV infection. In AIDS patients, GSH levels are 63% of normal in CD4+ T cells (p less than 0.0001) and are 62% of normal in CD8+ T cells (p less than 0.0001). Similarly, in AIDS-related complex (ARC) patients, GSH levels are 66% of normal in CD4+ T cells (p less than 0.003) and are 69% of normal in CD8+ T cells (p less than 0.003). These findings suggest that low intracellular GSH levels may be an important factor in HIV infection and in the resulting immunodeficiency.
View details for Web of Science ID A1992HG48900025
View details for PubMedID 1540417
Reactive oxygen species (ROS), including superoxide anions, play an important role in mediating acute lung injury. We examined whether polyethylene glycol-conjugated superoxide dismutase (PEG-SOD) attenuates lung injury in Escherichia coli-treated guinea pigs. Twenty-four guinea pigs were divided into four groups: (1) control group; (2) septic group, in which live E. coli (2 x 10(9)/kg) were injected intravenously; (3) pretreatment group, in which PEG-SOD (2,000 IU/kg) was injected intravenously 15 min before E. coli; and (4) posttreatment group, in which PEG-SOD (2,000 IU/kg) was injected intravenously 30 min after E. coli. Lung injury was assessed by the concentration ratio of 125I-labeled albumin in lung tissue and bronchoalveolar lavage (BAL) fluid relative to plasma (L/P and BAL/P), lung wet-to-dry weight ratio, and the number of neutrophils in BAL fluid. Plasma half-life of PEG-SOD in normal guinea pigs was 13.5 h. L/P, lung wet-to-dry weight ratio, and the number of neutrophils in BAL fluid decreased in both pretreatment and posttreatment groups compared with the septic group. BAL/P decreased in the pretreatment group but not in the posttreatment group compared with the septic group. After the animal model studies, we investigated the effect of PEG-SOD on the human neutrophil extracellular generation of ROS stimulated by phorbol myristate acetate (PMA) in lucigenin-dependent chemiluminescence (CL). PEG-SOD at concentrations greater than or equal to 0.1 U/ml inhibited PMA-induced CL in a dose-dependent manner. We also examined the effect of PEG-SOD on the neutrophil intracellular generation of ROS using flow cytometry to assess intracellular hydroethidine oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1992HC99800025
View details for PubMedID 1736747
Iron participates in a range of reactions that are necessary for cell viability and cell proliferation. Iron is an essential component in DNA synthesis and in respiratory and oxidative metabolism. These functions relate to the properties of unremitting proliferation and a more anaerobic metabolism, that may contribute to a selective advantage of neoplastic cells over nonneoplastic cells. Clinical correlations have been made linking cellular iron content to the development of cancer in humans. The clinical entities include disease states in which there is abnormal accumulation of iron as part of the disease process, and cases in which neoplasms have developed as a result of administered iron preparations. The molecular mechanisms regulating cellular iron incorporation and the iron-dependent formation of reactive oxygen intermediates that can cause cell injury have been recently elucidated and provide a basis for better understanding the relationship of these processes to neoplastic development.
View details for Web of Science ID A1992HB31900002
View details for PubMedID 1543547
The steady-state levels of mRNAs encoding alkaline phosphatase isoenzymes were examined in two human breast carcinoma cell lines. MDA-MB-157 cells expressed the phenotypic breast alkaline phosphatase and BT20 cells expressed the nonphenotypic placental alkaline phosphatase isoenzyme, frequently reexpressed in neoplasms. Dexamethasone (DEX), which elicits a general effect on phosphatase expression, and 1,25-dihydroxy vitamin D3 (1,25(OH)2D3), a promoter of cell differentiation that correspondingly effects embryonic phosphatase expression, were chosen as perturbing agents for these experiments. RNA blot analysis showed a single RNA species of approximately 2.6 kb under all treatment conditions in BT20 cells and a single RNA species of 2.6 kb under each condition in MDA-MB-157 cells. The results showed that the expression of both the AP isoenzyme mRNA phenotypic of breast produced by MDA-MB-157 cells and the embryonic alkaline phosphatase isoenzyme (PLAP) mRNA produced by BT20 cells was increased by treatment with DEX. By comparison 1,25(OH)2D3 caused an increase in the tissue-unspecific AP mRNA in the MDA-MB-157 cells, but caused a decrease in PLAP mRNA levels in BT20 cells. The level of each isoenzyme mRNA species is altered by either hormone in a dose- and time-dependent manner in both cell lines. In BT20 cells, treatment with cycloheximide showed that ongoing protein synthesis is not required to potentiate the PLAP mRNA response to DEX, but is required for the action of 1,25(OH)2D3. However, protein synthesis is required for the action of both hormones in the MDA-MB-157 cells which make the breast phenotypic AP. These data demonstrate that the DEX- and 1,25(OH)2D3-regulated expression of both of these alkaline phosphatase isoenzymes occurs via a complex mechanism involving control of mRNA abundance, not translational control of constant message levels.
View details for Web of Science ID A1990DD95200015
View details for PubMedID 2335189
The pattern of inheritance of a Pst I restriction fragment length polymorphism (RFLP) of the human placental alkaline phosphatase gene was studied in nine nuclear families by Southern blot hybridization analysis of genomic DNA. The dimorphic RFLP is defined by the presence of allelic fragments 1.0 kilobase and 0.8 kilobase long. The results of this study show that the two alleles of the PstI RFLP of the placental alkaline phosphatase gene segregate as codominant traits according to Mendelian expectations. For a polymorphism to be useful as a genetic marker the probability that an offspring is informative (PIC) must be at least 0.15. The allelic frequency of the 1.0-kilobase allele is 0.21, which correlates to a probability that an offspring is informative of 0.275 and is indicative of a useful polymorphism. By using probes derived from different regions of the placental alkaline phosphatase cDNA, the mutated Pst I site causing the RFLP was located in the penultimate intron 2497 base pairs downstream from the transcriptional initiation site.
View details for Web of Science ID A1988Q580700055
View details for PubMedID 2902636
The expression of human placental cell surface antigens was examined in cells of lymphoid origin, including peripheral blood lymphocytes and cultured lymphoblastoid cells of bone marrow or thymus derivation. A select group of this defined set of surface antigens was detected on all three cell preparations. The most remarkable observation was the conspicuous absence of three subunits previously demonstrated to be present on all human cell surfaces examined to date. Antiserum directed against several placental components prevents adhesion and spreading of cells which grow attached to surfaces. These results suggest a role for these three glycoproteins in mediating cellular adhesion.
View details for Web of Science ID A1980JD74100011
View details for PubMedID 9537047
A nucleic acid photocross-linking technology was used in the development of a direct assay for factor V Leiden, a point mutation in the factor V gene (G1691A) that is the most common inherited risk factor for thrombosis. This cross-linking hybridization assay included two allele-specific capture probes and six signal-generating reporter probes; all were modified with a photoactivated cross-linking compound. By using two different capture probes complementary to a 16-base sequence at the factor V Leiden mutation site, but differing in the nucleotide opposite the mutation site (C vs T), wild-type and factor V Leiden alleles were differentiated in purified DNA specimens. The assay was also successfully applied to genomic DNA in leukocytes isolated from whole blood; the factor V status of 122 patients as determined by this method was in complete concordance with a standard PCR-based assay and clearly discriminated between healthy individuals and factor V Leiden heterozygotes.
View details for Web of Science ID A1997XV89700033
View details for PubMedID 9299963
Acetaminophen is frequently administered to infants and children for its antipyretic and analgesic properties. Oral administration is the route of choice in daily practice. In some circumstances this is impractical. Rectal administration of acetaminophen is an alternative route. This study measures plasma concentrations following rectal administration of acetaminophen 20 mg.kg-1 (10% Infants' Tylenol Drops, McNeil Consumer Product Co., diluted with an equal volume of sterile water) in five preterm neonates. Serial arterial blood samples were obtained at 0, 15, 30, 60, 120, and 240 min. Pharmacokinetic parameters were (mean +/- SD): Cmax (maximum plasma concentration) of 8.38 +/- 3.92 micrograms.ml-1 and Tmax (time to reach maximum plasma concentration) of 78.0 +/- 40.2 min. Our results show that 20 mg.kg-1 of acetaminophen rectally results in low plasma levels in preterm neonates.
View details for Web of Science ID A1997YE09300005
View details for PubMedID 9365971