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Biomedical subjects

W E Haefeli

Publications and source records attributed to W E Haefeli.

At least 55 records · Page 3Linked to original sources
PubMed1998

Evidence for disturbed S-adenosylmethionine : S-adenosylhomocysteine ratio in patients with end-stage renal failure: a cause for disturbed methylation reactions?

BACKGROUND: Elevated homocysteine concentrations have been associated with premature arteriosclerosis and with impairment of key methylation reactions through accumulation of the homocysteine metabolite S-adenosylhomocysteine. In end-stage renal failure high homocysteine concentrations are commonly found but thus far the concentrations of related adenosylated metabolites in plasma have not been assessed. METHODS: In this prospective study we determined plasma homocysteine and related metabolites in 25 patients on regular haemodialysis, and in 40 healthy volunteers. Blood samples from patients were drawn immediately before and in 10 patients additionally after the dialysis session. RESULTS: Folic acid and vitamin B12 in plasma were similar in patients (mean +/- SEM 25+/-2 nmol/l and 400+/-41 pmol/l respectively) and controls (24+/-3 and 324+/-23 respectively). In patients plasma homocysteine, S-adenosylmethionine and S-adenosylhomocysteine were markedly elevated (36.6+/-3.6 micromol/l, 381+/-32nmol/l and 1074+/-55 nmol/l respectively) compared to the control values (6.8+/-0.4 micromol/l, 60+/-3 nmol/l and 24.4+/-1.1 nmol/l respectively) whereas the molar ratio of plasma S-adenosylmethionine and S-adenosylhomocysteine was significantly decreased (0.36+/-0.02 and 2.7+/-0.2 in patients and controls respectively). Haemodialysis failed to normalize the abnormal levels of these metabolites. CONCLUSION: Since the ratio of S-adenosylmethionine : S-adenosylhomocysteine is closely linked to the activity of numerous enzymatic methylation reactions, these results suggest that methylation may be impaired in these patients.

Adult↗
PubMed1998

Safety and efficacy of a two-compartment Bayesian feedback program for therapeutic tobramycin monitoring in the daily clinical use and comparison with a non-Bayesian one-compartment model.

The predictive value of a two-compartment Bayesian feedback program for tobramycin dose optimization was retrospectively evaluated in 199 hospitalized patients and compared with that of a simple non-Bayesian one-compartment model. Before dose adjustment, 64% of the patients were underdosed indicating that tobramycin monitoring is still necessary to avoid ineffective antibiotic therapy. When physicians adhered to the dose instructions calculated with the Bayesian method, 90% of the patients had optimal concentration-time profiles as opposed to only 53% of the 43 patients in whom dose recommendations were not followed. In young patients with normal renal function, precision and accuracy of the Bayesian feedback and the one-compartment method were well correlated, whereas in elderly patients (> 60 years) and patients with impaired renal function (estimated creatinine clearance < 60 ml/minute), the Bayesian method was significantly more precise. Multiple regression analysis revealed that renal function was the only independent variable predicting the performance of the Bayesian program. The results of this study indicate that the Bayesian feedback method is a reliable method for the therapeutic tobramycin monitoring under clinical conditions and in particular, elderly patients in whom renal impairment is frequent.

Absorption↗
PubMed1998

Acetaminophen is an inhibitor of hepatic N-acetyltransferase 2 in vitro and in vivo.

Slow acetylators of the polymorphic N-acetyltransferase 2 (NAT2, EC 2.3.1.5) suffer more often from side-effects of NAT-substrates than fast acetylators. Since concomitant administration of drugs may inhibit NAT2, we studied the influence of acetaminophen on NAT2 in human hepatic cytosol in vitro and in healthy individuals. In-vitro acetylation was assessed in liver homogenate of one fast and one slow acetylator using sulfamethazine as a test substrate. Acetaminophen competitively inhibited sulfamethazine acetylation in fast and slow acetylator liver samples with Ki values of acetaminophen of 2144 micromol/l and 712 micromol/l, respectively. In additional experiments, exposure of human liver cytosol to p-aminophenol, a putative precursor of acetaminophen in this reaction, revealed production of substantial amounts of acetaminophen, which indirectly suggests that acetaminophen may bind to the active site of NAT2. In-vivo acetylation was quantified with a urinary caffeine assay in 20 healthy volunteers at baseline and after repetitive oral administration of 1000 mg acetaminophen every 6 h for 1 day. The ratio of the acetylated caffeine metabolite acetyl-amino-6-formylamino-3-methyluracil to 1-methylxanthine was reduced by 30.9% (range 11.0-50.1%) in fast acetylators (n = 10) and by 19.3% (range 0.2-36.5%) in slow acetylators (n = 10). Acetaminophen, a widely used over-the-counter drug, which shares structural similarities with acetylated products, inhibits NAT2 both in vitro and in vivo. These findings suggest that even compounds which are not metabolized by NAT2 may inhibit the enzyme and reduce its metabolic capacity.

Acetaminophen↗
PubMed1998

Human neuropeptide Y potentiates alpha1-adrenergic blood pressure responses in vivo.

Human neuropeptide Y (hNPY) potentiates the postjunctional vasoconstrictor effects of alpha1-adrenoceptor agonists in animals and in human hand veins in vivo. We therefore hypothesized that such an interaction might also occur in the human arterial bed. With the present single-blind cross-over study in 12 healthy volunteers, the effect of subpressor doses of hNPY on the blood pressure response to alpha1-adrenoceptor stimulation was evaluated. Dose-response curves were constructed to intravenously infuse phenylephrine with and without coinfusion with two different doses of hNPY (1.4 and 14.3 pmol . kg-1 . min-1). Blood pressure, heart rate, and forearm blood flow were recorded, and plasma hNPY was determined. During infusion of the higher hNPY dose, which increased hNPY from 24.0 +/- 12.0 to 495.1 +/- 12.6 pmol/l, blood pressure curves were 2.4-fold shifted toward lower phenylephrine dose rates (P < 0.001). Forearm vascular resistance showed a similar trend, whereas the counterregulatory decrease of heart rate was similar in both groups. In contrast, the lower hNPY dose rate producing a fourfold increase in hNPY concentrations did not modify the response to phenylephrine. This in vivo study in humans demonstrates that hNPY induced potentiating effects on alpha1-adrenergic constriction also in the systemic arterial circulation and suggests that circulating hNPY may participate in the control of vascular tone.

Adrenergic alpha-Agonists↗
PubMed1998

Functional activity of bronchi from an organ donor with fatal asthma: studies on cryopreserved bronchi.

Human bronchi were taken from the lungs of a single asthmatic and 5 nonasthmatic organ donors. The tissues were slowly frozen to -70 degrees C and stored for 1-28 months in liquid nitrogen (-196 degrees C) while suspended in Krebs-Henseleit solution containing 1.8 M dimethyl sulfoxide and 0.1 M sucrose as cryoprotectants. After thawing, bronchial rings were suspended in 10 ml organ baths for isometric tension recording. Spontaneously developed tone (1.13 +/- 0.12, n = 22, vs. 0.56 +/- 0.07 g, n = 33, p < 0.001) and maximal contractile responses to histamine (1.93 +/- 0.12, n = 34, vs. 1.02 +/- 0.14 g, n = 30, p < 0.001) were significantly stronger in asthmatic than in nonasthmatic bronchi. The potency of histamine was 4 times less in asthmatic than in nonasthmatic bronchi (p < 0.001). Comparison of the maximal responses to histamine after storage at -196 degrees C for up to 28 months revealed no significant reduction of the contractile function by time of cryostorage. Salbutamol and the potassium channel opener SDZ PCO 400 were 3-4 times less potent in asthmatic than in nonasthmatic bronchi. For antagonism of histamine by ketotifen in asthmatic bronchi (pD'2 = 8.04 +/- 0.13, n = 5) 4 times higher concentrations were necessary than in nonasthmatic bronchi (pD'2 = 8.63 +/- 0.06, n = 15, p < 0.001). These data support the contention that in spite of a diminished sensitivity to histamine after fatal asthma, isolated bronchi show enhanced spontaneous and agonist-induced contractile responses whereas relaxant responses appear to be impaired.

Adult↗
PubMed1997

Inverse correlation between endothelin-1-induced peripheral microvascular vasoconstriction and blood pressure in glaucoma patients.

BACKGROUND: The potent vasoconstrictor peptide endothelin-1 has been shown to participate in the control of peripheral vascular tone and in the regulation of ocular perfusion. In glaucoma patients vasospasms and arterial hypotension have been identified as risk factors for the progression of glaucomatous damage, and the regulation of endothelin-1 release is disturbed in some of these patients. The aim of this study was to assess the relationship between resting blood pressure and cutaneous vascular responsiveness to endothelin-1 and phenylephrine in patients with glaucoma and in matched controls. METHODS: In 9 patients with primary open-angle glaucoma (POAG), 7 patients with normal tension glaucoma (NTG), and 16 age- and sex-matched controls, endothelin-1 and phenylephrine responses were assessed in the human forearm microcirculation using laser Doppler flowmetry during intra-arterial drug administration. Blood pressure was measured intra-arterially. RESULTS: In contrast to alpha 1-adrenergic effects, endothelin-1 responses were inversely correlated to both systolic (r2 = 0.27, P = 0.05) and diastolic (r2 = 0.54, P = 0.001) blood pressure in glaucoma patients, whereas there was no such correlation in controls. Patients with lower blood pressure values were more sensitive to the vasoconstrictor effects of endothelin-1. Cutaneous responsiveness to endothelin-1 and phenylephrine was similar in glaucoma patients and in controls. CONCLUSION: These results reveal that glaucoma patients appear to have peripheral microvascular abnormalities which are exhibited as altered responsiveness to endothelin-1. Thus, this study supports the hypothesis that endothelin-1-related microvascular dysfunction may be involved in the pathogenesis of glaucomatous damage.

Adult↗
PubMed1997

Functional recovery of human mesenteric and coronary arteries after cryopreservation at -196 degrees C in a serum-free medium.

PURPOSE: Long-term patency of cryopreserved vascular grafts is determined by maintained cellular and tissue viability, which implies preservation of various biochemical, smooth muscle, and endothelial functions. Therefore, it was investigated whether the presence of fetal calf serum (FCS) in the cryomedium improves the postthaw contractile and endothelial function of human arteries. METHODS: Rings from human mesenteric (HMA) and left circumflex coronary arteries (HCA) obtained from organ donors were randomized into three groups and studied either unfrozen or after storage for 3 to 6 weeks at -196 degrees C while suspended in Krebs-Henseleit solution without or with 20% FCS as the vehicles and 1.8 mol/L dimethyl sulfoxide and 0.1 mol/L sucrose as cryoprotecting agents. The samples were slowly frozen to -70 degrees C and then stored in liquid nitrogen. Before use, the tissues were thawed within 3 minutes in a 40 degrees C water bath. RESULTS: After thawing the sensitivity to various agonists and maximal responses to the endothelium-independent relaxing agent sodium nitroprusside were unchanged. However, after cryopreservation of HMA was performed without and with FCS, maximal contractile responses to noradrenaline were significantly reduced to 10.1 +/- 0.7 gm and 9.9 +/- 0.9 gm compared with 13.3 +/- 0.6 gm in unfrozen HMA (mean +/- SEM, n = 15). After cryopreservation of HCA was performed without and with FCS, maximal contractile responses to prostaglandin F2 alpha (6.9 +/- 0.4 gm in unfrozen HCA) were significantly reduced to 4.3 +/- 0.3 gm and 3.8 +/- 0.2 gm (mean +/- SEM, n = 6). In both types of arteries cryopreservation also attenuated significantly the endothelium-dependent relaxant responses to bradykinin during U46619 (10 nmol/L)-induced tone. In HMA the maximal bradykinin-induced relaxation (85% +/- 4%) was significantly diminished to 29% +/- 7% and 38% +/- 9% after cryopreservation without and with FCS (mean +/- SEM, n = 6). In HCA maximal bradykinin-induced relaxation (88% +/- 4%) was significantly diminished to 26% +/- 10% and 36% +/- 11% after cryopreservation without and with FCS (mean +/- SEM, n = 6). This result was reflected by a marked endothelial denudation in all groups of cryopreserved arteries. Neither functional nor morphologic preservation of the endothelial cell lining was significantly improved by FCS supplementation of the cryomedium. CONCLUSIONS: Cryopreservation diminished contractile and endothelium-dependent relaxant responses of human arteries. The presence of FCS in the cryomedium did not modify these changes.

Animals↗
PubMed1997

Angiotensin-converting enzyme inhibitor-induced angioedema: late onset, irregular course, and potential role of triggers.

Angioedema is a rare but potentially life-threatening adverse effect of angiotensin-converting enzyme inhibitors (ACEI) which usually occurs within the first weeks of therapy. We report three patients in whom ACEI-induced angioedema began with a late onset of 12-33 months, and who had an irregular, unpredictable course under ACEI therapy. In two patients, other drugs or trauma appeared to trigger some of the episodes. After withdrawal of the ACEI, the trigger drugs were well tolerated in provocation tests and upon re-exposure. To avoid putting some patients unnecessarily at risk for long periods, one should consider this irregular pattern of ACEI-induced angioedema and regularly monitor patients for this adverse effect.

Aged↗
PubMed1997

Quinaprilat induces arterial vasodilation mediated by nitric oxide in humans.

The beneficial therapeutic effects of angiotensin-converting enzyme (ACE) inhibitors are the result of reduced angiotensin II formation and possibly also of an accumulation of bradykinin that is inactivated by ACE. In particular, recently developed ACE inhibitors with tissue-penetrating properties, such as quinaprilat, may exert vascular effects via the bradykinin B2-receptor. To test direct arterial effects of quinaprilat and enalaprilat and to study their effects on vasodilation induced by bradykinin, venous occlusion plethysmography was used during local intra-arterial drug administration into the brachial artery in healthy volunteers. The response to bradykinin was augmented by both ACE inhibitors, but the effect of quinaprilat (3.9 nmol/min) was exclusively attributable to its direct vasodilator action. Enalaprilat (13 nmol/min) did not change baseline blood flow in the human forearm circulation. In contrast, quinaprilat significantly increased arterial flow from 3.5 +/- 0.5 to 4.6 +/- 0.7 mL/100 mL tissue/min, which was inhibited by N(G)-monomethyl-L-arginine (8 micromol/min IA). Moreover, the effect of sodium nitroprusside (0.023 to 22.9 nmol/min) was substantially attenuated during concomitant administration of quinaprilat. These results suggest that quinaprilat induces vascular effects beyond the inhibition of angiotensin II formation; it causes vasodilation by increasing vascular nitric oxide production and thereby attenuates the relaxing effect of the nitric oxide donor sodium nitroprusside.

Adult↗
PubMed1997

Role of nitric oxide in the regulation of the mechanical properties of peripheral conduit arteries in humans.

Whether nitric oxide (NO) contributes to the regulation of the mechanical properties of large arteries in humans is not known. We measured the effect of local administration of the inhibitor of NO synthesis N(G)-monomethyl-L-arginine (L-NMMA; 1 and 4 micromol x L[-1] x min[-1] for 5 minutes) and acetylcholine (3 and 30 nmol x L[-1] x min[-1] for 3 minutes) on radial artery diameter and wall thickness in 11 healthy volunteers using an echo-tracking system coupled to a measurement of radial blood flow (Doppler) and arterial pressure. At the highest dose, L-NMMA reduced radial blood flow but surprisingly decreased incremental elastic modulus (from 1.36+/-0.22 to 1.00+/-0.22 kPa x 10[3]; P<.05) and increased arterial compliance (from 3.20+/-0.46 to 4.07+/-0.45 m2 x kPa x 10(-8), P<.05), without affecting radial artery internal diameter, wall thickness or midwall stress, thus reflecting a decrease in vascular tone. Acetylcholine decreased incremental elastic modulus (from 1.27+/-0.08 to 0.88+/-0.07 kPa x 10[3]; P<.05) and increased arterial diameter, radial blood flow, and compliance (from 2.82+/-0.16 to 5.30+/-0.62m2 x kPa x 10[-8]; P<.05). These results demonstrate in vivo that NO is involved in the regulation of the mechanical properties of large arteries in humans. However, the effects of L-NMMA, ie, a decrease in arterial wall rigidity and an increase in arterial compliance, which occur in the absence of any changes in blood pressure or arterial geometry, suggest that inhibition of NO synthesis is associated in humans with a paradoxical isometric smooth muscle relaxation. This effect could be due to the development of compensatory vasodilating mechanisms after NO synthesis inhibition.

Acetylcholine↗
PubMed1997

Acute von Willebrand factor secretion from the endothelium in vivo: assessment through plasma propeptide (vWf:AgII) Levels.

Elevated plasma concentrations of von Willebrand factor (vWf) are increasingly recognized as a cardiovascular risk factor, and are used as a marker of endothelial activation. However, the factors which determine the rate of vWf release from the endothelium in vivo have not been defined clearly. In addition, vWf plasma levels may also be influenced by adhesion of vWf to the vascular wall or to platelets, and by its rate of degradation. The propeptide of vWf (also called vWf:AgII) is stored and released in equimolar amounts with vWf. In the present study we attempted to determine whether this propeptide could be a more reliable marker of endothelial secretion than vWf itself. To accomplish this we developed an ELISA based on monoclonal antibodies. The propeptide levels in normal plasma were found to be 0.7 microgram/ml, more than 10 times lower than vWf itself. Administration of desmopressin (DDAVP) induced a rapid relative increase in propeptide (from 106 to 879%) and in vWf (from 112 to 272%). However, the increases in vWf and propeptide were equivalent when expressed in molar units. A time course study indicated a half-life of the propeptide of 3 h or less. In a baboon model of disseminated intravascular coagulation (DIC) induced by FXa, vWf increased by less than 100%, whereas the propeptide concentrations increased by up to 450%. In view of the massive thrombin generation (as assessed by fibrinogen depletion), the increases in vWf are small, compared to the strong secretory response to thrombin and fibrin previously observed in vitro. Our results suggest that due to its rapid turnover, the propeptide could provide a sensitive plasma marker of acute endothelial secretion.

Adult↗
PubMed1997

Influence of oral S-adenosylmethionine on plasma 5-methyltetrahydrofolate, S-adenosylhomocysteine, homocysteine and methionine in healthy humans.

Elevated plasma homocysteine concentration is an independent risk factor for vascular disease in humans. In addition to nutritional and genetic factors, an interruption of the coordinate regulatory function of S-adenosylmethionine has been proposed to be involved in the occurrence of hyperhomocysteinemia. The effect of oral S-adenosylmethionine on homocysteine metabolism in humans is unknown. We investigated the effect of oral S-adenosylmethionine (400 mg) on plasma levels of 5-methyltetrahydrofolate, which is the active form of folate in the remethylation of homocysteine to methionine, S-adenosylhomocysteine, the demethylated product of S-adenosylmethionine, homocysteine and methionine over 24 hr in 14 healthy subjects. After oral administration, S-adenosylmethionine increased from 38.0 +/- 13.4 to 361.8 +/- 66.4 nmol/liter (mean +/- S.E., P < .001) and returned to base-line values with a half-life of 1.7 +/- 0.3 hr. Both S-adenosylhomocysteine and 5-methyltetrahydrofolate showed a significant transient increase (from 29.9 +/- 3.7 to 51.7 +/- 7.1 nmol/liter, and from 25.1 +/- 2.5 to 36.2 +/- 3.5 nmol/liter, respectively, P < .001), although homocysteine and methionine did not change over the time of measurement. These changes were not found in subjects without previous S-adenosylmethionine administration. The observed metabolic changes suggest that S-adenosylmethionine, at least in concentrations obtained in this study, does not inhibit 5,10-methylenetetrahydrofolate reductase, the 5-methyltetrahydrofolate forming enzyme. Rather they indicate a positive effect on 5-methyltetrahydrofolate, a key cofactor in homocysteine metabolism, which should be considered in homocysteine lowering strategies for the prevention of vascular disease.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗
PubMed1996

[Clinico-pharmacological case (4). Epileptic seizure as an unwanted drug effect on theophylline poisoning].

In spite of the better understanding of the pharmacokinetics and optimized galenics of oral theophylline formulations, therapy with this bronchodilator still bears risks because of its narrow therapeutic window combined with substantial inter- and intra-individual variability of theophylline metabolism. In particular, the comedication with a variety of drugs inhibiting theophylline metabolism requires consideration as a potential source of toxicity. Besides mild, self-limited adverse effects, potentially life-threatening toxic manifestations such as ventricular tachyarrhythmias, shock, and seizures can occur especially with high plasma concentrations. We report the case of a 72-year-old patient with chronic obstructive pulmonary disease who was admitted for surgical treatment of an ulcer of the foot. During combined therapy with theophylline and ciprofloxacin he developed signs of theophylline toxicity with a single episode of partial seizures. These symptoms rapidly improved with repetitive application of activated charcoal and sorbitol. Clinically relevant drug-drug interactions with theophylline and the role and mechanism of action of activated charcoal in intoxicated patients are discussed.

Aged↗
PubMed1996

N-acetyltransferase 2 polymorphism in patients infected with human immunodeficiency virus.

OBJECTIVES: To evaluate the prevalence of slow acetylation of hepatic N-acetyltransferase 2 (NAT2) in patients with different stages of human immunodeficiency virus (HIV) infection, to assess the relationship between acetylation capacity and the degree of immunosuppression, and to study the concordance between NAT2 phenotype and genotype. METHODS: This prospective study in a consecutive sample of HIV-infected patients was performed in the outpatient department of a university hospital that provides primary and tertiary care. The NAT2 genotype was assessed by polymerase chain reaction and restriction fragment length polymorphism, the NAT2 phenotype was determined by caffeine test (urinary metabolic ratio of the caffeine metabolites 5-acetylamino-6-formylamino-3-methyluracil and 1-methylxanthine). RESULTS: Fifty patients with Centers for Disease Control HIV infection stages A (10 patients), B (20 patients), and C (20 patients) were included in the study after each gave informed consent. According to genotyping and phenotyping, 32 (64%) patients were slow acetylators, with a concordance of the two methods of 96%. The overall distribution was similar to distributions reported in other white populations. The slow acetylator phenotype was found in seven, 16, and nine patients with stage A, B, and C, respectively. Eight of the 10 patients with previous adverse reactions to sulfonamides had slow acetylator phenotypes. Acetylation capacity was independent of CD4 cell counts. CONCLUSIONS: This study revealed an excellent agreement between genotypes and phenotypes of NAT2 in patients with HIV infection. There was no increase in prevalence of slow acetylation in patients with advanced stages of the disease. This apparent discrepancy to an earlier study may be the result of differences in co-medication of the patients studied and may point to the relevance of drug interactions in the treatment of patients with HIV infection.

Acetylation↗
PubMed1996

Substance P in human hand veins in vivo: tolerance, efficacy, potency, and mechanism of venodilator action.

OBJECTIVES: To study potency, efficacy, development of tolerance, and mechanism of action of substance P, an endothelium-dependent vasodilator neurokinin, in human hand veins in vivo. METHODS: Thirty-three healthy subjects were studied with use of the hand vein compliance technique. In hand veins preconstricted with the alpha 1-agonist phenylephrine, substance P and antagonists of nitric oxide formation (L-NG-mono-methyl-arginine, L-NMMA), adenosine triphosphate (ATP)-dependent potassium channels (glyburide), angiotensin converting enzyme (enalaprilat), and cyclooxygenase (acetylsalicylic acid) were infused and the venodilator effect was measured. RESULTS: Substance P proved to be the most potent venodilator known thus far (the dose-rate exerting 50% of mean maximum dilation [ED50], geometric mean: 0.105 pmol/min). Rapid development of tolerance occurred in seven of eight volunteers studied. Glyburide decreased the venodilator action of a single dose of substance P (1.5 pmol/min) from 81% to 28% of baseline venodilation (p < 0.05), suggesting that substance P acts through release of endothelium-derived hyperpolarizing factor. The cyclooxygenase-inhibitor acetylsalicylic acid reduced substance P-induced venodilation from 53% +/- 7% to 34% +/- 8% (p < 0.05), whereas L-NMMA had no effect. CONCLUSIONS: Unlike in other vessels, substance P-induced venodilation in hand veins is not mediated through nitric oxide but to a significant extent through a glyburide-sensitive pathway. Therefore it appears likely that substance P activates ATP-dependent potassium channels on vascular smooth muscle cells through the release of endothelium-derived hyperpolarizing factor.

Adult↗