Markus Wenk

Endothelin-1 plasma levels in normal-tension glaucoma : abnormal response to postural changes

Abstract• Background: Endothelin-1 (ET-1) is a potent vasoconstrictor peptide produced by vascular endothelial cells. ET-1 may have a role in the pathogenesis of various vascular diseases. There are reports in the literature that ET-1 plasma levels are raised in normal-tension glaucoma (NTG) patients. • Methods: ET-1 concentration, plasma renin activity, and 24-h blood pressure were measured in 2I high-tension glaucoma (HTG) patients, 19 NTG patients, and 20 non-glaucomatous controls in supine and upright positions.• Results: ET-1 plasma levels tended to be higher in NTG patients (3.2 ± 2.2 pg/ml) than in HTG patients (2.2 ±0.6 pg/ml) and controls (2.6 ±0.7 pg/ml). The differences, however, were not statistically significant. The individual scatter was significantly greater in the NTG group, indicating that our NTG patients are a heterogeneous population. The physiological increase in ET-1 plasma level after changing from the supine to the upright position was absent in NTG patients. Plasma renin activities tended to be lower in NTG patients (1.2 ±1.2 ng/ml/h) than in HTG patients (1.30.8 ng/ml/h) and controls (2.0 ± 1.7 ng/ml/h). This may explain why NTG patients had relatively low blood pressure despite high ET-1 levels. • Conclusions: Our data support the hypothesis that vascular dysfunction may be involved in the pathogenesis of optic nerve damage in normal-tension glaucoma.

Endothelin-1 in Pulmonary Hypertension Associated With High-Altitude Exposure

BACKGROUNDnEndothelin-1 is involved in chronic pulmonary hypertension. Its role in acute pulmonary hypertension due to hypoxia in humans is not clear. We therefore studied the influence of hypoxia caused by exposure to high altitude on plasma endothelin-1 levels, arterial blood gases, and pulmonary arterial pressure in subjects taking nifedipine or placebo.nnnMETHODS AND RESULTSnTwenty-two healthy volunteers were investigated at low altitude (490 m) and high altitude (4559 m). Arterial blood gases were analyzed immediately, endothelin-1 was measured by radioimmunoassay, and pulmonary artery pressure was assessed by Doppler echocardiography. After baseline investigations, the mountaineers were allocated in a randomized double-blind fashion to receive either placebo or nifedipine (20 mg TID) during rapid ascent to high altitude within 22 hours. Tests were repeated at the high-altitude research laboratories located in the Capanna Regina Margherita (Italy, 4559 m). Plasma endothelin-1 was increased twofold at high altitude (5.9 +/- 2.2 pg/mL compared with 2.9 +/- 1.1 pg/mL, P < .05), was inversely related to arterial PO2 (r = -.46, P < .001), and correlated with pulmonary artery pressure (r = .52, P < .002). At high altitude, arterial endothelin-1 was lower (4.3 +/- 1.6 pg/mL) than venous endothelin-1 (5.9 +/= 2.2 pg/mL, P < .001), indicating either predominant production in the venous vasculature or pronounced clearance in the pulmonary circulation. The calcium antagonist nifedipine, which lowered pulmonary artery pressure at high altitude (32 +/- 5 versus 42 +/- 11 mm Hg, P < .05), had no influence on plasma endothelin-1 levels. The administration of 35% O2 at high altitude normalized arterial PO2, tended to decrease endothelin-1, and decreased pulmonary artery pressure accordingly.nnnCONCLUSIONSnWe conclude that plasma endothelin-1 is increased at high altitude, but whether or not it represents an important pathogenetic factor for pulmonary hypertension remains to be investigated.

Octyl-beta-D-glucopyranoside partitioning into lipid bilayers: thermodynamics of binding and structural changes of the bilayer.

The interaction of the nonionic detergent octyl-beta-D-glucopyranoside (OG) with lipid bilayers was studied with high-sensitivity isothermal titration calorimetry (ITC) and solid-state 2H-NMR spectroscopy. The transfer of OG from the aqueous phase to lipid bilayers composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) can be investigated by employing detergent at concentrations below the critical micellar concentration; it can be defined by a surface partition equilibrium with a partition coefficient of K = 120 +/- 10 M-1, a molar binding enthalpy of delta H degrees D = 1.3 +/- 0.15 kcal/mol, and a free energy of binding of delta G degrees D = -5.2 kcal/mol. The heat of transfer is temperature dependent, with a molar heat capacity of delta CP = -75 cal K-1 mol-1. The large heat capacity and the near-zero delta H are typical for a hydrophobic binding equilibrium. The partition constant K decreased to approximately 100 M-1 for POPC membranes mixed with either negatively charged lipids or cholesterol, but was independent of membrane curvature. In contrast, a much larger variation was observed in the partition enthalpy. delta H degrees D increased by about 50% for large vesicles and by 75% for membranes containing 50 mol% cholesterol. Structural changes in the lipid bilayer were investigated with solid-state 2H-NMR. POPC was selectively deuterated at the headgroup segments and at different positions of the fatty acyl chains, and the measurement of the quadrupolar splittings provided information on the conformation and the order of the bilayer membrane. Addition of OG had almost no influence on the lipid headgroup region, even at concentrations close to bilayer disruption. In contrast, the fluctuations of fatty acyl chain segments located in the inner part of the bilayer increased strongly with increasing OG concentration. The 2H-NMR results demonstrate that the headgroup region is the most stable structural element of the lipid membrane, remaining intact until the disordering of the chains reaches a critical limit. The perturbing effect of OG is thus different from that of another nonionic detergent, octaethyleneglycol mono-n-dodecylether (C12E8), which produces a general disordering at all levels of the lipid bilayer. The OG-POPC interaction was also investigated with POPC monolayers, using a Langmuir trough. In the absence of lipid, the measurement of the Gibbs adsorption isotherm for pure OG solutions yielded an OG surface area of AS = 51 +/- 3 A2. On the other hand, the insertion area AI of OG in a POPC monolayer was determined by a monolayer expansion technique as AI = 58 +/- 10 A2. The similar area requirements with AS approximately AI indicate an almost complete insertion of OG into the lipid monolayer. The OG partition constant for a POPC monolayer at 32 mN/m was Kp approximately 320 M-1 and thus was larger than that for a POPC bilayer.

Netilmicin in the neonate: Population pharmacokinetic analysis and dosing recommendations

Netilmicin pharmacokinetics were studied in neonates of 27 to 42 weeks gestational age and 0.8 to 5.0 kg body weight in their first 2 weeks of life by the population pharmacokinetic approach. The data were best described by a two‐compartment model. Clearance depends on body weight, gestational age, and postnatal age. Volume of distribution of the central and peripheral compartments was also related to body weight. Including these patient characteristics in the population pharmacokinetic regression model resulted in a marked reduction of the unexplained interindividual variability. This enabled us to derive dosage recommendations that result in peak and average concentrations within the desired range for 95% of the neonates with gestational age above 31 weeks, thus avoiding the need for individual drug‐level monitoring in a well‐defined large group of patients. Only for infants with gestational age less than 31 weeks who are less than 6 days old is individual dose adjustment based on serum concentration measurements required.

N‐Acetyltransferase 2 polymorphism in patients infected with human immunodeficiency virus

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.

Calcium Gluconate in Severe Verapamil Intoxication

To the Editor: Intoxication with verapamil is a serious and often fatal condition, complicated by severe hypotension and cardiac-conduction abnormalities1–4. The current therapeutic approach involves intravenous atropine, catecholamines, ventilation, and the insertion of a pacemaker. A 65-year-old woman treated with sustained-release verapamil for hypertension was admitted to our hospital in a coma (Glasgow coma score, 4). The blood pressure was 83/63 mm Hg, and the heart rate was 42 beats per minute (atrioventricular nodal rhythm with right bundle-branch block). The results of a routine drug screening were negative. Verapamil overdose was suspected, and gastric lavage was performed. The .xa0.xa0.

Traditional Aqueous Kava Extracts Inhibit Cytochrome P450 1A2 in Humans: Protective Effect Against Environmental Carcinogens?

o the Editor: A recent review in the Journal has drawn attention to the otential risk of herb-drug interactions. Because studies have hown that psychoactive kavalactones have an inhibitory efect on cytochrome P450 (CYP) enzymes in vitro, we were nterested in determining whether clinically relevant interacions were to be expected from the consumption of the aqueus extract of kava root (Piper methysticum Forst f), which is ommon in the South Pacific. We studied 6 healthy subjects from New Caledonia (age, 9-55 years; 1 woman; 3 cigarette smokers). All had been egular consumers of the traditional aqueous kava extract for ore than 6 years and drank an estimated 7 to 27 g of avalactones per week up to the beginning of the study, which ad been approved by the institutional ethics committee. The articipants gave informed consent to stop kava consumption or 30 days without any other change in their lifestyle includng diet, smoking, and medication and to undergo 2 sessions f CYP phenotyping by use of model compounds. Metabolic atios for 5 different probe drugs (Table I) reflecting the ctivities of different CYP isozymes were determined before nd after a 30-day complete abstinence from kava. The caffeine metabolic ratio increased 2-fold, from 0.3 ith the consumption of kava to 0.6 at 30 days after cessation f kava (Fig 1); the latter value corresponds to published etabolic ratios in healthy control subjects. No significant hanges were observed for the other probe drugs (Table I).

Influence of intensive physical training on urinary nitrate elimination and plasma endothelin-1 levels in patients with congestive heart failure

BACKGROUNDnCongestive heart failure (CHF) is associated with increased peripheral vascular resistance. Exercise-induced shear stress may release endothelial relaxing factors, such as nitric oxide (NO), and inhibit the production of vasoconstrictors such as endothelin-1 (ET-1) thereby modulating vascular tone. We examined the effect of intensive training on ET-1 plasma concentrations and NO-metabolite elimination in patients with CHF after acute myocardial infarction.nnnMETHODSnSeventeen patients with CHF after a myocardial infarction were randomized to an exercise group (n = 9), who performed physical training for 8 weeks, or a control group (n = 8) who received usual care. A physical examination, pulmonary function test, and a maximum exercise test were performed, and 24-hour urinary nitrate elimination and ET-1 in plasma were determined before and at the end of the study period.nnnRESULTSnMaximal oxygen uptake remained unchanged in controls (17.9 +/- 1.4 to 18.1 +/- 1.5 mL/(kg min) but increased in the exercise group (from 20.4 +/- 0.75 to 26.7 +/- 1.4 mL/(kg min). After 8 weeks the urinary nitrate elimination in controls was significantly decreased (1.25 +/- 0.20 to 1.03 +/- 0.22 mmol/24 hours; P < 0.001), while it was unchanged in the exercise group (1.26 +/- 0.23 to 1.39 +/- 0.28; P = 0.71). Plasma ET-1 levels did not change after 8 weeks (7.87 +/- 0.62 versus 7.57 +/- 0.75 and 7.13 +/- 0.6 versus 7.35 +/- 0.7 pg/mL for control and exercise groups, respectively).nnnCONCLUSIONnIn patients with CHF after acute myocardial infarction nitrate elimination decreases over the subsequent 2 months. This trend was reversed by training. Because nitrate elimination mirrors endogenous NO production, these results suggest that training may positively influence endothelial vasodilator function.

Rapid prediction of steady-state serum theophylline concentration in patients treated with intravenous aminophylline.

SummaryIn 15 acutely ill asthmatics the steady-state serum theophylline concentration was predicted by the method of Chiou et al. using two serum concentration measurements obtained 1 and 5h after starting a continuous infusion of aminophylline. Two theophylline assays with different precision characteristics were compared. With a precise HPLC-assay the prediction was excellent: prediction error (predicted minus measured concentration)=−0.22±1.97 mg/l (mean ± SD); r=0.922. When the theophylline concentration was determined by a rapid enzyme immunoassay of lower precision, but convenient for clinical use, the prediction was less accurate (prediction error=0.58±3.88, r=0.852). However, it was still clearly superior to dosing recommendations based on the population average of theophylline clearance, even after taking into consideration the effect of smoking, congestive heart failure and cirrhosis (prediction error=3.62±13.36, r=0.560). As employed in this study, the method may be useful in helping the physician to choose the optimal dose in severely ill asthmatics.

Isoniazid plus Sulphadoxine-Pyrimethamine Can Reduce Morbidity of HIV-Positive Patients Treated for Tuberculosis in Africa: A Controlled Clinical Trial

An annual 20% excess mortality rate is observed in HIV-seropositive patients after treatment for tuberculosis. An affordable secondary prophylaxis against main opportunistic diseases is needed, i.e. against tuberculosis, toxoplasmosis, pneumocystosis and other infections occurring in this target population. This open prospective randomized study assessed morbidity and mortality in 2 cohorts of HIV-seropositive patients having recently recovered from pulmonary tuberculosis: 134 patients assigned to prophylactic treatment with isoniazid (INH, 300 mg once daily) plus sulphadoxine-pyrimethamine (S, 500 mg/P, 25 mg once weekly), and 129 were controls, comparable for sex, age, weight and HIV-serology. Patients were followed-up for up to 2 years: 192 person-years (PY) in the prophylaxis group and 142 PY in the control group. Four patients developed tuberculosis and 20 patients died in the prophylaxis group, compared to 10 and 23 controls, respectively. Sick days were reported by 22 patients in the prophylaxis group and by 77 patients in the control group. This prophylaxis was associated with a moderate decrease of mortality (log rank test: p = 0.1736), a significant decrease of tuberculosis incidence (log rank test: p = 0.0234), a highly significant reduction of adverse events and sick days, and a prevention of wasting (p = 0.008) and anaemia (p = 0.045). No death from toxoplasmosis occurred in the prophylaxis group as compared to 2 possible cases among controls; toxoplasmosis IgG levels declined in treated patients, but increased in controls (p = 0.01). There was no adverse drug reaction due to SP (10,006 doses) or to INH. Compliance with SP intake was good, but moderate as with INH intake. We conclude that a secondary prophylaxis with INH+SP represents a cost-effective measure to improve health conditions of HIV-infected adults in Côte d’Ivoire, following a full treatment course against tuberculosis.