Dilatory effects of phosphodiesterase inhibitors on human hand veins in vivo

Objective: To compare the venodilator potencies of the phosphodiesterase (PDE) III inhibitors amrinone and enoximone with the unspecific PDE inhibitors theophylline and pentoxifylline in human hand veins in vivo. Methods: Eighteen healthy nonsmokers (16 men and two women) were studied using the dorsal hand vein technique. After preconstriction with the selective α₁-adrenergic-receptor agonist phenylephrine dose–response curves were constructed for amrinone (1–270 μg · min⁻¹), enoximone (1–270 μg · min⁻¹), theophylline (5–1500 μg · min⁻¹) and pentoxifylline (2–877 μg · min⁻¹) in a random order on separate occasions. Due to limitation in the maximum dose infused in order to avoid systemic effects, full dose–response curves could not be constructed for pentoxifylline. In this case, the individual dose of pentoxifylline and theophylline producing 50% venodilation were compared. Results: All PDE inhibitors induced dose-dependent venodilation. The value of maximum venodilation was the same for amrinone, enoximone and theophylline. The infusion rate needed to induce 50% of maximum venodilation (ED₅₀) was not significantly different for amrinone (geometric mean, 8.8 μg · min⁻¹) and enoximone (14.2 μg · min⁻¹), whereas the ED₅₀ of theophylline (84.0 μg · min⁻¹) was significantly higher than either amrinone or enoximone. The dose necessary to dilate the vein to 50% the maximum dilation (as determined during sodium chloride infusion) was significantly higher for pentoxifylline than for theophylline (409 vs 71 μg · min⁻¹). Conclusions: These findings demonstrate that enoximone and amrinone have similar venodilatory potency which is six times higher than that of theophylline. The least potent vasodilator in this study was pentoxifylline. Received: 16 September 1997 / Accepted in revised form: 4 December 1997     

Associations between CYP2E1 promoter polymorphisms and plasma 1,3-dimethyluric acid/theophylline ratios

Objective Theophylline is metabolized to 1,3-dimethyluric acid (1,3-DMU), 3-methylxanthine, and 1-methylxanthine by CYP1A2 and partly by CYP2E1. Because 1,3-DMU is the major metabolite of theophylline, the 1,3-DMU/theophylline ratio is viewed as a good indicator of theophylline metabolic clearance. Here, we investigated the associations between 1,3-DMU/theophylline ratios and genetic polymorphisms of CYP2E1 and CYP1A2.Methods Polymerase chain reaction (PCR) and direct sequencing or PCR-restriction fragment length polymorphism (RFLP) were performed to analyze CYP2E1 and CYP1A2 promoter polymorphisms in 62 Korean asthma patients. Plasma theophylline and 1,3-DMU levels were measured by liquid chromatography-tandem mass spectrometry.Results Eleven polymorphisms including Ins₉₆, −1566 T>A, −1515 T>G, −1414 C>T, −1295 G>C, −1055 C>T, −1027 T>C, −930 A>G, −807 T>C, −352 A>G, and −333 T>A were detected in the 5′ flanking region of the CYP2E1 gene (numbering according to GenBank Accession number NT_017795). Of these, five single nucleotide polymorphisms (SNPs) (−1566 T>A, −1295 G>C, −1055 C>T, −1027 T>C, and −807 T>C) were closely linked. Another three polymorphisms (Ins_96, −930 A>G, and −352 A>G) and two polymorphisms (−1515 T>G and −333 T>A) were also closely linked. The five closely linked polymorphisms were associated with significantly different 1,3-DMU/theophylline ratios between heterozygotes plus homozygotes of a rare allele (n=23, 0.0368±0.0171) and common allelic homozygotes (n=39, 0.0533±0.0343) (p=0.024 by Mann-Whitney U test). In the CYP1A2 gene, the −2964G>A polymorphisms exhibited a significant difference in 1,3-DMU/theophylline levels between heterozygotes plus homozygotes of a rare allele (n=30, 0.0406±0.0272) and homozygotes of a common allele (n=32, 0.0534±0.0316) (p=0.032).Conclusion We confirm that hydroxylation at the 8 position of theophylline (1,3-DMU) is significantly affected by genetic polymorphism in CYP2E1 in addition to CYP1A2.     

EVIDENCE OF AN ADENOSINE-DEPENDENT MECHANISM IN THE HYPOTENSIVE EFFECT OF l-ARGININE IN MAN

1. The hypothesis that endogenous adenosine could play a role in the haemodynamic response to l-arginine is investigated. 2. The study has been divided into two parts. The first part was a single blind, randomized, placebo-controlled study in which L-arginine i.v. infusion (0.07 mmol/kg per min) in five healthy volunteers caused a significant fall in systolic (-14.2%, from 129.0 ± 8.2 to 110.6 ± 8.5 mmHg; F= 62.89, P<0.0l), diastolic (-16%, from 80.0 ± 7.9 to 67.2 ± 7.0 mmHg; F= 18.97, P < 0.0l) and mean (-15.5%, from 96.4 ± 6.7 to 81.4 ± 6.5 mmHg; F= 28.78, P< 0.01) arterial blood pressure, with a concomitant increase of plasma adenosine concentration (from 244.0 ± 32.2 to 637.0 ± 43.4 nmol/L; F= 79.3 P<10.01). Maximal effects were obtained at the end of L-arginine infusion: haemodynamic parameters returned to basal values in about 30 min while adenosine concentrations normalized in about 15 min. Saline infusion had no effect on these parameters. 3. In the second study the effect of L-arginine i.v. infusion on arterial blood pressure, lower limb blood flow and plasma adenosine, before and after theophylline treatment (1000 mg/day for 3 days, p.o.) was examined. In 10 healthy volunteers the i.v. infusion of l-arginine (0.07 mmol/kg per min) was followed by the same haemodynamic changes as reported above and by a Significant increase in lower limb blood flow (+ 36.7%, from 2.18 ± 0.40 to 2.98 ± 0.71mL/min/lOOmL;t = 4.61, P< 0.01). Pretreatment with theophylline, an adenosine-receptor antagonist, did not affect basal values of arterial pressure, lower limb blood flow and adenosine concentration. The pretreatment with theophylline reduced maximal decrease in systolic pressure (- 8.2 vs -15%), in mean pressure (- 9.9 vs -13.7%) and maximal increase in lower limb blood flow (+19 vs + 37%) caused by i.v. infusion of l-arginine (0.07 mmol/kg per rnin). Such a treatment allowed a progressive restoration of basal blood pressure values and of blood flow, during the second half of l-arginine infusion. This observation was confirmed by the analysis of the area under the curves (AUC). A significant difference in AUC values before and after treatment was obtained for systolic pressure (t = 8.25, P< O.Ol), mean pressure (t= 6.67, P<0.0l) and blood flow (t= 2.31, P<0.05). 4. Theophylline study suggested that the endogenous adenosine increase is sufficient to participate at least in part in the haemodynamic changes caused by l-arginine and that it is involved in a secondary response to l-arginine.     

HIV and Chronic Methamphetamine Dependence Affect Cerebral Blood Flow

Human immunodeficiency virus (HIV) and methamphetamine (METH) dependence are independently associated with neuronal dysfunction. The coupling between cerebral blood flow (CBF) and neuronal activity is the basis of many task-based functional neuroimaging techniques. We examined the interaction between HIV infection and a previous history of METH dependence on CBF within the lenticular nuclei (LN). Twenty-four HIV−/METH−, eight HIV−/METH+, 24 HIV+/METH−, and 15 HIV+/METH+ participants performed a finger tapping paradigm. A multiple regression analysis of covariance assessed associations and two-way interactions between CBF and HIV serostatus and/or previous history of METH dependence. HIV+ individuals had a trend towards a lower baseline CBF (−10%, p = 0.07) and greater CBF changes for the functional task (+32%, p = 0.01) than HIV− subjects. Individuals with a previous history of METH dependence had a lower baseline CBF (−16%, p = 0.007) and greater CBF changes for a functional task (+33%, p = 0.02). However, no interaction existed between HIV serostatus and previous history of METH dependence for either baseline CBF (p = 0.53) or CBF changes for a functional task (p = 0.10). In addition, CBF and volume in the LN were not correlated. A possible additive relationship could exist between HIV infection and a history of METH dependence on CBF with a previous history of METH dependence having a larger contribution. Abnormalities in CBF could serve as a surrogate measure for assessing the chronic effects of HIV and previous METH dependence on brain function.     

Lower Glial Metabolite Levels in Brains of Young Children with Prenatal Nicotine Exposure

Many pregnant women smoke cigarettes during pregnancy, but the effect of nicotine on the developing human brain is not well understood, especially in young children. This study aims to determine the effects of prenatal nicotine exposure (PNE) on brain metabolite levels in young (3–4 years old) children, using proton magnetic resonance spectroscopy (¹H MRS). Twenty-six children with PNE and 24 nicotine-unexposed children (controls) were evaluated with a structured examination, a battery of neuropsychological tests, and MRI/¹H MRS (without sedation). Concentrations of N-acetyl compounds (NA), total creatine (tCR), choline-containing compounds (CHO), myo-inositol (MI), and glutamate+glutamine (GLX) were measured in four brain regions. Children with PNE had similar performance to controls on neuropsychological testing. However, compared to controls, the PNE group had lower MI (repeated measures ANOVA—p = 0.03) and tCr levels (repeated measures ANOVA–p = 0.003), especially in the basal ganglia of the girls (−19.3%, p = 0.01). In contrast, GLX was elevated in the anterior cingulate cortex of the PNE children (+9.4%, p = 0.03), and those with the highest GLX levels had the poorest performance on vocabulary (r = −0.67; p < 0.001) and visual motor integration (r = −0.53; p = 0.01). The amount of prenatal nicotine exposure did not correlate with metabolite concentrations. These findings suggest that PNE may lead to subclinical abnormalities in glial development, especially in the basal ganglia, and regionally specific changes in other neurometabolites. These alterations were not influenced by the amount of nicotine exposure prenatally. However, the effects of PNE on energy metabolism may be sex specific, with greater alterations in girls.     

Urotensin II acutely increases myocardial length and distensibility: potential implications for diastolic function and ventricular remodeling

Urotensin II (U-II) is a cyclic peptide that may be involved in cardiovascular dysfunction. In the present study, the acute effects of U-II on diastolic properties of the myocardium were investigated. Increasing concentrations of U-II (10⁻⁸ to 10⁻⁶ M) were added to rabbit papillary muscles in the absence (n = 15) or presence of: (1) damaged endocardial endothelium (EE; n = 9); (2) U-II receptor antagonist, urantide (10⁻⁵ M; n = 7); (3) nitric oxide (NO) synthase inhibitor, N^G-Nitro-l-Arginine (10⁻⁵ M; n = 9); (4) cyclooxygenase inhibitor, indomethacin (10⁻⁵ M; n = 8); (5) NO synthase and cyclooxygenase inhibitors, N^G-Nitro-l-Arginine (10⁻⁵ M) and indomethacin (10⁻⁵ M), respectively, (n = 8); or (6) protein kinase C (PKC) inhibitor, chelerythrine (10⁻⁵ M; n = 9). Passive length–tension relations were constructed before and after a single concentration of U-II (10⁻⁶ M; n = 3). U-II concentration dependently decreased inotropy and increased resting muscle length (RL). At 10⁻⁶ M, active tension decreased 13.8 ± 5.4%, and RL increased to 1.007 ± 0.001 L/L _max. Correcting RL to its initial value resulted in an 18.1 ± 3.0% decrease in resting tension, indicating decreased muscle stiffness, which was also suggested by the down and rightward shift of the passive length–tension relation. This effect remained unaffected by EE damage and PKC inhibition. In contrast, the presence of urantide and NO inhibition abolished the effects of U-II on myocardial stiffness, while cyclooxygenase inhibition significantly attenuated them. U-II decreases myocardial stiffness, an effect that is mediated by the urotensin-II receptor, NO, and prostaglandins. This represents a novel mechanism of acute neurohumoral modulation of diastolic function, suggesting that U-II is an important regulator of cardiac filling. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. Presented in part at the American Heart Association Scientific Sessions conference, 2006, in Chicago, Illinois.     

Cardiovascular effects of different infusion rates of sufentanil in patients undergoing coronary surgery

   Objective: Pharmacokinetics and haemodynamic effects of a total dose of 15 μg · kg⁻¹ sufentanil, an opioid anaesthetic agent, were studied in patients undergoing aortocoronary bypass surgery at three infusion rates of 30 (group I), 5 (group II), and 2 (group III) μg · kg⁻¹ · min⁻¹, respectively. Results: Plasma concentrations of sufentanil could be optimally characterized by a linear biexponential pharmacokinetic model. Non-compartmental analyses indicated that there was no significant difference in the values of clearance (11.6, 13.3, 14.3 ml · min⁻¹ · kg⁻¹), steady-state volume of distribution (0.220, 0.255 and 0.331 l · kg⁻¹) and mean residence time (18.8, 13.3 and 14.3 min) among the groups. The observed mean C_max values of 421 (group I), 125 (group II), and 53 (group III) ng · ml⁻¹ and observed mean AUC values from 0 to 3 min were all consistent with the dosing regimens. There were large inter-individual variations in haemodynamic response. Compared to plasma data, a delay in haemodynamic effects was found. Times to reach peak haemodynamic effect ranged from 4.3 to 4.9 min for group I, from 4.6 to 6.1 min for group II, and from 9.9 to 11.3 for group III. Except heart rate, peak haemodynamic effects in these study patients generally ranged from 20.9% to 35.2%. Significant reductions in the area under the effect-time profiles of mean arterial blood pressure and systemic vascular resistance were observed in group II and group III, but not in group I. Significant reductions in the area under the effect-time profiles of left ventricular stroke work index were observed in group III only. No effect on heart rate was found in any group. Conclusion: Our findings suggested that a slower infusion rate of sufentanil at a dose of 15 μg · kg⁻¹ tends to give a greater reduction in mean arterial blood pressure, systemic vascular resistance, and left ventricular stroke work index than does a faster infusion rate. Received: 23 August 1995 / Accepted in revised form: 19 August 1996     

Nicotinic acetylcholine receptor (nACh-R) agonist-induced changes in brain monoamine turnover in mice

The aim of the present study was to evaluate the effects of nicotinic acetylcholine receptor (nACh-R) agonists such as (−)-nicotine and related compounds on brain monoamine turnover. A single administration of (−)-nicotine (0.04, 0.2, 1.0, and 5.0 mg/kg SC) increased both noradrenaline (NA) and dopamine (DA) turnover in a dose-dependent manner, and the maximum effects were achieved 30 min after treatment with (−)-nicotine (1.0 mg/kg). The effect of (−)-nicotine on serotonin (5-HT) turnover was complicated; 5-HT turnover was increased at a low dose of (−)-nicotine (0.04 mg/kg) but decreased at a high dose (1.0 mg/kg). The (−)-nicotine (1.0 mg/kg)-induced changes in monoamine turnover were blocked by pretreatment with the centrally acting nACh-R channel blocker mecamylamine (2.0 mg/kg IP) but not by hexamethonium (2.0 mg/kg IP). These findings indicate that systemically administered (−)-nicotine can enhance brain NA and DA turnover and affect 5-HT turnover, both of which are mediated by central nACh-R. The changes in the monoamine turnover induced by (±)-anabasine were similar to those induced by (−)-nicotine, while (−)-lobeline and (−)-cytisine had little effect, and 1,1-dimethyl-4-phenyl-piperazinium (DMPP) increased NA and 5-HT turnover but not DA turnover at all doses tested. (S)-3-Methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole (ABT-418), a selective neuronal nACh-R agonist, increased NA, DA and 5-HT turnover, but had a weaker effect on DA turnover than NA and 5-HT turnover. In addition, 9-amino-1,2,3,4-tetrahydroacridine (THA), an acetylcholine esterase inhibitor, also increased monoamine turnover in the brain. Pretreatment with mecamylamine completely blocked the THA-induced increase in NA and 5-HT turnover, but not in DA turnover, suggesting that the nACh-R system is involved in the THA-induced increase in brain NA and 5-HT turnover. On the other hand, (−)-cytisine, a partial agonist for the β2 subunit containing nACh-R, completely inhibited the nACh-R agonist-and THA-induced increases in NA turnover, but not in DA turnover, and normalized the changes in 5-HT turnover. In conclusion, the subtypes of nACh-Rs mediating DA turnover may be different from those mediating NA and 5-HT turnover in the CNS. Received: 3 April 1996 /Final version: 18 June 1996     

Phosphodiesterases PDE3 and PDE4 jointly control the inotropic effects but not chronotropic effects of (−)-CGP12177 despite PDE4-evoked sinoatrial bradycardia in rat atrium

Acting through a low-affinity site of the β₁-adrenoceptor (β_1LAR), CGP12177 causes sinoatrial tachycardia and positive inotropic effects in left atrium but not in the ventricle of the rat. However, inhibition of either PDE3 or PDE4 also uncovers positive inotropic effects of CGP12177 in ventricle, but whether these phosphodiesterases also control the atrial agonist effects of CGP12177 was unknown. We, therefore, investigated the effects of the PDE3-selective inhibitor cilostamide (300 nM) and PDE4 inhibitor rolipram (1 μM) on the (−)-CGP12177-evoked increases of sinoatrial beating rate and force of paced left atria of the rat. Rolipram (n = 8) increased basal sinoatrial rate by 27 ± 5 bpm but cilostamide (n = 8) had no effect. The chronotropic potency of (−)-CGP12177 (−logEC₅₀M = 7.5) was not changed by rolipram and cilostamide or their combination. (-)-CGP12177 increased left atrial force with intrinsic activity 0.25 compared to (-)-isoprenaline. Rolipram (n = 8) and cilostamide (n = 8) did not change basal force of left atria but concurrent rolipram + cilostamide (n = 8) increased force by 52 ± 9% of the effect of 200 μM (−)-isoprenaline. Neither rolipram nor cilostamide affected the inotropic potency of (−)-CGP12177 (−logEC₅₀M = 7.4) but concurrent rolipram + cilostamide caused potentiation (−logEC₅₀M = 8.2) and converted (-)-CGP12177 into a full agonist compared to (-)-isoprenaline. Cyclic AMP appears to maintain sinoatrial rate and PDE4 elicits bradycardia through hydrolysis of cAMP in a compartment distinct from the β_1LAR-induced cAMP compartment through which (−)-CGP12177 causes tachycardia. In contrast to the (−)-CGP12177-evoked tachycardia, not controlled by PDE3 and PDE4, these isoenzymes jointly reduce (−)-CGP12177-evoked increases of left atrial contractility through β_1LAR.     

Psychomotor performance: investigating the dose-response relationship for caffeine and theophylline in elderly volunteers

Objective: The aim of this study was to investigate the dose-response relationship for psychomotor performance, caffeine and theophylline in healthy elderly volunteers. Methods: In a randomized, double-blind, placebo-controlled, six-period cross-over study we compared the effect of three doses of theophylline (predicted peak concentrations of 3, 6 mg · l⁻¹ and 12 mg · l⁻¹), two doses of caffeine (predicted peak concentrations of 4.5 mg · l⁻¹ and 9 mg · l⁻¹) and placebo on ten healthy elderly volunteers. Psychomotor performance was measured using a continuous attention task, symbol digit substitution test and choice reaction time. Subjective effects were assessed using visual analogue scales. Following drug administration, subjects received the test battery at 30-min intervals, up to 150 min. Maximum and mean effects from baseline on each variable were included in the analysis. Results: Significant improvement on the continuous attention task was seen at the lowest concentration of caffeine and theophylline used, while at higher concentrations there was a non-significant trend towards placebo scores. There was little effect of either drug on the subjective effects measured by visual analogue scales. Conclusion: Caffeine and theophylline increase psychomotor performance measures of attention at low plasma concentrations in healthy elderly volunteers. This effect is not increased by higher drug concentrations and there is trend towards a return to placebo scores. The lack of effect of both caffeine and theophylline on subjective measures is consistent with previous studies of caffeine in the elderly. Received: 11 December 1997 / Accepted in revised form: 18 March 1998     

Effects of sumatriptan and eletriptan on diseased epicardial coronary arteries

Background: Triptans are contraindicated in patients with known or suspected coronary artery disease (CAD); however, few studies have evaluated triptans in patients with obstructive CAD to quantify the vasoconstrictive effect on diseased coronary vessels. Methods: Patients undergoing percutaneous transluminal coronary angioplasty for symptomatic single-vessel CAD were randomised to one of three parallel cohorts to receive (1) 6 mg intravenously (IV) infused eletriptan plus subcutaneous (SC) placebo, (2) IV infused placebo plus 6 mg SC sumatriptan or (3) IV infused placebo plus SC placebo, as simultaneous administrations in a double-blind manner. Serial arteriograms, hemodynamic indices, electrocardiography and triptan plasma concentrations were obtained. Results:. Fifteen minutes after triptan challenge, median (95% confidence interval) changes in coronary artery diameter (CADM) at the focal point of the stenosed segment were: dilation of 2.6% (−5.0, 11.4), eletriptan 6 mg IV (n=18); constriction of 6.8% (−12.6, 0.4), sumatriptan 6 mg SC (n=17), and constriction of 4.5% (−7.0, 7.9), placebo (n=10). One patient had angiographic evidence of a new thrombus at the stenosis site, necessitating termination of study infusion and successful stenting of the lesion. There was no correlation between effects on CADM and triptan concentration, or between hemodynamic or electrocardiograph changes and the presence (n=13) or absence (n=33) of chest pain. Conclusions: Triptans had very little effect on diseased epicardial coronary arteries in a small group of angina sufferers with established CAD. Results should be interpreted cautiously since there may be instances where even modest triptan-associated epicardial constriction is sufficient to precipitate myocardial ischemia in patients with severe obstructive CAD.     

Prevalence of <Emphasis Type="Italic">UGT1A9</Emphasis> and <Emphasis Type="Italic">UGT2B7</Emphasis> nonsynonymous single nucleotide polymorphisms in West African,Papua New Guinean,and North American populations

Objective UDP-glucuronosyltransferases (UGTs) UGT1A9 and UGT2B7 are involved in the metabolism of antimalarial dihydroartemisinin and antiretroviral zidovudine. Our aim was to analyze the prevalence of UGT1A9 (chromosome 2) and UGT2B7 (chromosome 4) nonsynonymous single nucleotide polymorphisms (SNPs) in West African (WA), Papua New Guinean (PNG), and North American (NA) populations. Methods Using a post-PCR ligation detection reaction-fluorescent microsphere assay, frequencies of UGT1A9 (8G > A, 98T > C, 766G > A) and UGT2B7 (211G > T, 802C > T, 1192G > A) SNPs were determined in WA (n = 133, 5 countries), PNG (n = 153), and NA (n = 350, 4 ethnic groups) individuals. Results The UGT1A9 variant alleles were not common in the study populations. None of the SNPs were present in WA and PNG. Among NA, all 3 SNPs were present (1% each) in Asian-Americans, while 98T > C was present only in Caucasian-Americans (1%) and Hispanic-Americans (1%). Regarding UGT2B7 SNPs, the prevalence of 802C > T was 21% in WA, 28% in PNG, and 28–52% in NA. The SNP 211G > T was present only in Asian-Americans (9%) and Hispanic-Americans (2%), while 1192G > A was not present in any of the subjects. No significant linkage was observed at UGT1A9, UGT2B7, and between both the loci in any of the study populations. Conclusions Taken together, the UGT1A9-UGT2B7 polymorphism profile in WA and PNG populations is similar to African-Americans, but different from Asian-Americans. It is important to determine if these differences, along with previously reported differences in cytochrome P450 2B6 allele frequencies, are associated with altered metabolism/effectiveness of artemisinin drugs. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible for authorized users.     

Unchanged serum levels of advanced glycation endproducts in patients with liver disease

Advanced glycation end products (AGEs), e.g., carboxymethyllysine (CML) or imidazolone are involved in several age-related disorders. Concerning their accumulation, the importance of hepatic and renal function is controversially discussed. To test whether impairment of hepatic or renal function will affect their accumulation, both AGEs have been measured in various populations, such as 52 patients with liver disease [viral hepatitis C without (n = 19) and with (n = 10) fatty liver; nonalcoholic fatty liver (n = 13), nonalcoholic steatohepatitis (n = 10)]. Serum concentrations of both AGEs have been compared to those in 20 healthy controls and 24 patients with moderate renal impairment (creatinine clearance 23–55 ml/min). Concerning CML (95% C.I. 803–1200 ng/ml), no differences between the various groups could be observed. Likewise, serum levels of imidazolone (95% C.I. 1.3–5.6 units) were similar in all populations. In conclusion, moderate impairment in hepatic or in renal function did not affect serum levels of CML and imidazolone. Apparently, any increase observed in severe cirrhosis or renal failure seems to be rather a consequence than a cause of both disorders.     

Effects of general anaesthetic procedures on mitochondrial function of human skeletal muscle

Background: General anaesthetics inhibit mitochondrial function in animal models. However, very few studies have been performed in humans, and the results have not been conclusive. Methods: We prospectively studied the oxygen consumption and the individual enzyme activity of each complex of the mitochondrial respiratory chain of skeletal muscle mitochondria in 54 healthy individuals who underwent general anaesthesia for orthopaedic surgery. The control group (n = 54) was made up of individuals submitted to the same orthopaedic procedure under regional anaesthesia (n = 31), and patients who underwent muscle biopsies for diagnostic purposes by local anaesthesia (n = 23). Results: We found a significant decrease in the oxidation of glutamate (−36%), succinate (−25%) and ascorbate (−29%) in the general anaesthetic group compared with the controls (P < 0.001 for all substrates). The level of such inhibition was similar for volatile anaesthetics with strong (halothane) or weak (isoflurane) negative inotropic effect. By contrast, the enzymatic activity of all individual complexes and the coupling of oxidative phosphorylation did not differ between the two groups. Conclusion: We conclude that during general anaesthetic procedures there is an extensive inhibition of substrate oxidation in human muscle mitochondria, and that it is not caused by a direct effect on complexes of the mitochondrial respiratory chain or through uncoupling oxidative phosphorylation. Received: 27 July 1998 / Accepted in revised form: 27 October 1998     

Combined and Independent Effects of Chronic Marijuana Use and HIV on Brain Metabolites

The effects of chronic marijuana (MJ) use on brain function remain controversial. Because MJ is often used by human immunodeficiency virus (HIV) patients, the aim of this study was to evaluate whether chronic MJ use and HIV infection are associated with interactive or additive effects on brain chemistry and cognitive function. We evaluated 96 subjects (30 seronegative nondrug users, 24 MJ users, 21 HIV without MJ use, 21 HIV + MJ) using proton magnetic resonance spectroscopy and a battery of neuropsychological tests. The two primarily abstinent MJ user groups showed no significant differences on calculated estimates of lifetime grams of delta9-tetrahydrocannabinol exposure, despite some differences in usage pattern. The two HIV groups also had similar HIV disease severity (CD4 cell count, plasma viral load, HIV dementia staging, Karnofsky score). On two-way analyses of covariance, HIV infection (independent of MJ) was associated with trends for reduced N-acetyl aspartate (NA) in the parietal white matter and increased choline compounds (CHO) in the basal ganglia. In contrast, MJ (independent of HIV) was associated with decreased basal ganglia NA (−5.5%, p = 0.05), CHO (−10.6%, p = 0.04), and glutamate (−9.5%, p = 0.05), with increased thalamic creatine (+6.1%, p = 0.05). HIV + MJ was associated with normalization of the reduced glutamate in frontal white matter (interaction p = 0.01). After correction for age, education, or mood differences, MJ users had no significant abnormalities on neuropsychological test performance, and HIV subjects only had slower reaction times. These findings suggest chronic MJ use may lead to decreased neuronal and glial metabolites, but may normalize the decreased glutamate in HIV patients.     

Effects and pharmacokinetics of high dose metoprolol on chest pain in patients with suspected or definite acute myocardial infarction

Objective: Pain intensity and the plasma concentrations of metoprolol and its major metabolite α-hydroxymetoprolol as well as noradrenaline (NA), adrenaline (A) and neuropeptide Y (NPY) were determined in patients with pain due to definite or suspected acute myocardial infarction (AMI) after graded metoprolol infusion. Pain intensity and metoprolol kinetics were assessed over 8 h. Methods: Twenty-seven patients of either sex, aged 48–84 years with ongoing chest pain upon arrival to the Coronary Care Unit (CCU) were subdivided into two groups: (1) patients with ECG signs of threatening transmural myocardial damage (n=15); and (2) patients without such ECG signs (n=12). Pain intensity was assessed by a numerical rating scale (NRS) and venous blood was obtained for determination of plasma catecholamine and NPY concentrations. A continuous infusion of metoprolol (3 mg · min⁻¹ i.v) was started and serial blood samples for plasma catecholamines, NPY as well as metoprolol and its major metabolite α-hydroxymetoprolol were obtained from the contralateral arm. Results: Initial pain intensity was 5.9 (arbitrary units) and 5.4 in the groups with and without signs of transmural myocardial damage, respectively. One third of the patients with ST changes reported full pain relief (NRS=0) within 70 min after starting metoprolol infusion (accumulated dose, 15–180 mg). Among the patients without ST changes upon arrival, full pain relief was obtained in 70% (accumulated dose, 30–120 mg). There was a dose-dependent relation between accumulated metoprolol dose and pain relief. The diagnosis of acute myocardial infarction (AMI) was confirmed in all 15 patients with ECG signs on arrival of transmural myocardial damage. The mean metoprolol dose in this group was 91(12) mg. The mean metoprolol dose in the 12 patients without ST changes was 64(8) mg. In all, seven of these patients developed definite AMI. The terminal half-life of unchanged metoprolol ranged from 2.5 to 8.5 h in group 1 and from 2.2 to 5.2 h in group 2. In group 1, metoprolol half-life was 4.5 h and total plasma clearance (CL) 54.1 l · h⁻¹. In group 2, the metoprolol half-life was 3.7 h and total plasma clearance 75.4 l · h⁻¹. There was a significant difference in clearance between the groups. After the intravenous metoprolol infusion, α-hydroxymetoprolol concentrations increased gradually. In groups 1 and 2, maximal concentrations in plasma (C_max) were 143 and 135 nmol · l⁻¹ for α-hydroxymetoprolol and 2830 and 1653 nmol · l⁻¹ for metoprolol, respectively. Plasma NA or NPY did not differ between the groups. In contrast, plasma A was significantly higher during the initial 90 min of observation in patients with ECG signs of transmural myocardial damage. Conclusion: High-dose intravenous metoprolol was well tolerated in patients with suspected AMI. There was a more rapid and almost complete pain relief in patients without signs of transmural ischaemia compared with the patients with ECG signs of transmural AMI at arrival. In the later group of patients, plasma clearance of metoprolol was significantly reduced. Received: 23 August 1996 / Accepted in revised form: 6 March 1997     

Acute effects of candesartan cilexetil (the new angiotensin II antagonist) on systemic and renal haemodynamics in hypertensive patients

Objectives: This study was performed to assess the acute effects of the new angiotensin II antagonist, candesartan cilexetil, on systemic and renal haemodynamics in patients with sustained essential hypertension [diastolic blood pressure (DBP) 95–114 mmHg]. Methods: After 4 weeks of placebo treatment, systemic and renal haemodynamics were investigated in 17 patients with a mean age of 62 years and a mean systolic and diastolic blood pressure of 170/98 mmHg, just before (baseline) and for 4 h after administration of a single oral dose of candesartan cilexetil, 16 mg. Plasma concentrations of candesartan (the active compound formed from the pro-drug candesartan cilexetil), angiotensin II (Ang II), as well as plasma renin activity (PRA), were measured before and after dosing. Results: At 2, 3 h and 4 h after dosing with candesartan cilexetil, systolic blood pressure (SBP) and DBP, as well as mean arterial pressure (MAP), were significantly lower than at baseline. The mean reduction in MAP 4 h after dosing was 8.8 mmHg (−6.5%). This effect was due to a fall in total peripheral resistance (TPR), while heart rate (HR), stroke volume (SV) and cardiac output (CO) were virtually unchanged. After 4 h there was a marked reduction in renal vascular resistance (RVR) of 0.0273 mmHg · ml⁻¹ · min (−16%), resulting in an increased renal plasma flow of 64.9 ml · min⁻¹ (14%). The glomerular filtration rate was increased by 7.75 ml · min⁻¹ (8%), and the filtration fraction (FF) was not significantly changed. There was no apparent relationship between the changes observed in systemic and renal haemodynamic variables and plasma concentrations of candesartan. Plasma renin activity increased over the study period, but in general the patients had low PRA. Changes in plasma concentrations of angiotensin II were inconsistent between patients. Conclusion: A single oral tablet of candesartan cilexetil, 16 mg, induced systemic and renal arterial vasodilatation and blood pressure reduction, without compromising renal perfusion or filtration or affecting cardiac performance. Plasma renin activity which was low in general, increased over the study period, but changes in plasma concentrations of angiotensin II were inconsistent. Received: 7 May 1997 / Accepted in revised form: 20 April 1998     

The influence of hepatic impairment on the pharmacokinetics of the dipeptidyl peptidase IV (DPP-4) inhibitor vildagliptin

Objective Vildagliptin is a potent and selective dipeptidyl peptidase-IV (DPP-4) inhibitor that improves glycemic control in patients with type 2 diabetes mellitus by increasing α- and β-cell responsiveness to glucose. This study investigated the pharmacokinetics of vildagliptin in patients with hepatic impairment compared with healthy subjects. Methods This was an open-label, parallel-group study in patients with mild (n = 6), moderate (n = 6) or severe (n = 4) hepatic impairment and healthy subjects (n = 6). All subjects received a single 100-mg oral dose of vildagliptin, and plasma concentrations of vildagliptin and its main pharmacologically inactive metabolite LAY151 were measured up to 36 h post-dose. Results Exposure to vildagliptin (AUC_0–∞ and C_max) decreased non-significantly by 20 and 30%, respectively, in patients with mild hepatic impairment [geometric mean ratio (90% CI): AUC_0–∞, 0.80 (0.60, 1.06), p = 0.192; C_max, 0.70 (0.46, 1.05), p = 0.149]. Exposure to vildagliptin was also decreased non-significantly in patients with moderate hepatic impairment [−8% for AUC_0–∞, geometric mean ratio (90% CI): 0.92 (0.69, 1.23), p = 0.630; −23% for C_max, geometric mean ratio (90% CI): 0.77 (0.51, 1.17), p = 0.293]. In patients with severe hepatic impairment, C_max was 6% lower than that in healthy subjects [geometric mean ratio (90% CI): 0.94 (0.59, 1.49), p = 0.285], whereas AUC_0–∞ was increased by 22% [geometric mean ratio (90% CI): 1.22 (0.89, 1.68), p = 0.816). Across the hepatic impairment groups, LAY151 AUC_0–∞ and C_max were increased by 29–84% and 24–63%, respectively, compared with healthy subjects. The single 100-mg oral dose of vildagliptin was well tolerated by patients with hepatic impairment. Conclusions There was no significant difference in exposure to vildagliptin in patients with mild, moderate or severe hepatic impairment; therefore, no dose adjustment of vildagliptin is necessary in patients with hepatic impairment.     

Body condition and mercury concentration in apparently healthy goosander (<Emphasis Type="Italic">Mergus merganser</Emphasis>) wintering in the Odra estuary,Poland

Goosanders (Mergus merganser, ad, adult n = 42: M, males 33 and F, females 9; im, immature n = 17: M 8, F 9) were collected in 2005 at wintering site in the River Odra estuary (Poland). The body size (BM, body mass; BL, body length; KL, keel length), weights of organs (LM, liver; KM, kidneys; EM, encephalon), and two condition-related indices (BM/BL and BM/KL) were determined. Based on BM/BL and BM/KL indices, the birds were divided into 3 condition groups: A (very good), B (good), and C (moderate). Total mercury (Hg) concentrations (mg kg⁻¹ dry weight) were determined in liver, kidney, brain, breast muscle, and bone of 17 birds (ad, n = 8: 8 M, 1 F; im, n = 9: 6 M, 3 F). The highest Hg concentrations (in n = 17) were recorded in liver and kidney (14.7 and 9.9 mg kg⁻¹, respectively); the concentrations found in muscle and brain were lower (2.3 and 1.3 mg kg⁻¹, respectively), the lowest concentrations being typical of bone (0.08 mg kg⁻¹). Mercury concentrations in the same organs of immature and adult goosanders, as well as males and females, did not differ significantly. On the other hand, distinct differences in Hg concentrations in the organs studied (except for the liver) were observed between individuals assigned to Group A (n = 11) and C (n = 6). Mercury levels were higher in the birds characterised by very good condition, which was most probably related to those birds being more efficient hunters, consuming higher amounts of Hg-containing fish. Significant and negative correlations between the muscle Hg concentration and the two condition-related indices (r > –0.70) were recorded in Group A only: the higher the concentration, the lower the BM/LM and BM/KL values.     

Iloprost for prevention of contrast-mediated nephropathy in high-risk patients undergoing a coronary procedure. Results of a randomized pilot study

Objective The prevention of contrast-mediated nephropathy (CMN), which accounts for considerable morbidity and mortality, remains a vexing problem. Contrast induced renal vasoconstriction is believed to play a pivotal role in the CMN mechanism. The aim of this pilot study was to examine the safety and efficacy of two doses of the prostacyclin analogue iloprost in preventing CMN in high-risk patients undergoing a coronary procedure.Methods Forty-five patients undergoing coronary angiography and/or intervention who had a serum creatinine concentration ≥1.4 mg/dL were randomized to receive iloprost at 1 or 2 ng/kg/min or placebo, beginning 30–90 minutes before and terminating 4 hours after the procedure. CMN was defined by an absolute increase of serum creatinine ≥0.5 mg/dL or a relative increase of ≥25% measured 2 to 5 days after the procedure. Study drug infusion was discontinued in 2 patients in the low-dose iloprost group due to flush/nausea and in 5 patients in the high-dose group due to severe hypotension.Results The mean creatinine concentration change in the placebo group (0.02 mg/dL) was unfavorable compared to that in the low-dose iloprost group (−0.11 mg/dL; p=0.08) and high-dose iloprost group (−0.23 mg/dL; p=0.048). The difference between the absolute changes in creatinine clearance was favorable compared to placebo for both the low (mean difference 6.1 mL/min, 95%CI −0.5 to 12.8 mL/min, p=0.07) and the high-dose iloprost group (11.8 mL/min, 95%CI 4.7 to 18.8 mL/min, p=0.002). Three cases of CMN were recorded; all in the placebo group (p=0.032).Conclusions The results of this pilot study suggest that prophylactic administration of iloprost may effectively prevent CMN, but higher dosages are connected with substantial tolerability issues.