The effect of atorvastatin treatment on serum oxysterol concentrations and cytochrome P450 3A4 activity

Aims

Atorvastatin is known to both inhibit and induce the cytochrome P450 3A4 (CYP3A4) enzyme in vitro. Some clinical studies indicate that atorvastatin inhibits CYP3A4 but there are no well-controlled longer term studies that could evaluate the inducing effect of atorvastatin. We aimed to determine if atorvastatin induces or inhibits CYP3A4 activity as measured by the 4β-hydroxycholesterol to cholesterol ratio (4βHC : C).

Methods

In this randomized, double-blind, placebo-controlled 6 month study we evaluated the effects of atorvastatin 20 mg day⁻¹ (n = 15) and placebo (n = 14) on oxysterol concentrations and determined if atorvastatin induces or inhibits CYP3A4 activity as assessed by the 4βHC : C index. The respective 25-hydroxycholesterol and 5α,6α-epoxycholesterol ratios were used as negative controls.

Results

Treatment with atorvastatin decreased 4βHC and 5α,6α-epoxycholesterol concentrations by 40% and 23%, respectively. The mean 4βHC : C ratio decreased by 13% (0.214 ± 0.04 to 0.182 ± 0.04, P = 0.024, 95% confidence interval (CI) of the difference –0.0595, –0.00483) in the atorvastatin group while no significant change occurred in the placebo group. The difference in change of 4βHC : C between study arms was statistically significant (atorvastatin –0.032, placebo 0.0055, P = 0.020, 95% CI of the difference –0.069, –0.0067). The ratios of 25-hydroxycholesterol and 5α,6α-epoxycholesterol to cholesterol did not change.

Conclusions

The results establish atorvastatin as an inhibitor of CYP3A4 activity. Furthermore, 4βHC : C is a useful index of CYP3A4 activity, including the conditions with altered cholesterol concentrations.     

Bone turnover in hyperthyroidism before and after thyrostatic management

Hyperthyroidism is associated with enhanced osteoblastic and osteoclastic activity, and patients frequently have low bone mineral density and high bone turnover. The aim of this study was to examine the bone formation and resorption markers trend in 12 female patients, before and after normalization of thyroid activity. The following measurements were made at baseline and 1 and 6 months after hormone normalization induced by methimazole treatment: total alkaline phosphatase (ALP), bone alkaline phosphatase (BALP), collagen type C-terminal propeptide (PICP), osteocalcin (BGP), telopeptide (ICTP), urinary-hydroxyproline/urinary creatinine (uOHP/uCreat), urinary calcium/urinary creatinine (uCa/uCreat) and deoxypyridinoline crosslinks (D-Pyr). Compared with controls, all of these parameters were significantly increased (ALP p = 0.014; BALP p = 0.0001; PICP p = 0.013; BGP p = 0.009; ICTP p = 0.0001; uOHP/uCreat p = 0.002; uCa/uCreat p = 0.044; crosslinks p = 0.0001). After treatment the values of ALP, BALP and PICP in hyperthyroid patients showed an initial slight increase and then a significant downwards trend (ALP p = 0.008, BAP p = 0.001, PICP p = 0.026). Furthermore, resorption markers showed a significant decrease (uOHP/ uCreat p < 0.005 and D-Pyr p < 0.008). As regards lumbar BMD patients, measurements were significantly reduced in comparison with the control group (p = 0.005). Six months after serum thyroid hormones level normalization, we observed a significant increase (p=0.014 vs baseline). Both neoformation and resorption markers are useful to assess pathological bone turnover and bone involvement in hyperthyroidism. They could also be employed to monitor the effect of antithyroid treatment on bone and to indicate if bone antiresorption therapy should be considered.     

Relative Efficacy of Sacubitril-Valsartan,Vericiguat, and SGLT2 Inhibitors in Heart Failure with Reduced Ejection Fraction: a Systematic Review and Network Meta-Analysis

Cardiovascular Drugs and Therapy - Sacubitril/valsartan, vericiguat, and the sodium-glucose co-transporter-2 inhibitors (SGLT2i) dapagliflozin and empagliflozin proved effective in phase 3 trials...     

Cardiovascular magnetic resonance for the diagnosis and management of heart failure with preserved ejection fraction

Heart Failure Reviews - Heart failure with preserved ejection fraction (HFpEF) is characterized by an impaired ventricular filling resulting in the development of dyspnea and other HF symptoms....     

How to take arms against central apneas in heart failure

Introduction Despite being a risk mediator in several observational studies, central apneas are currently orphan of treatment in heart failure. After the neutral effects on survival of two randomized controlled trials (RCTs) based on the use of positive airway pressure (the CANPAP and SERVE-HF trials), two alternative hypotheses have been formulated:

1) Periodic breathing/Cheyne-Stokes respiration (PB/CSR) in HF is protective. Indeed, the Naughton’s hypothesis assumes that hyperventilation leads to increased cardiac output, lung volume, oxygen storage and reduced muscle sympathetic nerve activity, while central apnea to respiratory muscle rest and hypoxia-induced erythropoiesis.

2) The use of positive airway pressure is just a wrong treatment for PB/CSR. If this is the case, the search for novel potential alternative treatment approaches is mandatory in HF.

Areas covered This review will focus on the crucial issue of whether PB/CSR should be treated or not in HF, first by outlining the ideal design of pathophysiological studies to test the Naughton’s hypothesis and second by summarizing the treatment strategies so far proposed for PB/CSR in HF and identifying the most promising options to be tested in future RCTs.

Expert commentary It is likely that PB/CSR may be compensatory in some cases, but after a certain threshold (to be defined) it becomes maladaptive with negative prognostic meaning in HF. The development of a pathophysiologically based treatment targeting feedback resetting and neurohormonal activation underlying PB/CSR is likely to be the best option to obtain survival benefits in HF.     

The European Register for Specialists in Clinical Chemistry and Laboratory Medicine: Code of Conduct.

The European Communities Confederation of Clinical Chemistry and Laboratory Medicine (EC4) opened a Register for European Specialists in Clinical Chemistry and Laboratory Medicine in 1997. The operation of the Register is undertaken by a Register Committee (EC4RC). During the last 6 years more than 1500 specialists in clinical chemistry and laboratory medicine have joined the Register. In this article a Code of Conduct for Registrants which was approved at the EC4 Register Committee meeting in Amsterdam, 8 November 2003 is presented.     

Antibodies to measles virus surface polypeptides in an immunized student population before and after booster vaccination

Serum specimens collected from 82 students before and after booster immunization with live measles virus (MV) vaccine were tested for MV surface protein-specific antibodies using a previously developed competitive enzyme immunoassay (E1A). The specificity of the assay in measuring antibodies against three sites on the haemagglutinin (H) and two on the fusion (F) protein was demonstrated. All subjects in this study were vaccinated, as one to two year-olds, three times with inactivated killed vaccine and later once or more with live vaccine. Fifty-three students were administered only live measles virus vaccine (M), whereas 29 were vaccinated with the MV combined with mumps and rubella (MMR). There was a clear tendency to a lower increase in antibody titres when MMR vaccine was used. This difference between the groups was most pronounced in antibodies against the site defined by a monoclonal antibody (mAb) 129. Antibodies to the site defined by the mAb 16AG5 on the F protein had no correlation with any of the other tests which suggests that subjects originally vaccinated with killed vaccine may have developed a distinct response to this site.     

The Role of Zinc in the Modulation of Neuronal Proliferation and Apoptosis

Although a requirement of zinc (Zn) for normal brain development is well documented, the extent to which Zn can modulate neuronal proliferation and apoptosis is not clear. Thus, we investigated the role of Zn in the regulation of these two critical events. A low Zn availability leads to decreased cell viability in human neuroblastoma IMR-32 cells and primary cultures of rat cortical neurons. This occurs in part as a consequence of decreased cell proliferation and increased apoptotic cell death. In IMR-32 cells, Zn deficiency led to the inhibition of cell proliferation through the arrest of the cell cycle at the G₀/G₁ phase. Zn deficiency induced apoptosis in both proliferating and quiescent neuronal cells via the intrinsic apoptotic pathway. Reductions in cellular Zn triggered a translocation of the pro-apoptotic protein Bad to the mitochondria, cytochrome c release, and caspase-3 activation. Apoptosis is the resultant of the inhibition of the prosurvival extracellular-signal-regulated kinase, the inhibition of nuclear factor-kappa B, and associated decreased expression of antiapoptotic proteins, and to a direct activation of caspase-3. A deficit of Zn during critical developmental periods can have persistent effects on brain function secondary to a deregulation of neuronal proliferation and apoptosis.     

Morphologies and prognostic significance of left ventricular volume/time curves with cardiac magnetic resonance in patients with non-ischaemic heart failure and left bundle branch block

The International Journal of Cardiovascular Imaging - Patients with non-ischaemic systolic heart failure (HF) and left bundle branch block (LBBB) can display a wide or narrow pattern (WP/NP) of the...