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Biomedical subjects

Peter Gross

Publications and source records attributed to Peter Gross.

At least 19 recordsLinked to original sources
PubMed2004

Hyperkalaemia: again.

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Angiotensin-Converting Enzyme Inhibitors↗
PubMed2004

Reduced endothelin-1- and nitric oxide-mediated arteriolar tone in hypertensive renal transplant recipients.

BACKGROUND: The prevalence of hypertension is high in renal transplant recipients. It has been suggested that calcineurin inhibitors (CI) contribute to the development of post-transplant hypertension by stimulating endothelin (ET-1)-mediated and/or reducing nitric oxide (NO)-mediated vascular tone. METHODS: We tested this hypothesis using 2 groups of renal transplant recipients [normotensive patients without a need for antihypertensive medication (Normo-Tx), and hypertensive patients requiring antihypertensives (Hyper-Tx)] in the presence of CI-based immunosuppression. In addition, we studied matched control subjects (C). BQ 123 (ET-A receptor antagonist), BQ123 + BQ788 (ET-A/B-receptor antagonist), ET-1, L-NMMA (NO-synthase inhibitor), acetylcholine (ACH; endothelium-dependent vasodilator), glyceroltrinitrate (GTN, NO donor), and norepinephrine (NE, endothelium-independent vasoconstrictor) were infused into the brachial artery. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. RESULTS: Endothelium-independent vasomotion in response to GTN and NE was similar in all groups. Vascular responses to selective and combined blockade of ET receptors in both Normo-Tx and Hyper-Tx did not exceed those of C. In fact, we observed a significantly lower increase in FBF after BQ 123 (P= 0.03), as well as after BQ 123/788 (P= 0.03) in Hyper-Tx compared with Normo-Tx. This was associated with an increased vascular sensitivity to exogenous ET-1 in Hyper-Tx compared with Normo-Tx (P= 0.04). Vasoconstriction after L-NMMA was reduced in Hyper-Tx compared with Normo-Tx (P= 0.015), while the response to ACH was reduced in both groups of Tx patients to a similar degree (P= 0.005 vs. C). CONCLUSION: Our results do not support a major role for the vascular endothelin system in the hypertension of renal transplant recipients, whereas deficient baseline NO production may be a contributing factor.

Adult↗
PubMed2004

In type 2 diabetes, rosiglitazone therapy for insulin resistance ameliorates endothelial dysfunction independent of glucose control.

OBJECTIVE: Insulin resistance is an independent risk factor for arteriosclerosis and cardiovascular mortality. However, the mechanism by which insulin resistance contributes to arteriosclerosis is unknown. Conceivably, endothelial dysfunction could be involved. Therefore, we asked whether therapy for insulin resistance ameliorates any endothelial dysfunction. RESEARCH DESIGN AND METHODS: We performed a double-blind cross-over trial of 12 patients with recently diagnosed type 2 diabetes. They received rosiglitazone 4 mg b.i.d. for 12 weeks and nateglinide 60 mg b.i.d. for the same number of weeks in random order. To assess the degree of endothelial dysfunction, we used venous occlusion plethysmography. We studied vasodilation in response to acetylcholine (ACh) with and without exogenous insulin. The agents were infused into the brachial artery. Furthermore, we determined insulin resistance by euglycemic clamp. RESULTS: Glycemic control was comparable under rosiglitazone and nateglinide. Rosiglitazone ameliorated insulin resistance by 60% compared with nateglinide. ACh response was significantly increased after rosiglitazone treatment (maximum forearm blood flow 12.8 +/- 1.3 vs. 8.8 +/- 1.3 ml/100 ml after rosiglitazone and nateglinide, respectively; P < 0.05) but did not attain the level of healthy control subjects (14.0 +/- 0.7 ml/100 ml). Coinfusion of exogenous insulin increased ACh response further in the rosiglitazone group. N-monomethyl-L-arginine-acetate (L-NMMA), an antagonist of nitric oxide synthase, largely prevented the increased vasodilation after rosiglitazone, regardless of the presence or absence of insulin. Insulin sensitivity and blood flow response were found to be correlated (P < 0.01). CONCLUSIONS: Insulin resistance is a major contributor toward endothelial dysfunction in type 2 diabetes. Both endothelial dysfunction and insulin resistance are amenable to treatment by rosiglitazone.

Acetylcholine↗
PubMed2004

Increased total number but impaired migratory activity and adhesion of endothelial progenitor cells in patients on long-term hemodialysis.

BACKGROUND: Endothelial progenitor cells (EPCs), derived from bone marrow, contribute to vessel repair and neovascularization. Because uremia is a state of endothelial dysfunction associated with high cardiovascular mortality, as well as a state of reduced hematopoiesis, we studied the number and function of EPCs in patients on long-term hemodialysis (HD) therapy. METHODS: We counted the number of EPCs in 20 HD patients and 16 healthy volunteers. To assess EPC function, we measured migratory activity, adhesion to matrix proteins, and adhesion to endothelial cells. Furthermore, we measured blood levels of vascular endothelial growth factor (VEGF) and granulocyte-macrophage colony-stimulating factor, factors known to influence EPC kinetics. Circulating precursor cells (CD34+ , CD34+ /CD133+ , CD34+ /KDR+ cells) were counted by means of flow cytometric analysis. RESULTS: The number of EPCs in HD patients was significantly elevated compared with controls (459.7 +/- 92 versus 364.8 +/- 77.4 EPC/high-power field). However, migratory activity was markedly decreased in HD patients (47.5 +/- 27.7 versus 84.7 +/- 3.2 EPC/high-power field). EPCs of HD patients showed impaired adhesion to extracellular matrix and endothelial cells. VEGF blood levels in HD patients were 2-fold greater compared with controls. The number of circulating CD34+ and CD34+ /133+ cells was reduced in HD patients. There were no differences in total numbers of CD34+ /KDR+ cells. CONCLUSION: This study shows an elevated number, but pronounced functional impairment, of EPCs in patients on long-term HD therapy. The latter may result in limited endothelial repair, which, in turn, may contribute to endothelial dysfunction in this particular group of patients.

AC133 Antigen↗
PubMed2003

Kidney transplantation improves endothelium-dependent vasodilation in patients with endstage renal disease.

Kidney transplantation (Tx) improves the cardiovascular outcome of patients receiving hemodialysis (HD). Therefore, we asked whether Tx improves the endothelial dysfunction of HD patients. Eight patients were studied twice: (1) during HD and (2) after Tx. We also studied eight matched control subjects. We measured forearm blood flow by venous occlusion plethysmography. We administered intrabrachial infusions of three doses of norepinephrine, glycerol trinitrate, acetylcholine (ACH), and N-monomethyl-L-arginine. The response to ACH was reduced in HD patients compared with controls (P<0.001). The response to ACH in HD patients improved after Tx, and this change was significant for low-dose ACH (P<0.05 for dose one and two compared with HD). The response to glycerol trinitrate, which was reduced in HD patients compared with controls (P<0.01), remained unchanged after Tx. N-monomethyl-L-arginine and norepinephrine comparably reduced forearm blood flow in all groups. This is the first evidence showing an improvement of endothelial dysfunction in HD patients after Tx.

Acetylcholine↗
PubMed2003

Accumulation of tissue factor into developing thrombi in vivo is dependent upon microparticle P-selectin glycoprotein ligand 1 and platelet P-selectin.

Using a laser-induced endothelial injury model, we examined thrombus formation in the microcirculation of wild-type and genetically altered mice by real-time in vivo microscopy to analyze this complex physiologic process in a system that includes the vessel wall, the presence of flowing blood, and the absence of anticoagulants. We observe P-selectin expression, tissue factor accumulation, and fibrin generation after platelet localization in the developing thrombus in arterioles of wild-type mice. However, mice lacking P-selectin glycoprotein ligand 1 (PSGL-1) or P-selectin, or wild-type mice infused with blocking P-selectin antibodies, developed platelet thrombi containing minimal tissue factor and fibrin. To explore the delivery of tissue factor into a developing thrombus, we identified monocyte-derived microparticles in human platelet-poor plasma that express tissue factor, PSGL-1, and CD14. Fluorescently labeled mouse microparticles infused into a recipient mouse localized within the developing thrombus, indicating that one pathway for the initiation of blood coagulation in vivo involves the accumulation of tissue factor- and PSGL-1-containing microparticles in the platelet thrombus expressing P-selectin. These monocyte-derived microparticles bind to activated platelets in an interaction mediated by platelet P-selectin and microparticle PSGL-1. We propose that PSGL-1 plays a role in blood coagulation in addition to its known role in leukocyte trafficking.

Animals↗
PubMed2003

Pharmacokinetics of gemcitabine in a patient with end-stage renal disease: effective clearance of its main metabolite by standard hemodialysis treatment.

PURPOSE: Gemcitabine (2',2'-difluorodeoxycytidine) is a cytotoxic agent with a low toxicity profile and proven activity against a number of solid tumors. It is not known whether gemcitabine is safe to administer to patients with kidney failure, and if dose adjustment is necessary. We determined the tolerability and pharmacokinetics of gemcitabine and its noncytotoxic metabolite 2',2'-difluorodeoxyuridine (dFdU) in a patient with end-stage renal disease on maintenance hemodialysis therapy. PATIENT AND METHODS: A 64-year-old patient with pancreatic cancer and end-stage renal disease received two cycles of gemcitabine at a standard dose of 1000 mg/m(2) given as a 30-min infusion on days 1 and 10. A regular 3.5-h hemodialysis treatment was performed 24 h after each infusion. Plasma and dialysate concentrations of gemcitabine and dFdU were determined by HPLC. The tolerability of gemcitabine treatment was assessed by clinical and laboratory parameters. RESULTS: For gemcitabine, the maximal plasma concentration, terminal half-life (t(1/2)) and area under the concentration-time curve (AUC) were similar to those reported for patients with normal renal function. In contrast, end-stage renal disease resulted in a five- to tenfold prolongation of terminal half-life and a distinct increase in the AUC of plasma dFdU in this patient. Plasma dFdU was effectively eliminated by hemodialysis treatment. Both cycles of gemcitabine were tolerated well with no unexpected side effects observed. CONCLUSIONS: Gemcitabine treatment in end-stage renal disease with intermittent standard hemodialysis treatment is safe and well tolerated. The pharmacokinetic data suggest that dose adjustment of gemcitabine should be avoided to ensure its full cytotoxic activity, and that hemodialysis treatment should be initiated 6-12 h after its administration to minimize the potential side effects of the metabolite dFdU.

Antimetabolites, Antineoplastic↗
PubMed2003

Baseline blood flow and bradykinin-induced vasodilator responses in the human forearm are insensitive to the cytochrome P450 2C9 (CYP2C9) inhibitor sulphaphenazole.

A substantial portion of the vasodilator response elicited by bradykinin in the human forearm is unaffected by the combined inhibition of nitric oxide (NO) synthases and cyclo-oxygenases. The cytochrome P450 (CYP) 2C9 inhibitor sulphaphenazole was recently identified as a potent inhibitor of NO- and prostacyclin (PGI2)-independent relaxation in porcine coronary arteries. The aim of the present study was to determine the effect of sulphaphenazole on basal and bradykinin-induced NO/PGI2-independent changes in the forearm blood flow (FBF) of healthy subjects. Eleven healthy male volunteers participated in this placebo-controlled study. Test agents were infused into the brachial artery and FBF was measured by bilateral venous occlusion plethysmography. Sulphaphenazole (0.02-2 mg/min) alone did not affect basal blood flow. Inhibition of the NO synthases by NG-monomethyl-L-arginine (L-NMMA; 4 micromol/min) and cyclo-oxygenases by ibuprofen (1200 mg, orally) reduced FBF to 48 +/- 7% in the absence and 50 +/- 8% in the presence of sulphaphenazole (2 mg/min; P=not significant). After pretreatment with L-NMMA (16 micromol/min) and ibuprofen (1200 mg, orally), sulphaphenazole (6 mg/min) did not substantially inhibit bradykinin-induced vasodilation. We conclude that CYP2C9-derived metabolites (i) are not involved in the regulation of baseline blood flow, and (ii) do not mediate bradykinin-induced NO/PGI2-independent vasorelaxation in the human forearm. However, determining the contribution of this enzyme to regulation of blood flow in pathological conditions associated with endothelial dysfunction requires further studies.

Adult↗
PubMed2003

Therapy of hyponatremia in cirrhosis with a vasopressin receptor antagonist: a randomized double-blind multicenter trial.

BACKGROUND & AIMS: Dilutional hyponatremia is a frequent complication of cirrhosis partly because of nonosmotic vasopressin release. No effective therapy exists for this complication. Therefore, we investigated the effects of VPA-985, an orally active vasopressin V2 receptor antagonist, in patients with cirrhosis and dilutional hyponatremia. Primary endpoint was normalization of serum sodium (serum sodium >or=136 mmol/L). METHODS: Sixty patients with cirrhosis and dilutional hyponatremia were randomly assigned to 100 or 200 mg/day of VPA-985 or placebo in a double-blind study. Treatment was given with fluid restriction (1000 mL/day) until normalization of serum sodium or for 7 days. RESULTS: Normalization of serum sodium concentration was achieved in 27% and 50% of patients in the VPA-985 100 mg/day and 200 mg/day groups, respectively, but in none of the patients in the placebo group (P < 0.05 and P < 0.001, respectively). Treatment with VPA-985 was associated with a significant reduction in urine osmolality and body weight. Thirst sensation increased significantly in the VPA 200 mg group but not in the VPA 100 mg or placebo group. Serious adverse events were similar among the 3 groups. CONCLUSIONS: An orally active vasopressin receptor antagonist can correct hyponatremia in patients with cirrhosis and ascites. This represents a novel therapy of water retention in cirrhosis.

Antidiuretic Hormone Receptor Antagonists↗
PubMed2003

The influence of uraemia and haemodialysis on neutrophil phagocytosis and antimicrobial killing.

BACKGROUND: Neutrophil functions in haemodialysis (HD) patients are altered by uraemia and by HD procedure. We investigated details of the neutrophil dysfunction as its nature and origin is not well understood. This is reflected by conflicting results about neutrophil phagocytosis activity and by scarce data on the neutrophil killing capability in HD patients. METHODS: Using a flow-cytometric test system we have measured simultaneously phagocytosis and the production of reactive oxygen species (ROS) of neutrophils and in parallel antimicrobial killing of yeast by neutrophils. 117 whole-blood samples of healthy controls and 50 pre- and 50 post-dialysis samples of HD patients, half of them with diabetes mellitus (DM), have been evaluated. We have constructed a model to account for the dependence on the stimulus-to-cell ratio and obtain means for phagocytosis and killing at different incubation times. RESULTS: (i) HD patients have significantly lower neutrophil killing (20%) than healthy controls. (ii) Dialysis improves the killing capability by 10-15%, after dialysis the killing activity remains significantly (10%) below that of the controls. (iii) The percentage of neutrophils, which exhibit phagocytosis and produce ROS, does not differ significantly between HD patients and healthy controls. (iv) Age has no significant influence on phagocytosis and killing. CONCLUSION: The neutrophil killing capability is reduced in HD patients while the amount of neutrophils that phagocyte and produce ROS remains unchanged. Functional impairment of uraemic neutrophils is therefore mainly a result of their reduced capability to kill microorganisms intracellularly.

Adult↗
PubMed2003

Impact of initial antibiotic choice on clinical outcomes in community-acquired pneumonia: analysis of a hospital claims-made database.

BACKGROUND: Much controversy exists regarding the initial choice of antibiotics and selected outcomes for patients with community-acquired pneumonia (CAP). METHODS: The investigators analyzed a hospital claims-made database to assess the impact of initial antibiotic choice on 30-day mortality, total hospital costs, and hospital length of stay (LOS). Fine risk groups allowed for stratification for variations in the severity of illness. Patients were divided into five monotherapy groups (ie, ceftriaxone, "other" cephalosporins, fluoroquinolones, macrolides, or penicillins) and four groups that received dual therapy (ie, the agents listed above, except macrolides) plus macrolides. Patients also were stratified by age (ie, > 65 years of age and < 65 years of age). Severely ill patients were excluded. RESULTS: Overall, 44,814 persons met the criteria for inclusion. Among monotherapy patients, those who received macrolides had the least mortality but were the least ill. Patients who received dual therapy generally had shorter LOSs, lower total hospital charges, and decreased mortality compared with those who received monotherapy. Differences among dual-therapy regimens regarding outcomes studies were noted. Patients who were < 65 years of age had lower mortality rates, shorter LOSs, and lower hospital charges than did the more elderly patients. Within this group, those who received dual therapy had better outcomes than those who received monotherapy. CONCLUSIONS: We confirmed the value of dual therapy employing macrolides as a second agent in decreasing mortality from CAP, and we provided similar data regarding shorter LOSs and lower hospital charges. This appears to hold for a younger population. Differences among dual-therapy regimens (all employing macrolides) appear to exist and may be clinically relevant.

4-Quinolones↗