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V W Armstrong

Publications and source records attributed to V W Armstrong.

At least 73 records · Page 4Linked to original sources
PubMed1997

Monitoring of cyclosporin and azathioprine in organ transplantation.

Cyclosporin A (CsA) is a cyclic undecapeptide that was first isolated from the fungus Tricoderma polysporum. The introduction of this potent immunosuppressive compound significantly improved the outcome of solid organ and bone marrow allograft transplantation. There is now a large body of accumulated experience in the monitoring of this drug, and several consensus conferences have addressed this issue /1-3/. Azathioprine in CsA-based triple therapy with steroids is still widely used in organ transplantation even though it is known to carry the risk of severe myelosuppression. Measurement of white blood cell (WBC) and platelet counts is generally used to recognize azathioprine toxicity. However, recent reports /4-6/ have indicated that patients with a genetically determined deficiency in thiopurine methyltransferase (TPMT), an important enzyme in azathioprine metabolism, are at high risk for myelosuppression. Monitoring of active azathioprine metabolites, which are responsible both for the immunosuppressive action and for the toxicity of azathioprine, may be necessary in such cases. It should also be noted that the incidence of posttransplant lymphoproliferative disorder (PTLD) is a function of the intensity of immunosuppression /7,8/. Thus the combination of CsA, azathioprine and steroids is associated with an approximately three-fold higher incidence of PTLD than low dose CsA guided by therapeutic drug monitoring /8/.

Azathioprine↗
PubMed1997

The effect of recombinant human GH replacement therapy on lipoprotein(a) and other lipid parameters in adults with acquired GH deficiency: results of a double-blind and placebo-controlled trial.

The effect of GH substitution on serum lipids and lipoproteins, and in particular lipoprotein(a) (Lp(a)), was investigated in 32 adults with postoperative (acquired) GH deficiency as part of a double-blind, placebo-controlled trial. Seventeen men and fifteen women, aged 18-59 years (mean 42 years) from two centres (Hannover and Göttingen) were randomly assigned to two groups. Group P (placebo) received placebo for the first 12 months and recombinant human GH (rhGH) for the following 12 months (open phase). Group V (verum) was treated with rhGH for two consecutive periods of 12 months each. The target dose of rhGH was 2 U/m2 per day, given subcutaneously daily at bedtime. Serum concentrations of Lp(a), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides were determined at 0, 12 and 24 months. In group V, Lp(a) increased significantly in the first as well as in the second year of treatment (P=0.02, 12 months versus baseline; P=0.016, 24 months versus 12 months). In contrast, Lp(a) levels remained unchanged in group P during the first 12 months (P=0.826 versus baseline), but increased significantly (P=0.002) during the second year, when all patients were administered GH. The increase in Lp(a) after 12 months of rhGH replacement therapy in all 32 patients was significant for Lp(a) baseline concentrations both above and below 20 mg/dl and was independent of the apolipoprotein(a) isoforms. Total and LDL-C decreased significantly after 1 year and triglycerides after 2 years in group V. A significant reduction was also observed in the TC/HDL-C and the LDL-C/HDL-C ratios. Our study shows an unfavorable effect of rhGH replacement therapy on Lp(a) levels, which is, however, counteracted by a favorable effect of rhGH on TC, LDL-C and the TC/LDL-C and LDL-C/HDL-C ratios.

Adult↗
PubMed1996

Apolipoprotein E phenotype frequency and cerebrospinal fluid concentration are not associated with Creutzfeldt-Jakob disease.

OBJECTIVE: To analyze the distribution of apolipoprotein E (Apo E) phenotypes between patients with Creutzfeldt-Jakob disease (CJD) and control subjects. SETTING: University hospital, base of the German National CJD Surveillance Study. DESIGN: Prospective case-control study. SUBJECTS: Sixty-two patients with definite or probable CJD, 90 patients with initial suspected CJO, and 51 controls matched for age, sex, and place of residence. MAIN OUTCOME MEASURES: Phenotyping of Apo E in serum by isoelectric focusing, assessment of the gels by 3 independent investigators, measurement of of Apo E in cerebrospinal fluid using an enzyme-linked immunosorbent assay, and calculation of Kaplan-Meier cumulative survival plots. RESULTS: The most frequent phenotype was E 3-3 with 56% in patients and 59% in controls, followed by E 3-4 with a frequency of 29% vs 25%, respectively. The phenotype E 3-2 was much rarer (13% vs 16%, respectively). Patients with definite CJD had a mean (SD) Apo E concentration of 3.4 (2.0) mg/L; patients with probable CJD, 3.1 (1.6) mg/L; patients with possible CJD, 3.8 (2.2) mg/L; and subjects with other diseases, 3.0 (1.7) mg/L. Mean (SD) disease duration for patients with E 3-2 was 11.8 (9.8) months; for patients with E 3-3, 12.0 (9.02) months; and for patients with E 3-4, 14.2 (12.3) months. CONCLUSIONS: We found no significant difference in the distribution of Apo E phenotypes between patients with CJD and controls. The concentration of Apo E in cerebrospinal fluid cannot be taken as a biochemical marker for the disease. The Apo E phenotype had no influence on the duration of CJD. Our data do not support an association of Apo E4 with either the duration or time at onset of CJD.

Adult↗
PubMed1996

Should 6-thioguanine nucleotides be monitored in heart transplant recipients given azathioprine?

The commonly used immunosuppressive regimen after orthotopic heart transplantation consists of cyclosporine (CsA), azathioprine (AZA), and steroids. Although AZA therapy is generally regarded as unproblematic, its use can be associated with severe side effects, particularly myelosuppression. Since AZA is a prodrug, which must first be metabolized to its active metabolites, AZA therapy, in contrast to CsA therapy, cannot be controlled by measuring blood levels of this drug. Because of the myelosuppressive properties of the AZA metabolites, the 6-thioguanine nucleotides (6-TGN), the white blood cell count is usually monitored in patients on AZA therapy, and AZA is discontinued if neutropenia appears. In a group of 20 consecutive heart recipients, 6-TGN concentrations ranged from < 30 to 2,211 pmol/8 x 10(8) red blood cells (RBCs); levels < or = 450 pmol/8 x 10(8) RBCs were not associated with AZA-induced myelosuppression. Three cases of neutropenia were experienced, two of them with a fatal outcome. One patient died in septicemia owing to total myelosuppression. In this case an excessively high erythrocyte 6-TGN concentration (2,211 pmol/8 x 10(8) RBCs) was associated with a complete deficiency of thiopurine methyltransferase (TPMT), one of the main AZA detoxifying enzymes. The second patient, who had high RBC TPMT activity, developed neutropenia during rehabilitation, and AZA was withdrawn. Coincidentally, in this case the CsA blood level was only 132 g/L, and the RBC 6-TGN level was very low (maximum 46 pmol/8 x 10(8) RBCs). This patient rapidly developed cardiogenic shock with clinical signs of acute rejection and was given a second transplant on an emergency basis, but finally died from rejection of the second graft. Retrospectively, it was determined that neutropenia in this patient was not related to AZA toxicity. A high 6-TGN level (698 pmol/8 x 10(8) RBCs) was also seen in a third patient with mild neutropenia, who required allopurinol, an inhibitor of xanthine oxidase, the other major detoxifying enzyme for AZA. In this patient AZA therapy could be individually adapted by RBC 6-TGN monitoring. Based on our experience, we suggest that RBC 6-TGN monitoring allows for better individualization of treatment with AZA and may help avoid fatal complications.

Adolescent↗
PubMed1996

Prognostic value of the monoethylglycinexylidide test in pediatric liver transplant candidates.

The objective of this prospective study was to assess the prognostic value of dynamic and static liver function tests and clinical symptoms in pediatric patients with chronic end-stage liver disease in a serial examination including three evaluations at 3-month intervals. Of the 24 patients entering the study, six were given transplants within the observation period of 10 months. Of the remaining 18 patients who were considered in the final evaluation, five died before transplantation was possible. The variables included in the analysis were monoethylglycinexylidide (MEGX) formation from lidocaine, bilirubin, albumin, and creatinine serum concentrations, catalytic serum concentration of cholinesterase (CHE), prothrombin time (PT), factors II and V, serum amino acids, body weight, and presence of ascites. In nonsurvivors (n = 5), MEGX serum concentrations 30 min after intravenous administration of lidocaine (1 mg/kg body weight) were < 10 micrograms/L at the first examination. Statistically significant differences between nonsurvivors and survivors were observed for initial MEGX test results (p = 0.0089) and serum bilirubin concentrations (p = 0.009), as well as for the last available MEGX and bilirubin data from each patient (p = 0.017 and 0.016, respectively). At a diagnostic sensitivity of 100%, the corresponding diagnostic specificities for MEGX and bilirubin from the first examination were 77 and 62%, respectively. These data show that consistently low MEGX test results < 10 micrograms/L, obtained 30 min after intravenous administration of lidocaine (1 mg/kg body weight), are a prognostically unfavorable sign in pediatric transplant candidates.

Adolescent↗
PubMed1996

The value of serial determination of MEGX and hyaluronic acid early after orthotopic liver transplantation.

Post-transplant assessment of early graft function has become an essential part of monitoring, especially when deciding on retransplantation. If primary non-function is indicated, retransplantation is inevitable; early graft dysfunction may be related to subsequent complications. In a prospective study in 84 patients after orthotopic liver transplantation (OLT) we measured aspartate aminotransferase (AST), alanine aminotransferase (ALT), glutamate dehydrogenase (GLDH), bilirubin (BIL), prothrombin time, MEGX formation, hyaluronic acid (HA) and soluble interleukin-2 receptor (sIL-2R) concentrations during the first 2 postoperative weeks; graft outcome was followed over 4 months. The aim of this study was to determine whether graft survival could be predicted by such variables early after OLT. Compared with patients with stable graft function (n = 25), patients with post-transplant icteric cholestasis (n = 30) exhibited no difference in graft survival, despite a decrease in MEGX formation to a nadir median of 12 micrograms L-1 on day 10. Patients with rejection (n = 8) and septicaemia (n = 6) showed a marked decrease in MEGX values and an increase in HA and sIL-2R concentrations between postoperative days 3 and 7. Patients with primary non-function (PNF; n = 5) were characterized by strongly reduced MEGX formation (median 4 micrograms L) and increased HA values (median 2300 micrograms L-1) on day 3 after OLT. A total of 24/84 grafts were lost within 120 days. In a survival analysis using the Cox proportional hazards regression, HA and MEGX values on day 1 were the only independent variables entering the model that showed an adequate prognostic sensitivity. At cut-off points of 22 micrograms L-1 (MEGX) and 730 micrograms L-1 (HA) the combined use of these parameters in a parallel approach yielded a sensitivity of 58% with a corresponding specificity of 95% for 120-day graft survival. These findings suggest that the inclusion of MEGX and HA in postoperative monitoring of OLT patients may be helpful in the early prediction of graft survival.

Adolescent↗
PubMed1996

Decrease in lipoprotein(a) after renal transplantation is related to the glucocorticoid dose.

Serum lipoprotein(a) [Lp(a)] concentrations and apolipoprotein(a) phenotypes were determined in 46 patients with end-stage renal disease both before as well as 1 week and 1, 3 and 6 months after renal transplantation. Immunosuppressive therapy consisted of cyclosporin A, prednisone and azathioprine. Before transplantation median Lp(a) levels did not differ between the patients and a healthy control group. A highly significant decrease (P < 0.001) in Lp(a) levels was observed in both male and female patients 1 week after transplantation. This marked reduction in Lp(a) occurred at a time when patients were receiving the highest doses of corticosteroids. As steroid doses were gradually tapered, Lp(a) concentrations subsequently increased, although at 6 months levels were still significantly reduced (P < 0.01) in women. No significant correlation was observed between Lp(a) and whole-blood cyclosporin levels, nor was there any correlation with the azathioprine dose. The reduction in Lp(a) concentrations was seen for all apo(a) phenotypes observed in the study.

Adult↗
PubMed1996

Azathioprine pharmacogenetics: the relationship between 6-thioguanine nucleotides and thiopurine methyltransferase in patients after heart and kidney transplantation.

The commonly used immunosuppressive regimen after solid organ transplantation consists of cyclosporine A, azathioprine and steroids. Azathioprine, which is known to carry the risk of severe myelosuppression, is catabolized in vivo by xanthine oxidase and thiopurine methyltransferase, an enzyme which exhibits a common genetic polymorphism; 11% of Caucasians are heterozygous and 0.3% are homozygous with respect to thiopurine methyltransferase deficiency. Toxicity and immunosuppressive effects have been attributed to the 6-thioguanine nucleotides generated from azathioprine. We have studied thiopurine methyltransferase activity and 6-thioguanine nucleotide concentrations in erythrocytes from 39 heart and kidney recipients. Erythrocyte thiopurine methyl-transferase was determined by a radioenzymatic assay and erythrocyte 6-thioguanine nucleotide concentration with HPLC. Thiopurine methyltransferase activity [median (range, 10th-90th percentile)] was significantly (p < 0.05) higher in patients (n = 39) receiving azathioprine [285 (218-362) vs. 262 (160-352) mU/I erythrocytes] than in healthy blood donors as controls (n = 120). When stratified according to thiopurine methyltransferase phenotype, one patient homozygous for the low allele exhibited an excessive erythrocyte 6-thioguanine nucleotide concentration (2210 pmol/0.8 x 10(9) erythrocytes). Heterozygous patients had significantly higher 6-thioguanine nucleotide concentrations median: 435 pmol/0.8 x 10(9) erythrocytes) compared with concentrations in patients homozygous for the high allele (median: 86 pmol/0.8 x 10(9) erythrocytes; p < 0.01), although the azathioprine dosage did not differ (p = 0.66). Erythrocyte thiopurine methyltransferase determination therefore identifies patients at high risk of accumulating 6-thioguanine nucleotides. The monitoring of this enzyme may contribute to the safer management of immunosuppressive therapy with azathioprine. Alternative regimens such as cyclosporin A/mycophenolate mofetil or tacrolimus should also be considered for this patient group.

Azathioprine↗
PubMed1995

Idebenone protects hepatic microsomes against oxygen radical-mediated damage in organ preservation solutions.

The ability of the benzoquinone coenzyme Q-10 or its derivative QSA-10 (idebenone) to protect against lipid peroxidation and protein damage mediated by the pro-oxidative system NADPH/ADP/Fe3+ was tested in a rat liver microsomal model incubated in University of Wisconsin (UW) or histidine-tryptophan-ketoglutarate (HTK) solutions. Lipid peroxidation, as followed by direct determination of lipid hydroperoxides and by monitoring of malondialdehyde equivalents, was 1.8-fold enhanced in HTK and 3-fold attenuated in UW compared with HEPES buffer. Function and integrity of microsomal enzymes were investigated using glutathione S-transferase and cytochrome P-450 IIIA activity as assessed by lidocaine N-deethylation to monoethylglycinexylidide as well as by Western blot analysis of the cytochrome P-450 IIIA protein. Glutathione S-transferase activity was reduced by about 70% in HEPES compared with 50% in HTK and 36% in UW. Cytochrome P-450 IIIA was inactivated by about 75% in HEPES and HTK, compared with 55% in UW. The enzyme inactivation was paralleled by a loss of immunoreactive cytochrome P-450 IIIA protein. Supplementation of HTK with 0.1 mumol/L QSA-10 offered complete protection against lipid peroxidation, compared with 100 mumol/L with Q-10. QSA-10 (20 mumol/L) prevented protein damage in both preservation solutions, whereas Q-10 (20 mumol/L) offered only partial protection in UW and had no effect in HTK. The use of QSA-10 during liver transplantation may therefore have the potential of increasing the efficacy of organ preservation, maintaining donor organ quality, and preventing reperfusion injury. It is suitable for human use and has energy-conserving properties in addition to its antioxidant nature.

Adenosine↗
PubMed1995

Identification of two functionally distinct lysine-binding sites in kringle 37 and in kringles 32-36 of human apolipoprotein(a).

The well documented association between high plasma levels of lipoprotein(a) (Lp(a)) and cardiovascular disease might be mediated by the lysine binding of apolipoprotein(a) (apo(a)), the plasminogen-like, multikringle glycoprotein in Lp(a). We employed a mutational analysis to localize the lysine-binding domains within human apo(a). Recombinant apo(a) (r-apo(a)) with 17 plasminogen kringle IV-like domains, one plasminogen kringle V-like domain, and a protease domain or mutants thereof were expressed in the human hepatocarcinoma cell line HepG2. The lysine binding of plasma Lp(a) and r-apo(a) in the culture supernatants of transfected HepG2 cells was analyzed by lysine-Sepharose affinity chromatography. Wild type recombinant Lp(a) (r-Lp(a)) revealed lysine binding in the range observed for human plasma Lp(a). A single accessible lysine binding site in Lp(a) is indicated by a complete loss of lysine binding observed for r-Lp(a) species that contain either a truncated r-apo(a) lacking kringle IV-37, kringle V, and the protease or a point-mutated r-apo(a) with a Trp-4174-->Arg substitution in the putative lysine-binding pocket of kringle IV-37. Evidence is also presented for additional lysine-binding sites within kringles 32-36 of apo(a) that are masked in Lp(a) as indicated by an increased lysine binding for the point mutant (Cys-4057-->Ser), which is unable to assemble into particles. An important role of these lysine-binding site(s) for Lp(a) assembly is suggested by a decreased assembly efficiency for deletion mutants lacking either kringle 32 or kringles 32-35.

Amino Acid Sequence↗
PubMed1995

Monoethylglycinexylidide as an early predictor of posttraumatic multiple organ failure.

The prognostic value of a dynamic liver-function test, based on the hepatic conversion of lidocaine to monoethylglycinexylidide (MEGX), in predicting multiple organ failure (MOF) was prospectively investigated in 28 critically ill patients after multiple trauma. The MEGX test and conventional static liver tests (bilirubin, aspartate aminotransferase, glutamate dehydrogenase, and factor V) were performed on days 1, 3, 5, and 7 after trauma. Patients were classified by a modified MOF score into a group without (n = 18) and a group with the MOF syndrome (n = 10). One patient who developed MOF on the basis of a bacterial septicemia was excluded from the general evaluation. No significant differences were observed in the MEGX values of the two groups on day 1. All patients who subsequently developed MOF, however, displayed a sharp decrease in their MEGX values between days 1 and 3. Analysis of the data using receiver operating characteristic (ROC) curves revealed that the results of the MEGX test on day 3 provided the greatest discriminating power between patients with and without subsequent MOF. A cut-off MEGX value of 30 micrograms/L on day 3 was associated with a prognostic sensitivity of 89% and a prognostic specificity of 94%.

Adult↗
PubMed1995

Relationship of apolipoproteins AI, B and lipoprotein Lp(a) to hepatic function of liver recipients during the early post-transplant period.

To evaluate serum apo AI, apo B, Lp(a) and the ratio of unesterified cholesterol to total cholesterol as markers of hepatic synthetic capacity after orthotopic liver transplantation, serial measurements of these variables were performed on post-transplant days 1, 3, 5, 7, 10 and 14 in 70 patients. Liver function was assessed by a quantitative dynamic test based on the hepatic conversion of lidocaine to monoethylglycinexylidide (MEGX). Patients were divided into two groups on the basis of clinical and laboratory findings, those with evidence (n = 46) and those without evidence (n = 24) of hepatic dysfunction. Apo AI levels fell in both groups to day 5, but then began to increase in the group with good hepatic function, a highly significant (P < 0.001) positive correlation being found with the results of the MEGX test on post-transplant days 7, 10 and 14. The ratio of unesterified cholesterol to total cholesterol rose in both groups from days 1 to 7 and then began to fall in the group without hepatic dysfunction; a highly significant (P < 0.001) negative correlation was observed with the results of the MEGX test on days 10 and 14, Apo B levels rose in both groups from days 1 to 10, with no significant differences between the two groups; no correlation was observed with the results of the MEGX test on any study day.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗