Proton pump inhibitor co-medication reduces active drug exposure in heart transplant recipients receiving mycophenolate mofetil

Background

Proton pump inhibitors (PPIs) are often prescribed for gastrointestinal discomfort after heart transplantation. This study investigated the impact of PPI use on mycophenolic acid (MPA) pharmacokinetics in heart transplant recipients receiving mycophenolate mofetil (MMF) in combination with a calcineurin inhibitor (tacrolimus [TAC]/cyclosporine [CsA]) or mammalian target of rapamycin inhibitor (sirolimus/everolimus).

Methods

Abbreviated MPA areas under the curve (AUCs; 0, 30, and 120 minutes after morning intake) were obtained in 19 patients on a PPI (initial examination) and 1 month after PPI discontinuation (follow-up). Mean patient age was 58.2 ± 8.8 years, and mean time after transplantation was 2.3 ± 4.0 years (range, 0.2–13.0 years).

Results

At initial examination mean daily MMF dose was 2.2 ± 0.8 g. MMF dose was kept unchanged for the duration of study (P = ns). Mean predose (C0) MPA serum concentrations were insignificantly lower with PPI comedication (2.5 ± 2.2 mg/L vs 2.8 ± 1.7 mg/L; P = .15). Dose-adjusted abbreviated MPA AUCs (adjusted to morning dose) were significantly lower during PPI therapy (45.2 ± 20.3 vs 65.2 ± 38.8 mg · h/L · g [MMF]; P = .02).

Conclusions

Patients with PPI comedication during MMF therapy show significantly lower exposure to mycophenolic acid determined by dose-adjusted abbreviated MPA AUCs. Although the clinical relevance of this pharmacokinetic interaction was not determined in this study, MPA drug monitoring by limited sampling strategies might be helpful during changes in antacid comedication in patients on MMF.     

Seventeen-year survival of the cementless CLS Spotorno stem

Introduction

For primary uncemented hip arthroplasty, various stem designs are available. The cementless CLS^® Spotorno stem has been used for more than 20 years. We re-evaluated a group of patients previously examined for a 10-year follow-up to assess the clinical and radiological stem performance in the long run.

Materials and methods

Between 1987 and 1988, a consecutive series of 107 uncemented CLS^®-Spotorno stems (Zimmer Ltd., Germany) were implanted in 94 patients. The patients′ mean age at the time of surgery was 51 years (range 20–77 years); 80 hips out of 107 (86%) were available for a clinical examination [Harris Hip Score (HHS)] after a mean of 17 years (range 15–18 years). In addition, radiographs were available from 74 out of 80 examined hips (92%) and analyzed for radiolucency, stress shielding, stem migration and heterotopic ossification.

Results

Stable stem fixation was present in 64 hips (98.5%). With “non-traumatic loosening” as an endpoint, stem survival was 100% after 17 years. Two stems (3%) showed mild subsidence already in the 10-year follow-up with no progression after 17 years. The HHS described excellent results in 47 hips (59%), good results in 16 hips (20%) and fair or poor results in 7 hips (9%) and 10 hips (13%), respectively. Radiolucency and grades II and III stress shielding were progressive at 17 years compared with the 10-year results. Grade IV stress shielding associated with osteolysis was seen in 9 hips (14%). Thigh pain was present in 20 hips (25%).

Conclusion

The CLS^® Spotorno stem allows excellent long-term results in cementless hip arthroplasty, leaving only minimal options for substantial improvements. Our findings on progressive stress shielding point towards a more diaphyseal load transfer of the CLS stem.     

Re-expression of pro-fibrotic,embryonic preserved mediators in irradiated arterial vessels of the head and neck region

Purpose

Surgical treatment of head and neck malignancies frequently includes microvascular free tissue transfer. Preoperative radiotherapy increases postoperative fibrosis-related complications up to transplant loss. Fibrogenesis is associated with re-expression of embryonic preserved tissue developmental mediators: osteopontin (OPN), regulated by sex-determining region Y?box 9 (Sox9), and homeobox A9 (HoxA9) play important roles in pathologic tissue remodeling and are upregulated in atherosclerotic vascular lesions; dickkopf-1 (DKK1) inhibits pro-fibrotic and atherogenic Wnt signaling. We evaluated the influence of irradiation on expression of these mediators in arteries of the head and neck region.

Materials and methods

DKK1, HoxA9, OPN, and Sox9 expression was examined immunohistochemically in 24 irradiated and 24 nonirradiated arteries of the lower head and neck region. The ratio of positive cells to total cell number (labeling index) in the investigated vessel walls was assessed semiquantitatively.

Results

DKK1 expression was significantly decreased, whereas HoxA9, OPN, and Sox9 expression were significantly increased in irradiated compared to nonirradiated arterial vessels.

Conclusion

Preoperative radiotherapy induces re-expression of embryonic preserved mediators in arterial vessels and may thus contribute to enhanced activation of pro-fibrotic downstream signaling leading to media hypertrophy and intima degeneration comparable to fibrotic development steps in atherosclerosis. These histopathological changes may be promoted by HoxA9-, OPN-, and Sox9-related inflammation and vascular remodeling, supported by downregulation of anti-fibrotic DKK1. Future pharmaceutical strategies targeting these vessel alterations, e.?g., bisphosphonates, might reduce postoperative complications in free tissue transfer.

     

Galectin 3 expression in primary oral squamous cell carcinomas

Background

Immunologic factors can promote the progression of oral squamous cell carcinomas (oscc). The phylogenetic highly conserved protein Galectin 3 (Gal3) contributes to cell differentiation and immune homeostasis. There is evidence that Gal3 is involved in the progression of oscc and influences the regulation of macrophage polarization. Macrophage polarization (M1 vs. M2) in solid malignancies like oscc contributes to tumor immune-escape. However, the relationship between macrophage polarization and Gal3 expression in oscc is not yet understood. The current study analyzes the association between histomorphologic parameters (T-, N-, L- Pn-status, grading) and Gal3 expression resp. the ratio between Gal3 expressing cells and CD68 positive macrophages in oscc specimens.

Methods

Preoperative diagnostic biopsies (n?=?26) and tumor resection specimens (n?=?34) of T1/T2 oscc patients were immunohistochemically analyzed for Gal3 and CD68 expression. The number of Gal3 expressing cells and the ratio between CD68 and Gal3 expressing cells was quantitatively assessed.

Results

In biopsy and tumor resection specimens, the number of Gal3 positive cells as well as the Gal3/CD68 ratio were significantly (p?<?0.05) higher in T2 oscc compared to T1 cases. In biopsy specimens, a significantly (p?<?0.05) increased Gal3 expression and Gal3/CD68 ratio was associated with the progression marker lymph vessel infiltration (L1). Tumor resection specimens of cases with lymph node metastases (N+) had a significantly (p?<?0.05) increased Gal3 expression. Additionally, a high Gal3/CD68 ratio correlated significantly (p?<?0.05) with higher grading (G3) in tumor resection specimens.

Conclusion

High Gal3 expression in oscc is associated with tumor size (T-status) and parameters of malignancy (N-, L-status, grading). Gal3 might contribute to M2 macrophage mediated local immune tolerance. Gal3 expression shows association with prognosis in oscc and represent a potential therapeutic target.

     

Chronic Residential Exposure to Particulate Matter Air Pollution and Systemic Inflammatory Markers

Background

Long-term exposure to urban air pollution may accelerate atherogenesis, but mechanisms are still unclear. The induction of a low-grade systemic inflammatory state is a plausible mechanistic pathway. Objectives: We analyzed the association of residential long-term exposure to particulate matter (PM) and high traffic with systemic inflammatory markers.

Methods

We used baseline data from the German Heinz Nixdorf Recall Study, a population-based, prospective cohort study of 4,814 participants that started in 2000. Fine PM [aerodynamic diameter ≤ 2.5 μm (PM_2.5)] exposure based on a small-scale dispersion and chemistry transport model was assigned to each home address. We calculated distances between residences and major roads. Long-term exposure to air pollution (annual PM_2.5 and distance to high traffic) and concentration of inflammatory markers [high-sensitivity C-reactive protein (hs-CRP) and fibrinogen] on the day of the baseline visit were analyzed with sex-stratified multiple linear regression, controlling for individual-level risk factors.

Results

In the adjusted analysis, a cross-sectional exposure difference of 3.91 μg/m³ in PM_2.5 (interdecile range) was associated with increases in hs-CRP of 23.9% [95% confidence interval (CI), 4.1 to 47.4%] and fibrinogen of 3.9% (95% CI, 0.3 to 7.7%) in men, whereas we found no association in women. Chronic traffic exposure was not associated with inflammatory markers. Short-term exposures to air pollutants and temperature did not influence the results markedly.

Conclusions

Our study indicates that long-term residential exposure to high levels of PM_2.5 is associated with systemic inflammatory markers in men. This might provide a link between air pollution and coronary atherosclerosis.