Lung function impairment in relation to cognition and vascular brain lesions: the Rotterdam Study

Journal of Neurology - To investigate the association of chronic obstructive pulmonary disease (COPD) and Preserved Ratio Impaired Spirometry (PRISm) with cognitive performance and presence of...     

Nailfold capillaroscopy in systemic lupus erythematosus: A systematic review and critical appraisal

Nailfold capillaroscopy is an easy, non-invasive technique to assess microvascular involvement in rheumatic diseases. Multiple studies describe capillaroscopic changes in systemic lupus erythematosus (SLE), including a wide range of non-specific findings. On behalf of the European League Against Rheumatism (EULAR) study group on microcirculation in rheumatic diseases, a systematic review was done to obtain all original research studies (in English) in which SLE patients had capillaroscopy. Forty such studies are identified. This article firstly provides a résumé of the results of these studies according to capillaroscopic parameters (density, dimensions, morphology, haemorrhages), semi-quantitative assessment and qualitative assessment of capillaroscopy in SLE patients. Secondly, the correlations between capillaroscopic parameters in SLE patients and clinical and laboratory parameters (including auto-immune parameters) are outlined. The following capillaroscopic parameters are found to be significantly more prevalent in SLE patients compared to healthy controls: tortuous capillaries, abnormal morphology and haemorrhages. Hairpin-shaped capillaries are significantly less prevalent than in healthy persons. The semi-quantitatively determined nailfold capillaroscopic score (NFC score) in SLE patients is also higher than in healthy controls. Several correlations between clinical and laboratory parameters and capillaroscopic parameters are identified in the review. Disease activity is correlated with NFC score in seven studies, with abnormal morphology (i.e. “meandering”) in one study and with haemorrhages in one study. Frequent attacks of Raynaud's phenomenon (RP) and gangrene are significantly correlated with dilated capillaries. In two studies a possible correlation between anti-SSA antibodies and lower density of capillaries is withheld. About other immune parameters conflicting results are found. In one study a significant negative correlation is found between 24-hour proteinuria and abnormal morphology (i.e. “meandering”). For the first time, an overview of the nailfold capillaroscopic changes that have been described in SLE and their correlations with clinical and laboratory findings is given. Further large-scale research on the identification of capillaroscopic changes in SLE and their correlations with standardised clinical and laboratory parameters, is ongoing at the EULAR study group on microcirculation in rheumatic diseases.     

Effect of Probenecid on the Enantioselective Pharmacokinetics of Oxprenolol and Its Glucuronides in the Rabbit

Purpose. To study the effect of probenecid on the stereoselective pharmacokinetics of oxprenolol and its glucuronides in the rabbit. Methods. An oral dose of 50 mg/kg racemic oxprenolol was given to nine rabbits twice, in random sequence with and without the concurrent administration of probenecid. Oxprenolol enantiomers were determined in plasma and urine by an enantioselective HPLC method. Oxprenolol glucuronides were measured in plasma and urine after enzymatic hydrolysis. Results. The disposition of the oxprenolol enantiomers in rabbits is stereoselective, mainly due to a difference in metabolism. Renal excretion is only a minor elimination route for unchanged oxprenolol, and the renal clearances of the enantiomers are similar. Pre-treatment with probenecid did not affect the plasma concentrations of the oxprenolol enantiomers, but there was a slight decrease in their urinary excretion. The plasma concentrations of the oxprenolol glucuronides are much higher than those of the parent enantiomers, and those of (S)-glucuronide are about twice those of its antipode. About 10% of the oxprenolol dose is excreted in the urine as glucuronides. The renal clearances of both glucuronides are similar, and markedly higher than the creatinine clearance. After probenecid, the mean glucuronide plasma levels were markedly higher, with for both glucuronides a more than twofold increase in mean AUC. Probenecid decreased the renal clearance of both glucuronides to about 30%. Moreover, it decreased slightly the formation clearance of (S)-glucuronide, while the formation clearance of (R)-glucuronide was not significantly influenced. Conclusions. Our results show that in the rabbit, both oxprenolol glucuronide diastereomers are actively secreted by the kidney, and that this process is inhibited by probenecid.     

The oxidative metabolism of metoprolol in human liver microsomes: inhibition by the selective serotonin reuptake inhibitors

Objective: Biotransformation of metoprolol to α-hydroxymetoprolol (HM) and O-demethylmetoprolol (ODM) is mediated by CYP2D6. The selective serotonin reuptake inhibitors (SSRIs) are known to inhibit CYP2D6. The aim was to study in vitro the potential inhibitory effect of SSRIs on metoprolol biotransformation. Methods: Using microsomes from two human livers, biotransformation of metoprolol to α-hydroxymetoprolol (HM) and O-demethylmetoprolol (ODM) as a function of the concentrations of the SSRIs and of some of their metabolites was studied. Results: The kinetics of the formation of both metabolites are best described by a biphasic enzyme model. The estimated values of V_max and k_M for the high affinity site are for the α-hydroxylation in human liver HL-1 32 pmol mg⁻¹ min⁻¹ and 75 μmol · l⁻¹ respectively, and in human liver HL-9 39 pmol mg⁻¹ · min⁻¹ and 70 μmol · l⁻¹ respectively; for the O-demethylation in HL-1 131 pmol mg⁻¹ min⁻¹ and 95 μmol · l⁻¹ respectively, and in HL-9 145 pmol mg⁻¹ min⁻¹ and 94 μmol · l⁻¹ respectively. Quinidine is for both pathways a potent inhibitor of the high-affinity site, with K_i values ranging from 0.03 to 0.18 μmol · l⁻¹. Fluoxetine, norfluoxetine and paroxetine are likewise potent inhibitors, with K_i values ranging from 0.30 to 2.1 μmol · l⁻¹ fluvoxamine, sertraline, desmethylsertraline, citalopram and desmethylcitalopram are less potent inhibitors, with K_i values above 10 μmol · l⁻¹. Conclusion: The rank order of the SSRIs for inhibition of metoprolol metabolism is comparable to that reported in the literature for other CYP2D6 substrates, with fluoxetine, norfluoxetine and paroxetine being the most potent. These findings need further investigation to determine their clinical relevance. Received: 24 October 1997 / Accepted: 17 January 1998     

Characterization of the cytochrome P450 isoenzymes involved in the in vitroN-dealkylation of haloperidol

Aims The present study was carried out to identify the cytochrome P450 isoenzyme(s) involved in the N-dealkylation of haloperidol (HAL). Methods In vitro studies were performed using human liver microsomes and c-DNA-expressed human P450 isoforms. N-dealkylation of HAL was assessed by measuring the formation of 4-(4-chlorophenyl)-4-hydroxypiperidine (CPHP). Results There was a tenfold variation in the extent of CPHP formation amongst the nine human liver microsomal preparations. The CPHP formation rates as a function of substrate concentration, measured in three livers, followed monophasic enzyme kinetics. K_m and V_max values ranged respectively from 50 to 78 μm and from 180 to 412 pmol mg⁻¹ min⁻¹. CPHP formation rates in the nine liver preparations were significantly correlated with dextromethorphan N-demethylase activity (a marker of CYP3A4 activity), but not with the activity of dextromethorphan O-demethylase (CYP2D6), phenacetin O-deethylase (CYP1A2) or tolbutamide hydroxylase (CYP2C9). Ketoconazole, an inhibitor of CYP3A4, inhibited competitively CPHP formation (K_i=0.1 μm ), whereas sulphaphenazole (CYP2C9), furafylline (CYP1A2) and quinidine (CYP2D6) gave only little inhibition (IC₅₀>100 μm ). CPHP formation was, moreover, enhanced by α-naphtoflavone, an effect common to CYP3A4 mediated reactions. Anti-CYP3A4 antibodies strongly inhibited CPHP formation, whereas no inhibition was observed in the presence of CYP2D6 antibodies. Among the recombinant human CYP isoforms tested, CYP3A4 exhibited the highest activity with respect to CPHP formation rate, with no detectable effect of other CYP isoforms (CYP1A2, CYP2D6 and CYP2C9). HAL inhibited dextromethorphan O-demethylase (CYP2D6) with IC₅₀ values between 2.7 and 8.5 μm, but not (IC₅₀>100 μm ) dextromethorphan N-demethylase (CYP3A4), phenacetin O-deethylase (CYP1A2) or tolbutamide hydroxylase (CYP2C9). Conclusions These results strongly suggest that the N-dealkylation of HAL in human liver microsomal preparations is mediated by CYP3A4.