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Biomedical subjects

H H Neumayer

Publications and source records attributed to H H Neumayer.

At least 127 records · Page 7Linked to original sources
PubMed1993

Calcium antagonists and renal protection.

A growing body of evidence supports the notion that calcium antagonists exert a renal protective effect. Calcium antagonists may play an important future role in renal hemodynamics related to their reversal of renal vasoconstrictors. Calcium antagonists are also capable of blocking intracellular calcium overload induced by various types of ischemia or toxic stimuli. Features such as these may be of substantial value in ameliorating acute renal insufficiency secondary to renal ischemia, iodinated radiographic contrast media, or the administration of various nephrotoxic drugs. The latter includes agents such as the aminoglycoside antibiotics, cyclosporine A, and the cancer chemotherapeutic agent cisplatin. Recent prospective, controlled studies from our group indicate that calcium antagonists protected against postischemic acute renal failure in the setting of cadaveric renal transplantation. Moreover, in a prospective, randomized, controlled clinical trial, we were able to demonstrate that the prophylactic use of nitrendipine reduced the decrease in GFR in patients receiving radiographic contrast agents. Such protection may extend to favorably influencing the course of chronic renal insufficiency, particularly when the latter is complicated by hypertension. Seven putative mechanisms have been proposed by which calcium antagonists may ameliorate the decline in GFR associated with renal insufficiency. These are: (a) reduction in blood pressure per se, (b) reduction in renal hypertrophy, (c) modulation of mesangial traffic of macromolecules, (d) reduction in metabolic activity in remnant renal tissue, (e) amelioration of uremic nephrocalcinosis, (f) reduction of pressure-induced calcium entry into vessel walls, and (g) reduction of free radical formation. Experimental investigations in rats with reduced renal mass, desoxycorticosterone-induced hypertension, or chronic angiotensin II infusion, and in spontaneously hypertensive rats support such a view.

Animals↗
PubMed1993

Twenty-five years of renal transplantation from a single center: a risk factor analysis for short- and long-term outcomes.

Between 1966 and 1991 a total of 1000 renal transplants were performed in Erlangen-Nuremberg. Patients were operated upon in Erlangen and transferred immediately 25 km to Nuremberg for their postoperative and immunosuppressive care. Despite these considerable logistical obstacles, the 10-year graft survival rate in 785 consecutive transplants performed between 1980 and 1990 was 44%, while patient survival was 84%. Mismatch at the HLA-DR locus, preformed antibodies, multiple transplants, and kidneys from donors aged 10 years or younger or over 60 years were risk factors for decreased graft survival. An immunosuppressive regimen of cyclosporine and methylprednisolone resulted in better graft survival than did azathioprine and methylprednisolone, or reduced-dose cyclosporine, azathioprine, and methylprednisolone. The cyclosporine and methylprednisolone regimen had a better patient survival than azathioprine and methylprednisolone. A hazard analysis demonstrated a particular risk of late rejection between the 70th and 90th months, after transplantation. Our data indicate that favorable transplant results can be obtained despite major logistical disadvantages. Very close cooperation between referring centers, transplant surgeons, and nephrologists is indispensable for success.

Adolescent↗
PubMed1992

Amelioration of ischemic acute renal failure by dietary fish oil administration in conscious dogs.

The hypothesis that dietary fish oil would protect dogs from ischemic acute renal failure was tested. Fish oil (eicosapentaenoic acid, 55 mg/kg per day, and docosahexaenoic acid, 40 mg/kg per day was given to eight instrumented, female, beagle dogs for 6 wk, while seven control dogs received vehicle. After 3 wk, unilateral nephrectomy was performed and a pneumatic cuff with flow probe was placed around the remaining renal artery of each dog. Three weeks thereafter, the cuff was inflated for 120 min. Renal function, RBF, and prostanoid excretion were measured 24 and 72 h after ischemia. In dogs receiving fish oil, blood pressure, GFR, RBF, renal vascular resistance (RVR), cholesterol, triglycerides, and prostanoid excretion were measured weekly for 6 wk. Further, cytosolic calcium was measured before and five times after fish oil. Blood pressure decreased, serum cholesterol and triglycerides decreased, and the cytosolic calcium within platelets decreased. The urinary excretion (expressed as picograms per milligram of creatinine) of the thromboxane (TX) metabolite TXB2 and the excretion of prostaglandin (PG)E2, as well as the excretion of the PGI2 metabolite 6-keto PGF1 alpha were decreased. GFR, RBF (Cl inulin and Cl para-aminohippuric acid), and RVR were not influenced by fish oil. Unilateral nephrectomy decreased GFR and RBF and increased RVR as expected, whereas it further decreased prostanoid excretion. Acute renal ischemia caused a significant, reversible decrease in GFR and urine volume in vehicle-treated animals, whereas no significant effect on renal function or urine volume was observed in animals pretreated with fish oil.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗
PubMed1992

Protective effects of diltiazem and the prostazycline analogue iloprost in human renal transplantation.

To test the hypothesis that calcium antagonists decrease the incidence and severity of delayed graft function, we conducted three separate, prospective, randomized trials. In these trials, we investigated the effects of diltiazem and those of the prostacycline analogue iloprost. In the first study, 22 control patients and 20 diltiazem patients received grafts perfused with either vehicle or diltiazem 20 mg/L in the Euro-Collins solution. Subsequently, the diltiazem subjects were given the drug as a bolus of 0.28 mg/kg, followed by a continuous infusion of 0.002 mg/min/kg for the following 2 days. Thereafter, diltiazem 60 mg was given to the treated subjects orally for up to 4 years. In the second study, 11 control subjects and 10 diltiazem subjects received the same postoperative regimen, but all grafts were harvested without addition of diltiazem to the perfusion solution. In the third protocol, four groups were studied as follows: 19 control subjects who received no specific treatment, 16 subjects who received diltiazem, 16 subjects who were given iloprost, and 14 subjects who received both iliprost and diltiazem. The donor kidney of treated patients was perfused with either diltiazem, iloprost, or both drugs. Primary graft function occurred more commonly in the groups receiving diltiazem. Further, in the first study the number of hemodialyses per patient was reduced in those patients with delayed graft function. Fewer rejection episodes occurred in patients receiving diltiazem. Plasma levels of soluble interleukin-2 receptors decreased significantly during diltiazem treatment. Moreover, renal biopsies showed less severe signs of cyclosporin-A (CyA) nephrotoxicity in diltiazem-treated patients compared to controls, even though these patients also exhibited higher CyA trough levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗
PubMed1992

Protective effects of calcium antagonists in human renal transplantation.

To test the hypothesis that calcium antagonists decrease the incidence and severity of delayed graft function, we conducted three separate, prospective, randomized trials. In these trials, we investigated the effects of diltiazem and those of the prostacyclin analogue iloprost. In the first study, 22 control patients and 20 diltiazem patients received grafts perfused with either vehicle or diltiazem 20 mg/liter in the Euro-Collins solution. Subsequently, the diltiazem subjects were given the drug as a bolus of 0.28 mg/kg, followed by a continuous infusion of 0.002 mg/min/kg for the following two days. Thereafter, diltiazem 60 mg was given to the treated subjects orally for up to four years. In the second study, 11 control subjects and 10 diltiazem subjects received the same postoperative regimen, but all grafts were harvested without addition of diltiazem to the perfusion solution. In the third protocol, four groups were studied as follows: 19 control subjects who received no specific treatment, 16 subjects who received diltiazem, 16 subjects who were given iloprost, and 14 subjects who received both iloprost and diltiazem. The donor kidney of treated patients was perfused with either diltiazem, iloprost, or both drugs. Primary graft function occurred more commonly in the groups receiving diltiazem. Further, in the first study the number of hemodialyses per patient was reduced in those patients with delayed graft function. Fewer rejection episodes occurred in patients receiving diltiazem. Plasma levels of soluble interleukin-2 receptors decreased significantly during diltiazem treatment. Moreover, renal biopsies showed less severe signs of Cyclosporin A (CsA) nephrotoxicity in diltiazem-treated patients compared to controls, even though these patients also exhibited higher CsA trough levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗
PubMed1992

[Decreased blood pressure in sleep and left ventricular hypertrophy in patients with kidney transplants].

Since left-ventricular hypertrophy (LVH) has been identified as a poor prognostic indicator in patients with secondary hypertension, we investigated 38 renal transplant recipients on antihypertensive medication with 24-h ambulatory blood-pressure measurement (SpaceLabs 90207) and determined their left-ventricular mass by two-dimensional guided M-mode echocardiography. An increased left-ventricular mass correlated with a reduced fall of diastolic blood pressure during sleep (r = 0.29; p less than 0.05), as well as with a reduced fall of mean arterial pressure during sleep (r = 0.31; p less than 0.05). Therefore, a less pronounced afterload during sleep is related to more severe left-ventricular hypertrophy, suggesting a worse cardiovascular prognosis.

Adult↗
PubMed1992

The pharmacokinetics and pharmacodynamics of recombinant human erythropoietin in haemodialysis patients.

1. The pharmacokinetics of and therapeutic response to recombinant human erythropoietin (rcEPO) were studied in 12 patients under chronic haemodialysis on a thrice weekly intravenous rcEPO treatment scheme. The kinetics of rcEPO were also assessed after a subcutaneous injection during the initial period and during maintenance treatment. RcEPO was measured in plasma by radioimmunoassay. 2. After the first i.v. dose plasma erythropoietin concentrations were best described by a monoexponential disposition function with a mean (+/- s.d.) elimination half-life of 5.4 +/- 1.7 h. The volume of distribution was 70 +/- 5.2 ml kg-1 and the clearance was 10.1 +/- 3.5 ml h-1 kg-1 (n = 12). 3. After 3 months of continuous therapy, the plasma half-life of rcEPO decreased by 15% (P < 0.05, mean half-life during steady state: 4.6 +/- 2.8 h), while mean clearance and volume of distribution remained constant. 4. After the first s.c. injection the mean (+/- s.d.) absorption time was 22 +/- 11 h and systemic availability was 44 +/- 7%. 5. Changes in haemoglobin concentrations were described by a linear additive dose-response model, defined by an efficacy constant (Keff) and the mean erythrocyte lifetime (MRTHb). The sample mean (+/- s.d.) Keff was 0.043 +/- 0.017 g dl-1 Hb per 1000 units rcEPO and MRTHb was 10.02 +/- 1.75 weeks. The net effect of rcEPO treatment was described by the area under the unit-dose-response curve (AUEC) with a mean (+/- s.d.) value of 0.45 +/- 0.23 g dl-1 weeks. 6. RcEPO clearance showed a significant positive correlation (r2 = 0.41) with the effectiveness of rcEPO therapy, as measured by the parameters Keff or AUEC.

Adult↗
PubMed1991

[Effect of erythropoietin therapy on alpha receptor density in chronic dialysis patients].

The effect of a six months therapy with human recombinant erythropoietin (rHu-EPO) on blood pressure and on several parameters of sympathetic nervous activity was studied in chronic haemodialysis patients in a controlled and randomized trial in order to gain further insight into the mechanism of rHu-EPO-induced blood pressure elevation. Treatment was started at a dose of 3 X 80 IE/kg/week in eleven patients aiming to increase the initial hemoglobin concentration (7.0 +/- 0.3 [SEM] g%) to 10.0 g% by dose adjustments, while another untreated eleven patients served as a control group. Diastolic arterial pressure measured before and after haemodialysis increased on rHu-EPO treatment by 7 and 8 mm Hg respectively (p less than 0.05). Plasma noradrenaline concentration was increased (p less than 0.05) after the six months treatment period in the presence of unchanged dry weights. Conversely platelet alpha 2-adrenoceptor density (3H-yohimbine binding) and the fraction of high affinity binding sites for alpha 2-agonists (3H-UK 14.304) decreased (p less than 0.01) along with a decrease in reactivity to exogenous noradrenaline (p less than 0.05). None of these parameters changed in the control group compared to pretreatment values. The results obtained demonstrate that increased plasma noradrenaline concentrations may participate in rHu-EPO induced blood pressure increases. The decrease in platelet alpha 2-adrenoceptor densities and the decrease in noradrenaline reactivity in the presence of increased plasma noradrenaline concentrations suggest an intact regulation of alpha 2-adrenoceptors in chronic haemodialysis patients on chronic rHu-EPO therapy.

Blood Platelets↗
PubMed1991

Effects of diltiazem upon metabolism and immunosuppressive action of cyclosporine in kidney graft recipients.

It is widely believed that calcium antagonists such as diltiazem exert immunosuppressive effects in kidney graft recipients--however, the mechanism is unclear. In a randomized controlled trial, kidney graft recipients who received diltiazem during transplantation and for an average of 12 months thereafter experienced significantly fewer rejection episodes than patients treated with cyclosporine and steroids alone. Furthermore, 1-year (97% vs. 85%) and 4-year (80% vs. 70%) graft survival rates were higher in diltiazem-treated patients, but the difference was not statistically significant. In vitro, diltiazem had little immunosuppressive activity. Concentrations of diltiazem which blocked the proliferation of PHA-stimulated human peripheral blood mononuclear cells, or prevented activation-associated accumulation of interleukin-2 mRNA, or p50- and p70-IL-2 receptor mRNA exceeded pharmacological concentrations by more than 100-fold. Both, CsA and high doses of diltiazem caused an increase of IL-6 mRNA. In contrast to these findings, the IL-6 plasma concentrations were comparable in both groups, whereas the serum concentration of soluble IL-2 receptors was decreased in patients treated with diltiazem. Administration of diltiazem caused an alteration of CsA metabolism. The whole-blood concentration of CsA metabolite 17 was significantly increased in diltiazem-treated patients, resulting in a five-times-higher concentration of this metabolite in the cellular blood compartment compared with the parent drug. Changes in metabolites 1, 8, and 18 levels were less pronounced. Although direct immunosuppressive properties of diltiazem are unlikely, diltiazem could support immunosuppression by altering CsA metabolism, and promoting accumulation of certain metabolites.

Adult↗
PubMed1991

Renal protection with the calcium antagonists.

In addition to their role as highly potent antihypertensive drugs, calcium antagonists may also play an important future role in the area of tissue protection and preservation. Calcium antagonists exert favorable effects on renal hemodynamics related to their reversal of renal vasoconstrictors. Calcium antagonists are also capable of blocking intracellular calcium overload induced by various types of ischemic or toxic stimuli. Features such as these may be of substantial value in ameliorating acute renal insufficiency secondary to renal ischemia, iodinated radiographic contrast agents, or the administration of various nephrotoxic drugs. The latter includes agents such as the aminoglycoside antibiotics, cyclosporine A, and the cancer chemotherapeutic agent cisplatin. Recent prospective, controlled studies from our group indicate that calcium antagonists protected against postischemic acute renal failure in the setting of cadaveric renal transplantation. Moreover, in a prospective, randomized, controlled clinical trial, we were able to demonstrate that the prophylactic use of nitrendipine reduced the decrease in GFR in patients receiving radiographic contrast agents. Calcium antagonists may also play a beneficial role in preventing progressive renal disease. Data from a number of studies conducted in experimental animals, as well as information from clinical trials, support such a view. Although the mechanisms of action of calcium antagonists in the setting of chronic renal failure are not yet fully established, their beneficial effects may be related to protective actions such as the reduction in renal hypertrophy, modulation of mesangial cell uptake of macromolecules, changes in permselectivity of the glomerulus, and a decreased free radical formation. These various aspects will be the topic in this review.

Acute Kidney Injury↗
PubMed1990

Pharmacokinetic interaction between cyclosporin and diltiazem.

Previous reports have indicated that administration of the calcium antagonist diltiazem results in major changes in the pharmacokinetics of cyclosporin A (CyA). A new clinical trial was undertaken in 22 renal transplant patients receiving a constant dose of cyclosporin to further explore this interaction. Coadministration of diltiazem for one week produced an increase in the blood concentration of CyA and its metabolites 17 and 18 in almost all patients, but no increase in CyA metabolites 1 and 21. The mean whole blood CyA trough level determined by HPLC rose from 117 ng.ml-1 to 170 ng.ml-1 after one week on diltiazem, and the mean trough level of metabolite 17 rose similarly from 184 ng.ml-1 before to 336 ng.ml-1. Based on experiments with microsomes from human liver the effect of diltiazem was due to noncompetitive inhibition of CyA-metabolism by diltiazem, and the increased concentration of metabolite 17 might have been due to stronger inhibition of its secondary metabolism steps.

Adult↗
PubMed1990

Amelioration of postischaemic acute renal failure in conscious dogs by human atrial natriuretic peptide.

We studied the effect of human ANP (alpha-hANP)-99-126 on the course of postischaemic acute renal failure in unilaterally nephrectomised, conscious dogs subjected to 120 min of renal ischaemia. In contrast to a control group A (n = 7), the investigational group B (n = 9) received an intra-aortic bolus injection of 100 micrograms/kg alpha-hANP and an additional continuous infusion of 0.3 micrograms/kg per min x 180 min immediately after ischaemia. On days 1 and 2 after ischaemia, only the bolus injection was repeated. Administration of hANP resulted in a marked restoration of GFR (29 +/- 2 vs 18 +/- 4 ml/min, P less than or equal to 0.01), diuresis (0.8 +/- 0.1 vs 0.5 +/- 0.1 ml/min, P less than or equal to 0.05), and natriuresis (44 +/- 7 vs 25 +/- 4 mumol/min, P less than or equal to 0.05) on the first postischaemic day, which was mirrored by a reduction in nitrogen retention (Purea: 8 +/- 1 vs 12 +/- 2 mmol/l P less than or equal to 0.05, Pcrea: 137 +/- 20 vs 204 +/- 37 mumol/l). Renal perfusion, however, was only slightly improved on day 1 after ischaemia (198 +/- 20 vs 163 +/- 27 ml/min, N.S.). Our data clearly demonstrate that repeated bolus applications of hANP ameliorate postischaemic acute renal failure in conscious dogs. We assume that the observed beneficial effect on GFR might be the consequence of an increase in glomerular capillary pressure rather than an improvement of renal perfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗
PubMed1990

Effect of erythropoietin on parameters of sympathetic nervous activity in patients undergoing chronic haemodialysis.

The effect of erythropoietin (rHu-EPO) on blood pressure and on parameters of sympathetic nervous activity of patients undergoing chronic haemodialysis treatment was evaluated in a controlled and randomized 6-months study. Both groups did not differ significantly at the onset of the study in terms of dialysis protocol, haematological parameters, blood chemistry, weight, blood pressure and parameters of sympathetic nervous activity. Haemoglobin increased from 7.0 +/- 0.3 g dl-1 to 10.0 +/- 0.3 g dl-1 by 6 months on rHu-EPO (n = 11) and remained constant in the control group (n = 11). After 6 months diastolic blood pressure was higher in the treatment group compared with the control group as well as compared with pretreatment values, whereas reactivity to exogenous noradrenaline and platelet alpha 2-adrenoceptor densities ([3H]-yohimbine- and [3H]-UK 14,304-binding sites) were lower. Plasma noradrenaline concentration increased during rHu-EPO compared with pretreatment values, while dry weights were unchanged during the study. The results demonstrate alterations of some parameters of sympathetic nervous activity during rHu-EPO-therapy which were absent in the control group.

Blood Platelets↗
PubMed1990

Pharmacokinetics of iloprost in patients with chronic renal failure and on maintenance haemodialysis.

Iloprost is a potent, chemically stable prostacyclin-mimetic for which therapeutic efficacy has been proven in patients with peripheral arterial occlusive disease (PAOD) and in those suffering from Raynaud's phenomenon. In volunteers and PAOD-patients the pharmacokinetics of iloprost after intravenous (i.v.) infusion treatment was characterized by dose-dependent steady-state plasma levels, a terminal half-life of approximately 20-30 min, and a total clearance of 15-20 ml/min/kg. Bioinactivation was mainly due to beta-oxidation. In the present study the pharmacokinetics of iloprost was investigated in 21 patients suffering from renal insufficiency, which either required haemodialysis or not. They were treated by one hour i.v. infusion with 1 ng/kg/min and blood samples were taken during and after the end of infusion. Due to technical sampling problems iloprost pharmacokinetics could only be calculated for seven dialysis and eight non-dialysis patients. In the dialysis patients steady-state levels were 114 to 320 pg/ml as compared to 36 to 70 pg/ml in the non-dialysis group. Half-lives were similar in both groups: alpha-phase: 0.05 h and beta-phase: 0.5 h. The total clearance was 2.6 to 8.0 ml/min/kg (dialysis patients) and 13.2 to 25.8 ml/min/kg (non-dialysis patients). The present study demonstrated that the pharmacokinetic profile of iloprost in patients with renal failure (not subject to haemodialysis) was similar to that observed in PAOD-patients and volunteers. In patients on maintenance haemodialysis, iloprost clearance was reduced by a factor of four. The iloprost dose regimen required in general (due to interindividual variability in response) a careful dose titration.

Adult↗