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Biomedical subjects

H C Tillmann

Publications and source records attributed to H C Tillmann.

13 recordsLinked to original sources
PubMed2006

Efficacy and immunogenicity of novel erythropoietic agents and conventional rhEPO in rats with renal insufficiency.

Recombinant human erythropoietin (rhEPO) is used to treat anemia in chronic renal insufficiency. Erythropoietin (EPO) immunogenicity can lead to EPO-resistant anemia. Conjugating proteins with polyethylene glycol (PEG) can prolong elimination half-life and diminish protein immunogenicity. We investigated the efficacy of new erythropoietic agents, synthesized by single (Ro 50-3821) and multiple (MIX) integrations of PEG and succinimidyl butanoic acid with rhEPO, in rats with chronic renal insufficiency. Sprague-Dawley rats with surgically induced renal insufficiency received Ro 50-3821 or MIX subcutaneously (s.c.) over 4-12 weeks compared to rhEPO and NaCl. Hemoglobin and antibody levels served as primary efficacy and safety variables. Dosing intervals and dose-response characteristics were investigated. Ro 50-3821 (2.5 microg/kg once weekly) increased hemoglobin levels by 7 g/dl after 4 weeks compared to 1 g/dl in NaCl controls (P<0.05). MIX (2.5 microg/kg once weekly) and rhEPO (0.25 microg/kg three times weekly) increased hemoglobin levels by 3 g/dl. Ro 50-3821 administered for 12 weeks (0.75 microg/kg once weekly) increased hemoglobin levels (from 13 to 19 g/dl) more effectively than rhEPO (0.75 microg/kg once weekly, decline from 13 to 11 g/dl, P<0.05). No antibodies against Ro 50-3821 were detected after 12 weeks of treatment. Antibodies against rhEPO were seen in 69% of animals (P<0.00001). Ro 50-3821 increased hemoglobin levels with once weekly s.c. dosing. Multiple pegylated EPO is less effective. In rats, rhEPO failed to increase hemoglobin levels with once weekly long-term dosing. Antibody formation following rhEPO may explain this finding. Therefore, Ro 50-3821 may provide important clinical advantages compared to unpegylated EPO. It can be administered in longer dosing intervals and has a lower risk of unfavorable immunological responses.

Animals↗
PubMed2002

Comparison of the mechanisms of nongenomic actions of thyroid hormone and steroid hormones.

Steroids and thyroid hormone are thought primarily to act via binding to hormone-specific nuclear receptor superfamily members. The nuclear ligand-receptor complexes then initiate transcriptional activity. Actions of steroids and iodothyronines that are nongenomic or extranuclear in mechanism have been recognized recently and new insights into such mechanisms are available. Despite their distinct structures and biologic effects, the two families of hormones have similarities in the mechanisms of their nongenomic actions. That is, both steroids and thyroid hormone appear to interact with specific cell surface G protein-coupled receptors and to activate signal transducing kinases such as those involved in the mitogen-activated protein kinase (MAPK) pathway. Much is known about the ability of certain steroids such as estrogen and mineralocorticoids to increase [Ca2+]i acutely and stimulation of the MAPK cascade by L-T4 appears to depend upon a hormone-induced increase in [Ca2+]i via phosphoinositide pathway activation. At least in the case of iodothyronines, hormone activation of the MAPK pathway modulates the cellular activities of certain cytokines and growth factors. One of the two cell surface estrogen receptors (ERs) may be an expression of the same transcript as that for nuclear ER, whereas the mineralocorticoid and progesterone-binding proteins in the plasma membrane appear to be products of genes different from those of nuclear receptors. Iodothyronine structure-activity relationships at the plasma membrane binding site for thyroid hormone suggest that the cell surface receptor for T4 that also binds 3,5,3'-triiodo-L-T3 is different from the nuclear T3 receptor (TR). There are interfaces of nongenomic and genomic mechanisms for both steroids and thyroid hormone. For example, by nongenomic mechanisms, estrogen and thyroid hormone can promote serine phosphorylation, respectively, of nuclear ER and TR. Transcriptional activity of the nuclear receptor proteins can be altered by such phosphorylation.

Animals↗
PubMed2002

Seminal plasma hormone concentration after oral application of progesterone.

Previous studies have revealed beneficial in vitro effects of progesterone on sperm function. The aim of this pilot study was to prove if orally given micronized progesterone leads to elevations in progesterone and/or 17alpha-hydroxyprogesterone levels in seminal plasma, since higher seminal plasma levels of these hormones could possibly have a beneficial effect on sperm function as seen in in vitro investigations. Multiple application of micronized progesterone given over 4 days (daily dose 400 mg) to 6 healthy subjects resulted in elevated seminal plasma levels of progesterone (10.90 +/- 9.02 nmol/l vs. 1.43 +/- 0.56 nmol/l, p = 0.04) and 17alpha-hydroxyprogesterone (3.09 +/- 1.72 nmol/l vs. 1.62 +/- 1.26 nmol/l, p = 0.04) whereas no significant difference could be found in testosterone levels (34.82 +/- 13.00 vs. 30.91 +/- 8.56 nmol/l, p = 0.43). In contrast, androstendione levels in seminal plasma were reduced (2.68 1.28 nmol/l vs. 3.65 +/- 1.36 nmol/l, p = 0.01). Although micronized progesterone is rapidly metabolized, oral application resulted in pronounced elevations of progesterone and 17alpha-hydroxyprogesterone in seminal plasma. Further studies will show if oral application of micronized progesterone can induce beneficial effects on sperm function such as those seen in in vitro investigations.

17-alpha-Hydroxyprogesterone↗
PubMed2001

Hypoxia modulates rapid effects of aldosterone on oxidative metabolism in human calf muscle.

Non-genomic effects of aldosterone on oxidative metabolism of skeletal muscle have been shown, recently. To further characterize these rapid effects on the increase of phosphocreatine (PCr) in the recovery period after isometric exercise, a randomized cross-over placebo-controlled study was conducted on 9 healthy volunteers. Hypoxia was chosen to test the dependence of the effect on oxygen supply and thus its relation to oxidative vs non-oxidative metabolism. Parameters related to the energy metabolism of calf muscles were measured by 31P magnetic resonance spectroscopy during four repetitive contractions in four different tests (hypoxia [FiO2=0.13] vs normoxia [FiO2=0.21], +/- 0.5 mg aldosterone). The area-under-curves of post-exercise PCr levels after the 4th contraction were significantly increased by aldosterone vs placebo during normoxia (875.5 +/- 5.1 vs 857.2 +/- 8.3%-min; p=0.02). In addition, aldosterone induced an undershoot of inorganic phosphate (Pi) in the recovery after isometric exercise (77.5 +/- 5.4 vs 88.9 +/- 5.1 mmol/l x min; p=0.05). Hypoxia blocked effects of aldosterone on PCr overshoot and Pi undershoot. Concentrations of ATP, ADP, phosphomonoesters, and intracellular pH were not affected by those interventions. In conclusion, these data demonstrate rapid actions of aldosterone on post-excercise PCr and Pi levels in human calf muscle, which are blocked by hypoxia. We hypothesize that aldosterone rapidly interferes with oxidative metabolism probably by direct modulation of ATP-turnover, which is induced by an oxygen-dependent imbalance of the ATP-synthesis and utilization rate.

Adult↗
PubMed2001

Vaccination rate and age of premature infants weighing <1500 g: a pilot study in north-western Switzerland.

UNLABELLED: In Switzerland, there are no special vaccination recommendations for premature and low-birthweight infants with respect to a particular target vaccination age. Incomplete and delayed vaccination bears the inherent risk of preventable infections. Therefore, the vaccination rate and age of 60 premature infants in north-western Switzerland born in 1994/95 were investigated in a retrospective case-control study. For this group of patients these are the first data ever available for this region. At the age of 4-5 y, the vaccination rates for polio and diphtheria, tetanus, pertussis (DTP acellular) as well as Haemophilus influenzae b (Hib) were similar in both preterm and full-term infants. In both groups, the fourth dose of vaccine against DTP, Hib and polio was far less frequently administered than the first three. The vaccination age in preterm infants for most vaccinations was significantly higher than in age-matched full-term controls. This was particularly obvious for the first dose of vaccine against polio and DTP. In preterm infants, the median age (5th; 95th percentile) at the date of the first polio vaccination was 131 (89; 270) d and 82 (60; 182) in full-term controls (p < 0.00001). The age difference was even larger for the first DTP vaccination (62 d, p < 0.00001). The main reasons for delayed vaccination may include insufficient information given to parents as well as prolonged hospitalization. CONCLUSION: Vaccination of preterm infants should be discussed in every discharge communication, with emphasis on vaccine administration at the appropriate chronological age.

Age Factors↗
PubMed2001

Impact of plasmapheresis on platelet hemostatic capacity in healthy voluntary blood donors detected by the platelet function analyzer PFA-100.

Previous flow cytometry studies showed that platelet activation may occur during cytapheresis, cardiopulmonary bypass and hemodialysis. The aim of this pilot study was to determine if the impact of plasmapheresis leads to alterations in platelet hemostatic capacity. Plasmapheresis was carried out in 30 volunteers using an Autopherese C (Baxter) and an MCS3p (Haemonetics). Blood samples were collected and analyzed immediately before and after plasmapheresis. As a result of the plasmapheresis on the Autopherese C, the mean closure time (CT) for collagen/epinephrine (Col/Epi) increased from 118.2 +/- 25.1 to 149.9 +/- 35.0 s and from 88.7 +/- 16.9 to 98.5 +/- 26.3 s for collagen/ADP (Col/ADP), respectively. Seven subjects showed impaired CTs after plasmapheresis for Col/Epi. For Col/ADP, five subjects showed impaired CTs after apheresis. Statistical analysis (McNemar test) showed a significant difference before and after apheresis for Col/Epi (P = 0.024) but not for Col/ADP (P = 0.088). Similar results were shown for plasmapheresis carried out with the MCS3p. These findings show that plasmapheresis can cause an impairment of platelet function in healthy volunteers as measured by the PFA-100, an effect of so far unknown clinical significance.

Adult↗
PubMed2001

Interaction of rapid nongenomic cardiovascular aldosterone effects with the adrenergic system.

Interactions between the renin-angiotensin-aldosterone system and the adrenergic system are complex and have mainly been attributed to angiotensin II, with knowledge about aldosterone action much less advanced. Only recently has evidence been forthcoming that aldosterone blunts the baroreceptor reflex and lowers heart rate variability in humans. Both effects point to an adrenergic-like action of aldosterone. It has been proposed that this blunting of baroreceptor sensitivity is mediated nongenomically and that nongenomic aldosterone action itself is modulated by the adrenergic system. The aim of the present study was to prove the hypothesis of an interaction between the autonomic nervous system and rapid, nongenomic aldosterone effects. We conducted a randomized, double blind, 8-fold cross-over trial on 18 healthy male volunteers. After pretreatment with the beta-blocking agent esmolol, the beta-agonist dobutamine, the alpha(1)-agonist phenylephrine, or placebo, placebo (0.9% NaCl) or aldosterone (0.5 mg) was injected. After aldosterone injection the peak plasma levels were supraphysiological, reaching nanomolar concentrations. Primary target variables were differences in changes in mean arterial blood pressure, systemic vascular resistance, and cardiac output depending on the pretreatment. Cardiovascular parameters were measured by impedance cardiography during the maintained infusion of the adrenergic modulators for 45 min. Comparing pretreatments, diverse acute, and thus nongenomic, effects of aldosterone on mean arterial blood pressure were observed. After esmolol pretreatment, aldosterone caused an increase in mean arterial blood pressure by 4.1%, whereas after dobutamine pretreatment mean arterial blood pressure decreased by 1.6%, and the difference was statistically significant (P < 0.01). These effects were significant (P < 0.005) for the first 12 min, underlining their nongenomic nature. Our data support the hypothesis that aldosterone, via nongenomic mechanisms, has diverse effects on the cardiovascular system that depend on the preexisting adrenergic state. Furthermore, aldosterone blunts the blood pressure-lowering effect of the beta-blocking agent esmolol by a nongenomic mechanism.

Adrenergic alpha-Agonists↗
PubMed2001

Impact of pharmacotherapy on lymphocyte volumes and activity of the Na+/H+ exchanger in patients with congestive heart failure.

Previous studies in patients with congestive heart failure (CHF) have revealed abnormalities of cellular volume that might have an impact on the dysregulation of peripheral vascular resistance. Human mononuclear leukocytes (HML) represent a model for the study of cellular volume regulation. We investigated the impact of enalapril and carvedilol on HML volume and on the activity of the Na+/H+ exchanger in 26 patients with CHF and 20 volunteers. Over a period of 4 weeks, 18 patients received enalapril in addition to the previous therapy while 8 patients additionally received carvedilol. HML diameters and the activity of the Na+/H+ exchanger were measured by a Coulter Counter. Both patient groups showed abnormally increased initial volumes of HML compared to the volunteer group at baseline. Four weeks of therapy with enalapril in addition to therapy with diuretics and digoxin did not result in a statistically significant reduction of lymphocyte volume, whereas add-on therapy with carvedilol to therapy with ACE inhibitors, diuretics and digoxin reduced the volume significantly. Alterations could not be found in the activity of the Na+/H+ exchanger in either patient group compared to volunteers. Supplementary drug therapy with carvedilol in patients with CHF leads to a reduction of the increased lymphocytic volume, possibly reflecting the beneficial effect of beta-blockade.

Aged↗
PubMed2001

Does intention-to-treat analysis answer all questions in long-term mortality trials? Considerations on the basis of the ANZ trial.

AIMS: Intention-to-treat (ITT) analyses are the gold standard in endpoint analyses of randomized clinical trials. Valuable information, however, may be lost in this approach as the actual time on trial medication is not accounted for in patients who withdraw early. Since compliance per se can be a prognostic factor and the actual treatment time is a variable likely to influence clinical outcome, this information should be added to an ITT analysis concept. Thus, the aim is to elucidate the influence of actual treatment time on the results of ITT analysis using available data from a well-conducted, large-scale clinical trial. METHODS AND RESULTS: The ANZ trial, a carvedilol study in heart failure, is characterized by a considerable number of early withdrawals in the carvedilol group. Using the ANZ trial database, the percentage of withdrawals was calculated as well as the number of days on treatment. Fourteen out of 21 deaths (67%) in the carvedilol group occurred after discontinuation of carvedilol. At the time of death, 14 out of 29 (48%) patients in the placebo group had withdrawn from treatment. Mean time of patients on medication who withdrew and died later were 301 days for placebo, but only 204 days for carvedilol. We performed a conventional ITT analysis, and an ITT-based Cox-proportional hazards model (modified ITT) in which the actual time on trial medication was entered into the model as an explanatory variable. The risk ratio in conventional ITT analysis was 0.71 (95% confidence interval (CI) 0.41 to 1.24, p = 0.228) and 0.50 (95% CI 0.28-0.90, p < 0.001 ) in modified ITT analysis. CONCLUSIONS: Incorporation of the actual treatment time substantially influences the result of this exemplary ITT analysis. The resulting risk ratio is clearly in accordance with clinical implications and in close agreement with those of other beta-blocker trials in heart failure. Entering the actual treatment time into a Cox-proportional hazards model as an explanatory variable is reasonable if not necessary from a clinical point of view and thus may strengthen the validity of ITT analysis.

Aged↗
PubMed2000

Multiple actions of steroid hormones--a focus on rapid, nongenomic effects.

According to the traditional model, steroid hormones bind to intracellular receptors and subsequently modulate transcription and protein synthesis, thus triggering genomic events finally responsible for delayed effects. Based upon similarities in molecular structure, specific receptors for steroids, vitamin D(3) derivatives, thyroid hormone, retinoids, and a variety of orphan receptors are considered to represent a superfamily of steroid receptors. In addition, very rapid effects of steroids mainly affecting intracellular signaling have been widely recognized that are clearly incompatible with the genomic model. These rapid, nongenomic steroid actions are likely to be transmitted via specific membrane receptors. Evidence for nongenomic steroid effects and distinct receptors involved is presented for all steroid groups including related compounds like vitamin D(3) and thyroid hormones. The physiological and clinical relevance of these rapid effects is still largely unclear, but their existence in vivo has been clearly shown in various settings including human studies. Drugs that specifically affect nongenomic steroid action may find applications in various clinical areas such as cardiovascular and central nervous disorders, electrolyte homeostasis, and infertility. In addition to a short description of genomic steroid action, this review pays particular attention to the current knowledge and important results on the mechanisms of nongenomic steroid action. The modes of action are discussed in relation to their potential physiological or pathophysiological relevance and with regard to a cross-talk between genomic and nongenomic responses.

Animals↗
PubMed1997

A long-term comparison between enalapril and captopril on insulin sensitivity in normotensive non-insulin dependent diabetic volunteers.

BACKGROUND: There are conflicting reports about the effects of angiotensin converting enzyme inhibitors on insulin sensitivity and glycaemic control. In addition, the chronic effects of ACEI on insulin sensitivity in normotensive but insulin resistant individuals have been controversial. AIM: To determine the long-term effects of low-dose captopril or enalapril on insulin sensitivity and lipid parameters in normotensive non-insulin dependent diabetic volunteers. METHODS: Twenty-eight normotensive non-insulin dependent diabetes mellitus subjects on diet alone or diet plus oral hypoglycaemic agents were randomized in a single-blind cross-over study to receive either captopril (12.5 mg daily) or enalapril (5 mg daily). Initially, captopril was compared with enalapril for 28 days with a 28-day washout period between drug regimens. For the long-term study, the subjects then remained on the second ACEI for a further 11 months. Insulin sensitivity was measured using the isoglycaemic hyperinsulinaemic clamp (insulin infusion rate 20 mIU/kg/min) at the start and completion of each part of the cross-over study and then at 3, 6 and 12 months of drug therapy. Fasting glucose, insulin, HbA1, lipids and lipoproteins were measured at the start of each clamp. RESULTS: No first or second order carry-over effects were demonstrated between the ACEIs. No differences were detected between enalapril and captopril on insulin sensitivity at any of the time points. Statistically significant hypotension was avoided, and at doses used the ACEIs did not modify any parameters of glycaemic control over the 12-month study period. There were no significant alterations in plasma cholesterol, triglycerides, HDL cholesterol or Apo A1 levels during the study. CONCLUSIONS: Long-term low-dose ACEIs (captopril/enalapril) do not modify insulin sensitivity, glycaemic control or lipids in normotensive non-insulin dependent diabetic subjects.

Aged↗
PubMed1994

The effect of acute hyperinsulinemia on plasma cholesteryl ester transfer protein activity in patients with non-insulin-dependent diabetes mellitus and healthy subjects.

The effect of acute hyperinsulinemia on plasma cholesteryl ester (CE) transfer protein (CETP) activity was determined in 11 patients with non-insulin-dependent diabetes mellitus (NIDDM) and 10 healthy subjects. Plasma CETP activity was reduced significantly in NIDDM patients (-37 +/- 59 nmol/mL/h, P < .05) but not in healthy subjects (-7 +/- 37 nmol/mL/h) during insulin infusion. Saline infusion did not alter plasma CETP activity significantly. The change in plasma CETP activity was correlated significantly with the baseline plasma triglyceride (TG) concentration (r = -.523, n = 21, P = .01) and marginally with the concomitant decrease in these levels with acute hyperinsulinemia (r = .413, n = 21, P = .06) in NIDDM patients and healthy subjects combined. These data indicate that acute hyperinsulinemia reduces plasma CETP activity and probably plasma CETP concentration in NIDDM patients, and suggest coordinated regulation of CETP levels and TG metabolism by insulin.

Adult↗