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Numerous experimental and numerical studies on prismatic plate girders subjected to shear can be found in the literature. However, the real structures are frequently designed as non-uniform structural elements. The main objective of the research is the development of a new proposal for the calculation of the ultimate shear resistance of tapered steel plate girders taking into account the specific behaviour of such members. A new mechanical model is presented in the paper and it is used to show the differences between the behaviour of uniform and tapered web panels subjected to shear. EN 1993-1-5 design specifications for the determination of the shear strength for rectangular plates are improved in order to assess the shear strength of tapered elements. Numerical studies carried out on tapered steel plate girders subjected to shear lead to confirm the suitability of the mechanical model and the proposed design expression. En la literatura pueden encontrarse numerosos estudios experimentales y numéricos sobre vigas armadas de acero de canto constante sometidas a cortante. Sin embargo, muchas estructuras de acero se proyectan, frecuentemente, con elementos de canto variable. El objetivo del artículo es ofrecer una formulación para el cálculo de la resistencia última a cortante de paneles de alma de canto variable, basada en un nuevo modelo mecánico, que es utilizado para mostrar las diferencias de comportamiento entre paneles de alma de canto constante y variable, sometidos a cortante. Las reglas de cálculo de EN 1993-1-5 para determinar la resistencia a cortante de paneles de alma de canto constante se mejoran para poder evaluar la resistencia a cortante de paneles de canto variable. Los numerosos estudios numéricos llevados a cabo sobre vigas armadas de acero de canto variable confirman la idoneidad del modelo mecánico y de la nueva expresión propuesta para el cálculo.

This paper presents a new proposal for estimation of critical load for non-prismatic, thin plates simply supported on four edges subjected to shear. The research included wide parametric studies using more than 500 samples. The parameters taken into account were the web thickness, the panel aspect ratio and the inclination angle. The influence of each was analysed separately and then some simplifications were made in order to find coherent expressions to describe the behaviour of the studied panels. The numerical results were then used to validate the solution proposed in EN 1993-1-5. As a result of this comparison, it is concluded that new design formulations are needed for tapered plates with a considerable slope. Based on previous research by the authors concerning four various geometrical typologies of tapered panels, four expressions for the shear buckling coefficient kφ are proposed.

This paper presents an experimental and numerical research on tapered steel plate girders subjected to shear. Experimental tests included four small-scale tapered steel plate girders. Research was focused on both, critical shear load and ultimate shear resistance. Moreover, the post-buckling behaviour of tapered plates was studied. Further, some parametric studies with various geometries of tapered panels were done in order to find the most favourable design situations. The analysed parameters were: the panel aspect ratio, the inclined flange angle, the web and the flange slenderness. Numerical simulations allowed distinguishing four different typologies of tapered plate girders which should be considered separately in design because of their different behaviour. Verification of the simplified procedure for tapered plates proposed in Eurocode EN 1993-1-5 allowed concluding that for some cases the estimation of the ultimate shear resistance is situated on the unsafe side and need to be revised.

Mechanisms by which efavirenz diminishes methadone plasma concentrations are unknown. This investigation determined efavirenz influence on clinical methadone disposition and miosis, intravenous and oral alfentanil clearance (hepatic and intestinal cytochrome P450 3A4/5 (CYP3A4/5) activity), fexofenadine disposition (intestinal transporters activity), and efavirenz clearance and 8-hydroxylation (CYP2B6 activity), and human hepatocyte effects. Efavirenz induced systemic and oral alfentanil clearances two- to fivefold and induced efavirenz 8-hydroxylation. Efavirenz stereoselectively decreased methadone plasma concentrations 50-70%. Methadone systemic and oral clearances, hepatic clearance and extraction ratio, N-demethylation, and metabolite formation clearance were stereoselectively increased two- to threefold. Bioavailability decreased. Efavirenz shifted methadone concentration-miosis curves leftward and upward. Efavirenz induced hepatocyte CYP2B6 and CYP3A4 expression, activity, and methadone N-demethylation. Results show that efavirenz coinduced hepatic CYP2B6 and CYP3A4/5, coinduced hepatic and intestinal CYP3A4/5, and coinduced gastrointestinal CYP3A4/5 and efflux transporters. Methadone disposition was most consistent with efavirenz induction of hepatic CYP2B6-mediated methadone N-demethylation. Efavirenz may alter methadone pharmacodynamics.

Apolipoprotein B (apoB) metabolism was investi- gated in 20 men with plasma triglyceride 0.66-2.40 mmol/l and plasma cholesterol 3.95-6.95 mmol/l. Kinetics of VLDL 1 (S f 60-400), VLDL 2 (S f 20-60), IDL (S f 12-20), and LDL (S f 0-12) apoB were analyzed using a trideuterated leucine tracer and a multicompartmental model which al- lowed input into each fraction. VLDL 1 apoB production varied widely (from 5.4 to 26.6 mg/kg/d) as did VLDL 2 apoB production (from 0.18 to 8.4 mg/kg/d) but the two were not correlated. IDL plus LDL apoB direct production accounted for up to half of total apoB production and was inversely related to plasma triglyceride ( r 5 2 0.54, P 5 0.009). Percent of direct apoB production into the IDL/ LDL density range ( r 5 0.50, P , 0.02) was positively re- lated to the LDL apoB fractional catabolic rate (FCR). Plasma triglyceride in these subjects was determined princi- pally by VLDL 1 and VLDL 2 apoB fractional transfer rates (FTR), i.e., lipolysis. IDL apoB concentration was regulated mainly by the IDL to LDL FTR ( r 5 2 0.71, P , 0.0001). LDL apoB concentration correlated with VLDL 2 apoB pro- duction ( r 5 0.48, P 5 0.018) and the LDL FCR ( r 5 2 0.77, P , 0.001) but not with VLDL 1 , IDL, or LDL apoB produc- tion. Subjects with predominantly small, dense LDL (pat- tern B) had lower VLDL 1 and VLDL 2 apoB FTRs, higher VLDL 2 apoB production, and a lower LDL apoB FCR than those with large LDL (pattern A). Thus, the metabolic conditions that favored appearance of small, dense LDL were diminished lipolysis of VLDL, resulting in a raised plasma triglyceride above the putative threshold of 1.5 mmol/l, and a prolonged residence time for LDL. This lat- ter condition presumably permitted sufficient time for the processes of lipid exchange and lipolysis to generate small LDL particles. —Packard, C. J., T. Demant, J. P. Stewart, D. Bedford, M. J. Caslake, G. Schwertfeger, A. Bedynek, J. Shepherd, and D. Seidel. Apolipoprotein B metabolism and the distribution of VLDL and LDL subfractions. J. Lipid Res. 2000. 41: 305-317.

Methadone plasma concentrations are decreased by nelfinavir. Methadone clearance and the drug interactions have been attributed to CYP3A4, but actual mechanisms of methadone clearance and the nelfinavir interaction are unknown. We assessed nelfinavir effects on methadone pharmacokinetics and pharmacodynamics, intestinal and hepatic CYP3A4/5 activity, and intestinal P-glycoprotein transport activity. CYP3A4/5 and transporters were assessed using alfentanil and fexofenadine, respectively.Twelve healthy HIV-negative volunteers underwent a sequential crossover. On three consecutive days they received oral alfentanil plus fexofenadine, intravenous alfentanil, and intravenous plus oral methadone. This was repeated after nelfinavir. Plasma and urine analytes were measured by mass spectrometry. Opioid effects were measured by pupil diameter change (miosis).Nelfinavir decreased intravenous and oral methadone plasma concentrations 40-50%. Systemic clearance, hepatic clearance, and hepatic extraction all increased 1.6- and 2-fold, respectively, for R- and S-methadone; apparent oral clearance increased 1.7- and 1.9-fold. Nelfinavir stereoselectively increased (SR) methadone metabolism and metabolite formation clearance, and methadone renal clearance. Methadone bioavailability and P-glycoprotein activity were minimally affected. Nelfinavir decreased alfentanil systemic and apparent oral clearances 50 and 76%, respectively. Nelfinavir appeared to shift the methadone plasma concentration-effect (miosis) curve leftward and upward.Nelfinavir induced methadone clearance by increasing renal clearance, and more so by stereoselectively increasing hepatic metabolism, extraction and clearance. Induction occurred despite 50% inhibition of hepatic CYP3A4/5 activity and more than 75% inhibition of first-pass CYP3A4/5 activity, suggesting little or no role for CYP3A in clinical methadone disposition. Nelfinavir may alter methadone pharmacodynamics, increasing clinical effects.

Background Methadone clearance is highly variable, and drug interactions are problematic. Both have been attributed to CYP3A, but actual mechanisms are unknown. Drug interactions can provide such mechanistic information. Ritonavir/indinavir, one of the earliest protease inhibitor combinations, may inhibit CYP3A. We assessed ritonavir/indinavir effects on methadone pharmacokinetics and pharmacodynamics, intestinal and hepatic CYP3A activity, and intestinal transporters (P-glycoprotein) activity. CYP3A and transporters were assessed with alfentanil and fexofenadine, respectively. Methods Twelve healthy human immunodeficiency virus-negative volunteers underwent a sequential three-part crossover. On three consecutive days, they received oral alfentanil/fexofenadine, intravenous alfentanil, and intravenous plus oral (deuterium-labeled) methadone, repeated after acute (3 days) and steady-state (2 weeks) ritonavir/indinavir. Plasma and urine analytes were measured by mass spectrometry. Opioid effects were assessed by miosis. Results Alfentanil apparent oral clearance was inhibited more than 97% by both acute and steady-state ritonavir/indinavir, and systemic clearance was inhibited more than 90% due to diminished hepatic and intestinal extraction. Ritonavir/indinavir increased fexofenadine area under the plasma concentration-time curve four- to five-fold, suggesting significant inhibition of gastrointestinal P-glycoprotein. Ritonavir/indinavir slightly increased methadone N-demethylation, but it had no significant effects on methadone plasma concentrations or on systemic or apparent oral clearance, renal clearance, hepatic extraction or clearance, or bioavailability. Ritonavir/indinavir had no significant effects on methadone plasma concentration-effect relationships. Conclusions Inhibition of both hepatic and intestinal CYP3A activity is responsible for ritonavir/indinavir drug interactions. Methadone disposition was unchanged, despite profound inhibition of CYP3A activity, suggesting little or no role for CYP3A in clinical methadone metabolism and clearance. Methadone bioavailability was unchanged, despite inhibition of gastrointestinal P-glycoprotein activity, suggesting that this transporter does not limit methadone intestinal absorption.

OBJECTIVES To assess the cardiac auscultatory skills of health care professionals before and after an actual (not simulated) patient-centered cardiac auscultation conference and to determine the effectiveness of this clinical teaching method on improving diagnostic proficiency. SUBJECTS AND METHODS Seventy-eight participants at a conference on cardiac auscultation completed preconference and postconference examinations on their ability to diagnose a wide variety of heart sounds and murmurs. Among those tested, 46 (59%) were physicians: 17 (22%) were cardiologists, 19 (24%) were medical interns or residents, 7 (9%) were cardiology fellows, 2 (3%) were general practitioners, and 1 (1%) was a pediatrician. Thirty-two (41%) of this group of respondents were nonphysicians: 14 (18%) were nurse practitioners, 9 (12%) were nurses, 6 (8%) were physician assistants, 2 (3%) were medical students, and 1 (1%) was a nonmedical professional. All participants were tested on 14 clinically important cardiac auscultatory events directly recorded from actual (not simulated) patients and transmitted via wireless infrared stethophones. The auscultatory events tested were wide physiologic splitting of S 2 in right bundle branch block, fixed S 2 splitting and systolic murmur in atrial septal defect, midsystolic click and late systolic murmur of mitral valve prolapse, S 4 gallop, S 3 gallop, opening snap of mitral stenosis, innocent systolic murmur, systolic murmur of mitral regurgitation, systolic murmur of tricuspid regurgitation, systolic murmur of hypertrophic obstructive cardiomyopathy, continuous murmur of patent ductus arteriosus, pericardial friction rub, prosthetic valve sounds, and alternation of heart sounds, heart murmurs, and the S 3 gallop in congestive heart failure. RESULTS On the basis of the analysis of the 78 participants who completed preconference and postconference evaluations of the 14 selected cardiac auscultatory events, a preconference identification score of 26.3% and a postconference score of 44.7% were observed. This represents a statistically significant overall improvement in diagnostic proficiency ( P >.001). CONCLUSIONS Cardiac auscultatory skills among today's health care professionals are extremely poor, regardless of the level and/or type of training of the professional. An actual (not simulated) patient-centered teaching conference is an effective clinical method of improving cardiac auscultatory skills and diagnostic proficiency of health care professionals.

Tapered plate girders often form part of large-scale structures such as long continuous bridges or industrial buildings where due to considerable loads the higher resistance is required. There are several important reasons choosing non-prismatic girders. First of all, their tapered shape with gradually changing inertia allows for more effective stress distribution inside the web-panel and contributes to steel reduction and thereby to decrease the overall cost of the structure. Trapezoidal shape of such panels also may be desirable in structures with non-standard shape for example where pre-formed service openings are needed. Although rectangular plate girders were studied in many occasions in last few decades, the latest investigations have shown that the structural behaviour of tapered panels is more complex and different distribution of the internal forces takes place. Due to a lack of design rules for assessment of ultimate shear resistance of tapered plate structures with considerable angle of a slope (> 10 degrees), this research is focused on searching for a solution of the problem. The main body of the thesis is composed of four independent publications where each of them summarizes different phase of the research. The most relevant issues related to tapered panels discussed in the papers were: the critical shear load in tapered simple-supported plates, the influence of geometrical and structural imperfections, the optimal position of the longitudinal stiffener, the Resal effect, and finally the ultimate shear resistance of stiffened and unstiffened tapered plate girders. Nevertheless, the main objective of this work was the development of a reliable design tool to assess of the ultimate shear resistance of non-prismatic plate girders. The methodology applied in the research consists of the following stages: study of the bibliography and initial theoretical research, development of a numerical model, execution of two experimental programs, development of a wide parametric study, analysis of the experimental and numerical results, comparing them with those obtained according to EN 1993-1-5, and finally - development of a new design proposal for the assessment of the ultimate shear resistance for tapered steel plate girders. The PhD research was supported by two experimental programs focused on the structural behaviour of tapered plate girders. In the first program, transversally stiffened members subjected to shear and shear-bending interaction were tested. The second experimental program was focused on longitudinally stiffened tapered plate girders under shear. Results obtained from the experimental tests were used for the verification of the numerical model. Plate girders reveal tendency to possess a significant post-buckling resistance. This phenomenon can be observed as a diagonal tension field developing within the web-panel. In both experimental tests and numerical analyses, this characteristic behaviour was observed. Using verified the numerical model, a wide parametric study for a large number of tapered plate girders was carried out. All numerical results presented in this research were compared with those obtained according to EN 1993-1-5 and discussed. Finally, a new design method for the assessment of the ultimate shear resistance of tapered steel plate girders was presented. The new design proposal is based on the currently valid - Rotated Stress Field Method. The procedure maintains its simplicity and improves considerably results obtained for non-prismatic panels. This new reliable design tool, valid for any geometry and any typology of tapered steel plate girders, provides a solution of the main objective defined in this research

Nach erfolgreicher Erstinfektion des Wirtes besitzt das Herpes-Simplex-Virus die Fähigkeit sich der immunologischen Kontrolle zu entziehen, und es kommt zu einer „latenten Persistenz“ die lebenslang dauert. Durch verschiedene Provokationsfaktoren kann es zu einer endogenen Reaktivierung der in den Ganglien latent vorhandenen Herpes-Simplex-Viren kommen. Die Viren wandern auf neuralem Weg vom Ganglion zentrifugal in die Haut oder die Schleimhäute wo in Epidermis- bzw. Epithelzellen wieder eine Replikation stattfindet Eine HSV bedingte Infektion der Sakralganglien ruft das Klinische Bild eines Herpes genitalis hervor. Dabei kommt es in unterschiedlicher Häufigkeit zum rezidivierenden Befall der Haut und der Schleimhäute an und um die Geschlechtsorgane herum - mit den typischen Effloreszenzen: gruppierte Bläschen auf gerötetem Grund. Bei immunkompetenten Patienten heilt der Herpes genitalis für gewöhnlich komplikationslos binnen 7-10 Tage narbenfrei ab. Bei immunsupprimierten Patienten können disseminierte und fulminante Krankheitsverläufe mit lebensbedrohlichen Erkrankungen der innerer Organe und des ZNS auftreten. Durch mangelnde Aufklärung steigt das Risiko einer Übertragung. Die Zahl der Infizierten ist höher als zunächst vermutet werden kann. Der Leidensdruck der Betroffenen ist oft groß. Die wiederkehrenden Infekte mindern die Lebensqualität. Das effektivste Mittel mit dem man gegen die große Durchseuchung mit HSV kämpfen könnte, wäre eine Vakzinierung. Doch bis lang gibt es keinen Impfstoff, der einen sicheren Schutz vor einer HSV Infektion ermöglicht. So bleibt die Behandlung von HSV Infektion symptomorientiert. Es besteht nach wie vor die Notwendigkeit, nach einem wirksamen topischen Medikament zu forschen. Cyclodextrine sind cycklische Kohlenwasserstoffe und haben die besondere Fähigkeit Komplexe zu bilden mit in Wasser gelösten Molekülen, wie z.B. dem Cholesterin. Cholesterin ist einer der Bausteine von Lipid Rafts, welche wiederum einen wichtigen Bestandteil von Plasmamebranen und Virushüllen bilden. Diverse Studien haben belegt, dass eine Cholesterinextraktion in vielen Fällen zu einem Riß der Lipid Rafts oder zu einer herabgesetzten Infektiosität eines Virus führte. Der Einfluß von Cyclodextrinen auf die Heilung von genitalen HSV Infektionen ist bis jetzt nicht untersucht worden. Diese Arbeit legt die Ergebnisse über die klinische Erprobung eines Cyclodextrin Gels mit dem Wirkstoff 2-Hydroxypropyl ß-Cyclodextrin (2-HP-BCD) an Patienten mit einem rezidivierenden Herpes genitalis in der Prodromalphase dar. Diese multizentrische und doppelblinde Studie untersuchte dabei das Cyclodextrin Gel im Vergleich zu einem Placebo Gel. Insgesamt nahmen 218 Patienten an dieser Studie teil. Das topisch applizierte Cyclodextrin Gel erwies sich effektiver als das Placebo und gut verträglich für die Behandlung der Läsion einer genitalen Herpes Simplex Infektion. Bezüglich der Wirksamkeit vom Cyclodextrin Gel zeigte sich eine kürzere Dauer bis zur Verkrustung mit einer schnelleren Heilung und weniger Rötung sowie eine etwas kürzere Schmerzepisode im Vergleich zum Placebo. Das Medikament kann als sicher und unbedenklich erachtet werden. Aber obwohl die Überlegenheit des Cyclodextrin Gel im Vergleich zum Placebo signifikant ist sind die Unterschiede in der Wirkung nicht sehr groß. Sie stimmen jedoch optimistisch, weitere Untersuchung bezüglich Dosisfindung und Konzentrationsstärke zu machen., After the initial infection of the host, the herpes-simplex-virus (HSV) has the capability of eluding the immunological control and it results in a life- long latent persistence. The latent existing herpes-simplex-virus in the ganglia can be reactivated through various provocation factors. The virus travels centrifugally through the neural system from ganglion to the mucosa or epidermis and is replicated in the epithelial layer. A HSV resulted infection of the sacral ganglia induces the clinical symptoms of herpes genitalis. This generates, in various frequency, a recurrent affection of the cutis and mucosa on and around the genitals with the typical efflorescence grouped vesicle on reddened skin. In the cases of immunocompetent patients, the herpes genitalis virus generaly heals without complications, within 7-10 days, scar-free. Immunocompromised patients, can suffer from disseminated and fulminant etiopathology. Lack of education leads to higher risk of transmission. The number of infected persons is higher than assumed. The suffering of the infected is often high and reduces their quality of life. A vaccination would be the most effective method to avoid the large prevalence. Presently there is no vaccination available and the method of treatment is limited to its symptoms. There is still the need for an effective topically applied anti- viral medication. Cyclodextrins are cyclic hydrocarbons and have the ability to bind water solvent molecules into complexes, for example Cholesterol. Cholesterol is one of the components of lipid rafts, which are an important part of the plasma membrane of the viral coat. Various studies proved that an extraction of cholesterol leads to a tear in lipid rafts and decreases the risk of infection. The impact of cholesterol extraction with cyclodextrins to advance the healing of genital HSV has not been investigated. This work presents the results of the clinical trial with 2-Hydroxypropyl Beta- Cyclodextrin (2-HP-BCD) on patients with a recurring herpes genitalis in the prodromal stage. This multi-centric and double-blind trial, investigated the 2 -HP-BCD in comparison to a placebo gel. In total 218 patients took part in this study. The topically applied 2-HP-BCD proved to be more effective than the placebo and well tolerated. In comparison to the placebo, the 2-HP-BCD showed a shorter period to incrustation with a quicker healing and less reddening, as well as, a somewhat shorter period of pain. The medication proved to be safe and uncritical. Although the 2-HP-BCD showed a significant advantage over the placebo, the results of the differences were not immense. The results were however, optimistic enough to make further studies regarding dosage and concentration.

Lipoprotein(a) is a risk factor for cardiovascular disease composed of an apolipoprotein B-containing lipoprotein to which a second protein, apolipoprotein(a), is attached. We investigated in seven subjects with Lp(a) levels of 39--85 mg/dl the metabolism of four apo B-containing lipoproteins (VLDL(1), VLDL(2), IDL and LDL) together with that of apo B and apo(a) isolated from Lp(a). Rates of secretion, catabolism and where appropriate, transfer were determined by intravenous administration of d(3)-leucine, mass spectrometry for measurements of leucine tracer/tracee ratios and kinetic data analysis using multicompartmental metabolic modeling. Apo B in Lp(a) was secreted at a rate of 0.28 (0.17--0.40) mg/kg per day. It was found to originate from two sources -- 53% (43--67) were derived from preformed lipoproteins, i.e. IDL and LDL, the remainder was accounted for by apo B, directly secreted by the liver. The fractional catabolic rates (FCRs) of apo B and of apo(a) prepared from Lp(a) were determined as 0.27 (0.16--0.38) and 0.24 (0.12--0.40) pools per day, respectively, which is less than half of the FCR observed for LDL. Our in vivo data from humans support the view that Lp(a) assembly is an extracellular process and that its two protein components, apo(a) and apo B, are cleared from the circulation at identical rates.

Background: Dyslipidemia (predominantly hypertriglyceridemia) is frequently seen in patients receiving antiretroviral combination therapy (ART). However, the underlying mechanisms and long-term risks (e.g., cardiovascular events) are still unclear. Objectives/Methods: In 5 patients with ART-associated dyslipidemia, stable isotope labeled amino acid tracer (d3-Leu) kinetic analysis over 12 days was used to investigate the metabolism of apolipoprotein B-containing lipoproteins (very low density lipoproteins [VLDL] 1 , VLDL 2 , intermediate density lipoproteins [IDL] and low density lipoproteins [LDL]). Data were compared with those in 6 healthy normolipidemic controls. Results: The patients under ART showed significantly increased fasting triglycerides (359 vs. 77 mg/dl) and VLDL (54 vs. 15 mg/dl), compared with controls. They had significantly higher total cholesterol (213 vs. 157 mg/dl) and there was a nonsignificant trend toward higher LDL (136 vs. 93 mg/dl), and toward lower HDL (26 vs. 46 mg/dl). The ratio of large, buoyant LDL 1 over small, dense LDL 2 was markedly reduced in patients under ART (0.80 vs. 2.00). Total apo B synthesis was significantly increased (25.5 vs. 14.5 mg/kg/d) and shifted toward triglyceride rich VLDL I (18.5 vs. 8.7 mg/kg/d) in patients receiving ART. There was also a significantly reduced rate of apo B lipoprotein transfer from VLDLI to VLDL2 (3.7 vs. 20.7 pools/d). In addition, all patients revealed insulin resistance. Conclusions: These data indicate that increased triglycerides in HIV-infected patients with ART are primary due to reduced rates of VLDL transfer into denser lipoproteins implying a lower rate of lipoprotein lipase-mediated delipidation. In addition, total apo B synthesis was increased and shifted toward triglyceride-rich VLDLI. Overall, this lipoprotein profile in patients with ART-associated dyslipidemia implies an increased risk for cardiovascular events.

A simultaneous study of the metabolism of apolipoprotein B and albumin in nephrotic patients. Background The nephrotic syndrome is characterized by proteinuria, hypoalbuminemia and hyperlipidemia. Despite intensive research it is not clear at present what the causal links are between these pathological findings. Methods Stable isotope labeled amino acid tracer kinetic analysis was used to simultaneously investigate the metabolism of four apolipoprotein B-containing lipoproteins (VLDL 1 , VLDL 2 , IDL and LDL) and albumin in seven patients with nephrotic syndrome and marked hypercholesterolemia, in two additional nephrotic patients with concomitant renal failure and mixed hyperlipidemia, and in a matched group of normolipidemic controls. Results Increased concentrations of VLDL 2 , IDL and LDL were due to ( a ) impaired VLDL 2 and IDL delipidation, ( b ) reduced LDL catabolism, and ( c ) a trend towards an increased rate of total apolipoprotein B production. The rate of fractional albumin elimination was three times higher in patients than in controls and the rate of albumin synthesis was increased by 45%. No correlations were detectable between rates of apolipoprotein B production and the rate of albumin synthesis. Conclusions The results of this study suggest that hyperlipidemia in nephrotic syndrome is predominantly the result of delayed lipoprotein delipidation and catabolism. There is no evidence that it is driven by a general increase of the rate of hepatic protein synthesis.

Background We analysed incidence, predictors, histological features and specific treatment options of anti-tumour necrosis factor α (TNF-α) antibody-induced psoriasiform skin lesions in patients with inflammatory bowel diseases (IBD). Design Patients with IBD were prospectively screened for anti-TNF-induced psoriasiform skin lesions. Patients were genotyped for IL23R and IL12B variants. Skin lesions were examined for infiltrating Th1 and Th17 cells. Patients with severe lesions were treated with the anti-interleukin (IL)-12/IL-23 p40 antibody ustekinumab. Results Among 434 anti-TNF-treated patients with IBD, 21 (4.8%) developed psoriasiform skin lesions. Multiple logistic regression revealed smoking (p=0.007; OR 4.24, 95% CI 1.55 to 13.60) and an increased body mass index (p=0.029; OR 1.12, 95% CI 1.01 to 1.24) as main predictors for these lesions. Nine patients with Crohn9s disease and with severe psoriasiform lesions and/or anti-TNF antibody-induced alopecia were successfully treated with the anti-p40-IL-12/IL-23 antibody ustekinumab (response rate 100%). Skin lesions were histologically characterised by infiltrates of IL-17A/IL-22-secreting T helper 17 (Th17) cells and interferon (IFN)-γ-secreting Th1 cells and IFN-α-expressing cells. IL-17A expression was significantly stronger in patients requiring ustekinumab than in patients responding to topical therapy (p=0.001). IL23R genotyping suggests disease-modifying effects of rs11209026 (p.Arg381Gln) and rs7530511 (p.Leu310Pro) in patients requiring ustekinumab. Conclusions New onset psoriasiform skin lesions develop in nearly 5% of anti-TNF-treated patients with IBD. We identified smoking as a main risk factor for developing these lesions. Anti-TNF-induced psoriasiform skin lesions are characterised by Th17 and Th1 cell infiltrates. The number of IL-17A-expressing T cells correlates with the severity of skin lesions. Anti-IL-12/IL-23 antibody therapy is a highly effective therapy for these lesions.

Background Methadone disposition and pharmacodynamics are highly susceptible to interactions with antiretroviral drugs. Methadone clearance and drug interactions have been attributed to cytochrome P4503A4 (CYP3A4), but actual mechanisms are unknown. Drug interactions can be clinically and mechanistically informative. This investigation assessed effects of the protease inhibitor indinavir on methadone pharmacokinetics and pharmacodynamics, hepatic and intestinal CYP3A4/5 activity (using alfentanil), and intestinal transporter activity (using fexofenadine). Methods Twelve healthy volunteers underwent a sequential crossover. On three consecutive days they received oral alfentanil plus fexofenadine, intravenous alfentanil, and intravenous plus oral (deuterium-labeled) methadone. This was repeated after 2 weeks of indinavir. Plasma and urine analytes were measured by mass spectrometry. Opioid effects were measured by miosis. Results Indinavir significantly inhibited hepatic and first-pass CYP3A activity. Intravenous alfentanil systemic clearance and hepatic extraction were reduced to 40-50% of control, apparent oral clearance to 30% of control, and intestinal extraction decreased by half, indicating 50% and 70% inhibition of hepatic and first-pass CYP3A activity. Indinavir increased fexofenadine area under the plasma concentration-time curve 3-fold, suggesting significant P-glycoprotein inhibition. Indinavir had no significant effects on methadone plasma concentrations, methadone N-demethylation, systemic or apparent oral clearance, renal clearance, hepatic extraction or clearance, or bioavailability. Methadone plasma concentration-effect relationships were unaffected by indinavir. Conclusions Despite significant inhibition of hepatic and intestinal CYP3A activity, indinavir had no effect on methadone N-demethylation and clearance, suggesting little or no role for CYP3A in clinical disposition of single-dose methadone. Inhibition of gastrointestinal transporter activity had no influence of methadone bioavailability.

Methadone clearance is highly variable, and drug interactions are problematic. Both have been attributed to CYP3A, but actual mechanisms are unknown. Drug interactions can provide such mechanistic information. Ritonavir/indinavir, one of the earliest protease inhibitor combinations, may inhibit CYP3A. We assessed ritonavir/indinavir effects on methadone pharmacokinetics and pharmacodynamics, intestinal and hepatic CYP3A activity, and intestinal transporters (P-glycoprotein) activity. CYP3A and transporters were assessed with alfentanil and fexofenadine, respectively.Twelve healthy human immunodeficiency virus-negative volunteers underwent a sequential three-part crossover. On three consecutive days, they received oral alfentanil/fexofenadine, intravenous alfentanil, and intravenous plus oral (deuterium-labeled) methadone, repeated after acute (3 days) and steady-state (2 weeks) ritonavir/indinavir. Plasma and urine analytes were measured by mass spectrometry. Opioid effects were assessed by miosis.Alfentanil apparent oral clearance was inhibited more than 97% by both acute and steady-state ritonavir/indinavir, and systemic clearance was inhibited more than 90% due to diminished hepatic and intestinal extraction. Ritonavir/indinavir increased fexofenadine area under the plasma concentration-time curve four- to five-fold, suggesting significant inhibition of gastrointestinal P-glycoprotein. Ritonavir/indinavir slightly increased methadone N-demethylation, but it had no significant effects on methadone plasma concentrations or on systemic or apparent oral clearance, renal clearance, hepatic extraction or clearance, or bioavailability. Ritonavir/indinavir had no significant effects on methadone plasma concentration-effect relationships.Inhibition of both hepatic and intestinal CYP3A activity is responsible for ritonavir/indinavir drug interactions. Methadone disposition was unchanged, despite profound inhibition of CYP3A activity, suggesting little or no role for CYP3A in clinical methadone metabolism and clearance. Methadone bioavailability was unchanged, despite inhibition of gastrointestinal P-glycoprotein activity, suggesting that this transporter does not limit methadone intestinal absorption.

Ritonavir diminishes methadone plasma concentrations, an effect attributed to CYP3A induction, but the actual mechanisms are unknown. We determined short-term (2-day) and steady-state (2-week) ritonavir effects on intestinal and hepatic CYP3A4/5 (probed with intravenous (IV) and oral alfentanil (ALF) and with miosis) and P-glycoprotein (P-gp) (fexofenadine), and on methadone pharmacokinetics and pharmacodynamics in healthy volunteers. Acute ritonavir increased the area under the concentration-time curve (AUC)(0-infinity)/dose ratio (ritonavir/control) for oral ALF 25-fold. Steady-state ritonavir increased the AUC(0-Infinity)/dose ratio for IV and oral ALF 4- and 10-fold, respectively; reduced hepatic extraction (from 0.26 to 0.07) and intestinal extraction (from 0.51 to 0); and increased bioavailability (from 37 to 95%). Acute ritonavir inhibits first-pass CYP3A > 96%. Chronic ritonavir inhibits hepatic CYP3A (> 70%) and first-pass CYP3A (> 90%). Acute and steady-state ritonavir increased the fexofenadine AUC(0-infinity) 2.8- and 1.4-fold, respectively, suggesting P-gp inhibition. Steady-state compared with acute ritonavir caused mild apparent induction of P-gp and hepatic CYP3A, but net inhibition still predominated. Ritonavir inhibited both intestinal and hepatic CYP3A and drug transport. ALF miosis noninvasively determined CYP3A inhibition by ritonavir.

Ritonavir diminishes methadone plasma concentrations, an effect attributed to CYP3A induction, but the actual mechanisms are unknown. We determined ritonavir effects on stereoselective methadone pharmacokinetics and clinical effects (pupillary miosis) in healthy human immunodeficiency virus-negative volunteers. Subjects received intravenous plus oral (deuterium-labeled) racemic methadone after no ritonavir, short-term (3-day) ritonavir, and steady-state ritonavir. Acute and steady-state ritonavir, respectively, caused 1.5- and 2-fold induction of systemic and apparent oral R- and S-methadone clearances. Ritonavir increased renal clearance 40-50%, and stereoselectively (S > R) increased hepatic methadone N-demethylation 50-80%, extraction twofold, and clearance twofold. Bioavailability was unchanged despite significant inhibition of intestinal P-glycoprotein. Intestinal and hepatic CYP3A was inhibited > 70%. Ritonavir shifted methadone plasma concentration-miosis curves leftward and upward. Rapid ritonavir induction of methadone clearance results from increased renal clearance and induced hepatic metabolism. Induction of methadone metabolism occurred despite profound CYP3A inhibition, suggesting no role for CYP3A in clinical methadone metabolism and clearance. Ritonavir may alter methadone pharmacodynamics.

Kinetics of apo B and apo AI were assessed in 8 patients with mixed hyperlipidemia at baseline and after 8 weeks of atorvastatin 80 mg q.d. and micronised fenofibrate 200 mg q.d. in a cross-over study. Both increased hepatic production and decreased catabolism of VLDL accounted for elevated cholesterol and triglyceride concentrations at baseline. Atorvastatin significantly decreased triglyceride, total, VLDL and LDL cholesterol and apo B concentrations (-65%, -36%, -57%, -40% and -33%, respectively, Ptextless0.05). Kinetic analysis revealed that atorvastatin stimulated the catabolism of apo B containing lipoproteins, enhanced the delipidation of VLDL1 and decreased VLDL1 production. Fenofibrate lowered triglycerides and VLDL cholesterol (-57% and -64%, respectively, Ptextless0.05) due to enhanced delipidation of VLDL1 and VLDL2 and increased VLDL1 catabolism. Changes of HDL particle composition accounted for the increase of HDL cholesterol during atorvastatin and fenofibrate (18% and 23%, Ptextless0.01). Only fenofibrate increased apo AI concentrations through enhanced apo AI synthesis (45%, Ptextless0.05). We conclude that atorvastatin exerts additional beneficial effects on the metabolism of apo B containing lipoproteins unrelated to an increase in LDL receptor activity. Fenofibrate but not atorvastatin increases apo AI production and plasma turnover.