Pharmacokinetic,biologic and epidemiologic differences in MPA- and NET-based progestin-only injectable contraceptives relative to the potential impact on HIV acquisition in women

Access to safe and effective contraceptive choices is a reproductive right and contributes tremendously to improvements in maternal and child health. Progestin-only injectables, particularly intramuscularly injected depot medroxyprogesterone acetate (DMPA-IM), have received increased attention given findings suggesting a potential association with increased HIV risk. For women at high risk of HIV, the World Health Organization's Medical eligibility criteria for contraceptive use currently aggregate recommendations for all progestin-only injectables, including DMPA-IM, subcutaneously injected DMPA (DMPA-SC) and intramuscularly injected norethindrone/ norethisterone enanthate (NET-EN), except in the case of some drug interactions. We considered whether published data indicate differences or similarities between these injectables relevant to risk of acquiring HIV. In vitro data confirm different biological activities of these distinct progestins, including that MPA, and not NET, binds and activates the glucocorticoid receptor resulting in different biological effects relevant to immune function. Limited clinical data suggest changes in immunologic activity following DMPA-IM and NET-EN initiation, but interstudy variation and study design differences diminish ability to determine clinical relevance and the degree to which DMPA-IM and NET-EN could act differentially. The highest-quality epidemiologic studies suggest a potential 40% increase in HIV incidence in users of DMPA-IM relative to women not using hormonal contraception but no significant increase in risk in users of NET-EN. In our opinion, most of the available biologic activity and epidemiologic data indicate that DMPA and NET-EN are likely to act differently, and data remain too limited to evaluate differences between DMPA-IM and DMPA-SC.     

Differential effect of Pistacia vera extracts on experimental atherosclerosis in the rabbit animal model: an experimental study

Background

The association between modulation of detailed lipoprotein profiles and cholesterol ester transfer (CET) activity by peroxisome proliferator-activated receptor (PPAR)-a agonists in patients with coronary artery disease remains unclear. We assessed lipid profiles, plasma CET activity, and in-stent intimal hyperplasia after fenofibrate treatment in patients who underwent elective coronary stenting.

Methods

Forty-three consecutive patients who underwent elective coronary stenting were randomized to the fenofibrate group (300 mg/day for 25 weeks, n = 22) or the control group (n = 21). At baseline and follow up, CET activity and lipoprotein profiles were measured, and quantitative coronary angiography was performed.

Results

In the fenofibrate group, the levels of large very low-density lipoprotein cholesterol, and small low-density lipoprotein (LDL) cholesterol decreased and those of small high-density lipoprotein (HDL) cholesterol increased. Besides, CET activity decreased independent of the effect of fenofibrate on total and LDL cholesterol. The reduction of CET activity significantly correlated with the increase in LDL particle size (r = 0.47, P = 0.03) and the decrease of triglycerides in large HDL subclasses (r = 0.48, P = 0.03). Although there were no significant differences in restenosis parameters between the two groups, low CET activity significantly correlated with the inhibition of neointimal hyperplasia (r = 0.56, P = 0.01).

Conclusions

Fenofibrate inhibited CET activity and thereby improved atherogenic lipoprotein profiles, and reduced intimal hyperplasia after coronary stenting.     

Effect of a continuous regimen of contraceptive combination of ethinylestradiol and drospirenone on lipid, carbohydrate and coagulation profiles

Background

The objective of this study was to evaluate the effects of a contraceptive pill containing ethinylestradiol (30 mcg) and drospirenone (3 mg) in a continuous regimen on lipid, carbohydrate and coagulation parameters.

Study Design

This open, prospective, randomized study included 78 participants (mean age 27.8 years) who were randomized into two groups to use the pill continuously for 168 days or for six 28-day cycles with a 7-day hormone-free interval between cycles. Markers of lipid, carbohydrate and coagulation profiles were measured prior to initiation and after the 6 months of pill use.

Results

No statistically significant differences were found between the two contraceptive regimens with respect to carbohydrate or lipid profiles or in the parameters related to coagulation.

Conclusions

The contraceptive combination of ethinylestradiol and drospirenone used in a continuous regimen was associated with metabolic alterations similar to those found during the traditional cyclic regimen of oral contraceptive use.     

The proteasome inhibitor bortezomib drastically affects inflammation and bone disease in adjuvant‐induced arthritis in rats

Objective

To explore the effect of bortezomib in splenocytes and fibroblast‐like synoviocytes (FLS) and its in vivo potency in a rat model of adjuvant‐induced arthritis (AIA), which resembles human rheumatoid arthritis (RA).

Methods

AIA was induced with Freund's complete adjuvant. Splenocyte and FLS proliferation and apoptosis were measured by radioactivity incorporation and flow cytometry, respectively. The invasiveness of FLS from rats with AIA was tested in a Transwell system. The pattern of cytokine secretion was evaluated by cytometric bead array in splenocyte supernatants. Bortezomib was administered prophylactically or therapeutically, and arthritis was assessed clinically and histologically. Immunohistochemistry was performed for markers of inflammation and angiogenesis in joints. Hematologic and biochemical parameters were tested in peripheral blood (PB). Representative animals were examined by computed tomography (CT) scanning before and after bortezomib administration. The expression of Toll‐like receptor 2 (TLR‐2), TLR‐3, and TLR‐4 in PB and FLS was measured by real‐time polymerase chain reaction, and alterations in specific cell populations in PB and spleen were determined by flow cytometry.

Results

In vitro, bortezomib exhibited significant inhibitory and proapoptotic activity in splenocytes and FLS from rats with AIA, altered the inflammatory cytokine pattern, and reduced the invasiveness of FLS from rats with AIA. In vivo, bortezomib significantly ameliorated disease severity. Remission was associated with improved histology and decreased expression of CD3, CD79a, CD11b, cyclooxygenase 1, and factor VIII in target tissues as well as down‐regulation of TLR expression in PB and cultured FLS. CT scanning demonstrated a bone healing effect after treatment.

Conclusion

Our findings suggest that bortezomib affects AIA in a pleiotropic manner and that this drug may be effective in RA.

     

Role of stereotactic radiosurgery and fractionated stereotactic radiotherapy in pediatric brain tumors

Brain tumors are the most common solid tumor in childhood. Surgery and/or fractionated radiotherapy are conventional treatment modalities. Stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) are advanced radiation therapy techniques that have been frequently used in adults with brain tumors but they are less frequently used in pediatric patients. SRS and FSRT can potentially add to the armamentarium against brain tumors in children. This article will review the role of SRS and FSRT in the management of pediatric brain tumors.     

Changes in coronary flow reserve following stent implantation in the swine descending thoracic aorta.

PURPOSE: To evaluate coronary flow reserve (CFR) changes following stent implantation in the descending thoracic aorta (DTA) of a porcine model. METHODS: Six pigs (3 males; 40 to 44 kg) were anesthetized and kept on mechanical ventilation. A 6-F guiding right Judkins catheter was advanced under fluoroscopy to the right coronary artery, and a pressure wire with a temperature sensor was placed within the vessel lumen at a distance of 4 cm from the ostium. CFR was estimated by the thermodilution method before and after maximal coronary vasodilation with 20 mg of intracoronary papaverine. Aortography was also performed to measure aortic diameter. Subsequently, a self-expanding vascular stent was deployed into the DTA just below the left subclavian artery (LSA), and CFR was measured again. All animals were maintained for 3 weeks; at the end of this period, a further CFR was calculated using the same procedure. RESULTS: The mean aortic diameter below the LSA was 12.15+/-0.15 mm. Following stent deployment, the mean aortic diameter measured at the stented segment was 12.58+/-0.11 (p=0.001 versus baseline). The mean CFR value was 4.70+/-2.00 before stent implantation, 2.68+/-0.86 immediately after, and 4.05+/-1.15 at 3 weeks after stenting. Accordingly, CFR values were significantly depressed immediately after stent placement compared with baseline (p=0.027). However, CFR values obtained 3 weeks following stent deployment were similar to the initial values (p=0.59). CONCLUSION: Stent deployment in the normal swine DTA produces a significant immediate decrease in CFR, which is attenuated 3 weeks later. The clinical impact of CFR changes following DTA endografting remain to be elucidated.