Differential regulation of lipoprotein kinetics by atorvastatin and fenofibrate in subjects with the metabolic syndrome

The metabolic syndrome is characterized by insulin resistance and abnormal apolipoprotein AI (apoAI) and apolipoprotein B-100 (apoB) metabolism that may collectively accelerate atherosclerosis. The effects of atorvastatin (40 mg/day) and micronised fenofibrate (200 mg/day) on the kinetics of apoAI and apoB were investigated in a controlled cross-over trial of 11 dyslipidemic men with the metabolic syndrome. ApoAI and apoB kinetics were studied following intravenous d(3)-leucine administration using gas-chromatography mass spectrometry with data analyzed by compartmental modeling. Compared with placebo, atorvastatin significantly decreased (P < 0.001) plasma concentrations of cholesterol, triglyceride, LDL cholesterol, VLDL apoB, intermediate-density lipoprotein (IDL) apoB, and LDL apoB. Fenofibrate significantly decreased (P < 0.001) plasma triglyceride and VLDL apoB and elevated HDL(2) cholesterol (P < 0.001), HDL(3) cholesterol (P < 0.01), apoAI (P = 0.01), and apoAII (P < 0.001) concentrations, but it did not significantly alter LDL cholesterol. Atorvastatin significantly increased (P < 0.002) the fractional catabolic rate (FCR) of VLDL apoB, IDL apoB, and LDL apoB but did not affect the production of apoB in any lipoprotein fraction or in the turnover of apoAI. Fenofibrate significantly increased (P < 0.01) the FCR of VLDL, IDL, and LDL apoB but did not affect the production of VLDL apoB. Relative to placebo and atorvastatin, fenofibrate significantly increased the production (P < 0.001) and FCR (P = 0.016) of apoAI. Both agents significantly lowered plasma triglycerides and apoCIII concentrations, but only atorvastatin significantly lowered (P < 0.001) plasma cholesteryl ester transfer protein activity. Neither treatment altered insulin resistance. In conclusion, these differential effects of atorvastatin and fenofibrate on apoAI and apoB kinetics support the use of combination therapy for optimally regulating dyslipoproteinemia in the metabolic syndrome.     

Long-term survival in SCLC after treatment with paclitaxel,carboplatin and etoposide--a phase II study

PURPOSE: We evaluated the toxicity and feasibility of adding paclitaxel to a standard platinum/etoposide regimen in the first-line treatment of patients with small cell lung cancer (SCLC). PATIENTS AND METHODS: Eighty-nine patients with limited disease (LD) or extensive disease without distant metastases (ED I) were treated in this multi-centered phase II trial between April 1996 and June 1997. Paclitaxel administration (175 mg/m(2) by a 1 h intravenous infusion) was immediately followed by a 30 min infusion of carboplatin at an area under the concentration time curve (AUC) of 5 on day 1 and etoposide 50 mg orally twice daily (bid) was given on days 2-8. Courses were repeated every 21 days. Patients who had an objective response continued treatment for a maximum of 6 courses. RESULTS: Eighty-four patients were assessable for response. Overall response rate (RR) was 82.1% with 17.8% complete remissions and 64.3% partial remissions. Median survival for LD patients was 20.5 months with a 1 year survival rate of 71.4% and a 3 year survival rate of 21.4%. Median survival of ED I patients was 11 months with a 1 year survival rate of 31.3% and a 3 year survival rate of 3.1%. Overall median survival was 18.1 months with a 1 year survival rate of 56.8% and a 3 year survival rate of 14.8%. Median progression-free intervals were 12.3 months for patients with LD stage of the disease and 8 months with ED I stage. Grade 3/4 toxicity was primarily hematologic. Grade 3/4 leucopenia occurred in 16.0% of courses and febrile episodes were detected in 0.3% of courses. Non-hematologic toxicities were uncommon. Grade 3 GI-tract toxicities or peripheral neuropathy appeared in less than 1% of the courses. Toxicities were detected according to WHO toxicity criteria. CONCLUSION: Paclitaxel can be added at full dose (175 mg/m(2)) to a carboplatin/etoposide combination while maintaining a tolerable toxicity profile. Efficacy data, RR, progression-free interval and survival in both, extensive and limited stage patients compare favorably with other reported data. This new regimen will be further evaluated in comparison to standard regimens in a phase III trial.     

Pharmacokinetics and haemodynamics of candesartan cilexetil in hypertensive patients on regular haemodialysis

AIMS: The pharmacokinetic profile of candesartan cilexetil might be altered in patients with end-stage renal disease (ESRD). No data are available about the pharmacokinetics and haemodynamics of the angiotensin II receptor antagonist candesartan cilexetil in ESRD patients on regular haemodialysis (HD). METHODS: We performed a repeated dose study (8 mg candesartan cilexetil once daily) in eight male HD patients over a treatment period of 5 days with an additional observation period of 3 days. RESULTS: Pharmacokinetic analysis with nonlinear mixed effects modeling (NONMEM) over the whole treatment period revealed a dependency of the volume of distribution on body weight and of the metabolic clearance on age and body weight in the studied population. No significant drug elimination by HD was observed. The estimated metabolic and intercompartmental clearances were 83 ml min-1 (CV 39%) and 9.9 ml min-1, respectively. The unexplained random variability of the final two compartment model was 30%. In one patient with adult polycystic kidney disease oral clearance decreased during the observation period, attributable to a significant increase in bioavailability. Maximum observed changes in blood pressure were -50/-27+/-14/8 mmHg on day 5 with haemodialysis therapy as compared with changes in blood pressure of -14/-12+/-14/8 mmHg on day 1 without haemodialysis treatment. The observed maximum decrease in systolic blood pressure correlated with the amount of ultrafiltration during the HD session on day 5 (r=0.70, P<0.05). In two patients, one of whom was binephrectomized, severe hypotensive episodes were observed during this HD session. CONCLUSIONS: HD does not influence the elimination kinetics of candesartan. The observed inter- and intraindividual variability of oral clearance and the pronounced influence of HD-induced volume contraction on the haemodynamic effects of candesartan makes it mandatory to carefully monitor HD patients treated with candesartan cilexetil.     

Altered serotonin transporter availability in patients with multiple sclerosis

Purpose

Modulation of the immune system by the CNS may involve serotonergic regulation via the brain serotonin transporters (SERT). This regulation may be disturbed in patients with CNS disorders including multiple sclerosis (MS). Central serotonergic mechanisms have not been investigated in MS by in vivo imaging. The objective of the study was to assess the availability of SERT in antidepressant-naive patients with MS by means of PET.

Methods

Included in this study were 23 patients with MS and 22 matched healthy volunteers who were investigated with PET and the SERT-selective marker [¹¹C]DASB, and distribution volume ratios were determined. Clinical assessment of the patients included the expanded disability status scale, the MS fatigue scale Würzburger Erschöpfungsinventar bei MS (WEIMuS) and the Beck Depression Inventory (BDI). The PET data were analysed with both volume-of-interest and voxel-based analyses to determine regional SERT availability.

Results

Patients had lower SERT availability in the cingulate cortex, the thalamus and the insula, and increased availability in the orbitofrontal cortex. Patients with relapsing/remitting MS tended to have lower SERT in the hippocampus, whereas patients with primary progressive disease showed increased SERT availability in prefrontal regions. There was a positive correlation between SERT availability in the insula and both depression and fatigue scores (r?=?0.56 vs. BDI, p?=?0.02; r?=?0.49 vs. WEIMuS, p?=?0.05).

Conclusion

Serotonergic neurotransmission in MS patients is altered in limbic and paralimbic regions as well as in the frontal cortex that this appears to contribute to psychiatric symptoms of MS.     

Outcome of the frozen elephant trunk procedure as a redo operation

 Open in a separate windowOBJECTIVESThe goal of this study was to determine the outcome of patients undergoing an elective frozen elephant trunk (FET) procedure as a redo operation following previous cardiac surgery.METHODSOne hundred and eighteen consecutive patients underwent FET procedures between October 2010 and October 2019 at our centre. Patients were registered in a dedicated database and analysed retrospectively. Clinical and follow-up characteristics were compared between patients undergoing a FET operation as a primary (primary group) or a redo procedure (redo group) using logistic regression and Cox regression analysis. Emergency procedures (n = 33) were excluded from the analysis.RESULTSA total of 36.5% (n = 31) of the FET procedures were redo operations (redo group) and 63.5% (n = 54) of the patients underwent primary surgery (primary group). There was no significant difference in the 30-day mortality [primary group: 7.4%; redo group: 3.2%; 95% confidence interval (CI) (0.19–35.29); P = 0.63] and the 3-year mortality [primary group: 22.2%; redo group: 16.7%; 95% CI (0.23–3.23); P = 0.72] between redo and primary cases. Furthermore, the adjusted statistical analysis did not reveal significant differences between the groups in the occurrence of transient or permanent neurological deficit, paraplegia, acute renal failure and resternotomy. The redo group showed a higher rate of recurrent nerve palsy, which did not reach statistical significance [primary group: 3.7% (n = 2); redo group: 19.4% (n = 6); P = 0.091].CONCLUSIONSElective FET procedures as redo operations performed by a dedicated aortic team following previous cardiac surgery demonstrate an adequate safety profile.     

Selective degeneration of CA1 pyramidal cells by chronic application of bismuth

The heavy metal bismuth induces a new type of selective neuronal degeneration that shares some common aspects with that seen following hypoxia and ischemia. Continuous application of 3 μm bismuth to organotypic cultures of rat hippocampus resulted after 2–3 weeks in selective degeneration of CA1 pyramidal cells, while CA3 pyramidal cells, dentate granule cells, and subicular neurons were resistant. With 10 μm MK-801, a noncompetitive NMDA-antagonist, during the entire culturing period failed to prevent neuronal degeneration induced by 3 μm bismuth. GABA-immunoreactive interneurons were also affected by bismuth, but were generally less sensitive than CA1 pyramidal cells. Acute application of up to 100 μm bismuth did not change the electrophysiological properties of CA1 pyramidal cells. © 1994 Wiley-Liss, Inc.     

Effect of reduced exposure on natural rubber latex sensitization in health care workers.

BACKGROUND: Knowledge about the long-term course of allergy or sensitization to natural rubber latex (NRL) is insufficient. OBJECTIVE: To investigate the long-term effect of preventive measures on sensitization variables in health care workers who had been diagnosed as having NRL allergy (NRLA) or NRL sensitization (NRLS) without clinical symptoms. METHODS: Repeated follow-up investigations, skin prick tests, and NRL specific IgE serum antibodies were performed in 88 health care workers-33 with NRLA and 55 with NRLS. All workers had been instructed to avoid NRL exposure. At the workplace, powder-free NRL gloves for all other employees were gradually introduced. Re-evaluations were done at 14 +/- 3.7 (N = 86) and 38 +/- 4.0 (N = 78) months after the first examination. RESULTS: At the last follow-up, a loss of skin prick test reactivity to NRL was observed in 1 of 29 subjects with NRLA (3.4%) and 16 of 35 with NRLS (45.7%) with previous skin test reactions (P < .001). Among those subjects who demonstrated a kU/L level (CAP class) equal to or greater than class I to NRL at the initial examination, NRL-specific IgE was absent at the last follow-up in 8 (32.0%) of 25 subjects with NRLA and 14 (38.9%) of 36 with NRLS. At the final examination, we could no longer demonstrate sensitization to NRL by any method in 24 (27.3%) of 88 health care workers. Complete loss of NRL sensitization was less frequent in subjects with NRLA than in those with NRLS (1 of 33 or 3.0% vs 23 of 55 or 41.8%; P < .001). CONCLUSIONS: Implementation of simple preventive measures lowers markers of sensitization to NRL quickly in many health care workers with NRLA or NRLS.