Evaluation of consumer self-selection of a proposed over-the-counter, progestin-only daily oral contraceptive.

OBJECTIVES: In an effort to switch a norgestrel 0.075 mg progestin-only pill (Opill) from prescription to over-the-counter, we conducted this study to assess whether consumers can use the drug facts label alone to guide appropriate self-selection. STUDY DESIGN: Two studies assessed self-selection: (1) an all-comers, actual-use study evaluating self-selection before purchasing and using norgestrel 0.075 mg and (2) the Targeted Breast Cancer Self-Selection Study evaluating theoretical self-selection among participants with a history of breast cancer. RESULTS: In the actual-use study, based on the label, 1670/1772 participants (94%) were appropriate for use of norgestrel 0.075 mg; 102 (6%) were not appropriate. Of the 102, 66 (65%) correctly did not select and 36 (35%) responded it was okay for them to use norgestrel 0.075 mg. Of the 36 participants who incorrectly self-selected, one had a history of breast cancer and thus might have been adversely affected had they taken norgestrel 0.075 mg. In the Targeted Breast Cancer Self-Selection Study (N = 206), 97% of participants correctly stated norgestrel 0.075 mg was not appropriate for them. CONCLUSIONS: The proposed over-the-counter label enables 98% of potential users to self-select norgestrel 0.075 mg appropriately. Only 2% of potential purchasers may have bought and started to use norgestrel 0.075 mg inappropriately. For two-thirds of these, the potential benefits of their use of the method outweighed any theoretical risks. Adverse clinical consequences of norgestrel 0.075 mg use are unlikely even in those rare cases when the drug facts label was not followed. IMPLICATIONS: The balance of the risk of inappropriate selection to the benefit of taking an over-the-counter progestin-only pill appears to be very much in favor of an overall benefit in terms of unintended pregnancy prevention.

Evaluation of adherence to a daily progestin-only pill in a simulated over-the-counter setting.

OBJECTIVE: The Adherence with Continuous Dose Oral Contraceptive: Evaluation of Self-Selection and Use (ACCESS) study assessed whether consumers can adhere to the regimen for a progestin-only pill (norgestrel 0.075 mg) in an over-the-counter (OTC) setting. STUDY DESIGN: An actual use study in a simulated OTC environment assessed adherence to directions to take norgestrel 0.075 mg every day at the same time in 883 participants for up to 24 weeks. RESULTS: Eighty-five percent (747/883) of participants reported ≥85% adherence to taking norgestrel 0.075 mg every day and reported taking their dose within three hours of their scheduled dosing time on 96% of days. When accounting for use of a condom for 48 hours if a pill was missed, participants reported correctly following the label's directed use for 97% of doses overall, with 95% of participants following label directions for ≥85% of doses. The main limitations were related to finding a balance between intensely collecting data to ensure accurate assessment of adherence and leaving users to behave as they would in a real OTC situation without healthcare practitioner intervention. We observed that some participants reported taking more doses than they could have based on the supply of medication given to them. To fully examine the situation, and the impact on the conclusions, additional post hoc sensitivity analyses were performed, and showed remarkably consistent results. CONCLUSIONS: Consumers were highly adherent to taking norgestrel 0.075 mg when using only the information provided by the proposed OTC label. IMPLICATIONS: Adherence to a daily oral contraceptive pill was high when obtained OTC. This suggests that effectiveness of an OTC pill is likely to be like that of a prescribed pill and easier access to this effective contraceptive should allow more opportunity to prevent pregnancy.

Molecular effects of autoimmune-risk promoter polymorphisms on expression, exon choice, and translational efficiency of interferon regulatory factor 5.

The rs2004640 single nucleotide polymorphism and the CGGGG copy-number variant (rs77571059) are promoter polymorphisms within interferon regulatory factor 5 (IRF5). They have been implicated as susceptibility factors for several autoimmune diseases. IRF5 uses alternative promoter splicing, where any of 4 first exons begin the mRNA. The CGGGG indel is in exon 1A's promoter; the rs2004640 allele creates a splicing recognition site, enabling usage of exon 1B. This study aimed at characterizing alterations in IRF5 mRNA due to these polymorphisms. Cells with risk polymorphisms exhibited ~2-fold higher levels of IRF5 mRNA and protein, but demonstrated no change in mRNA stability. Quantitative PCR demonstrated decreased usage of exons 1C and 1D in cell lines with the risk polymorphisms. RNA folding analysis revealed a hairpin in exon 1B; mutational analysis showed that the hairpin shape decreased translation 5-fold. Although translation of mRNA that uses exon 1B is low due to a hairpin, increased IRF5 mRNA levels in individuals with the rs2004640 risk allele lead to higher overall protein expression. In addition, several new splice variants of IRF5 were sequenced. IRF5's promoter polymorphisms alter first exon usage and increase transcription levels. High levels of IRF5 may bias the immune system toward autoimmunity.

Insulin suppresses ischemic preconditioning-mediated cardioprotection through Akt-dependent mechanisms.

It is believed that the diabetic myocardium is refractory to cardioprotection by ischemic preconditioning (IPC) mainly because of impaired insulin signaling to phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PKB or Akt). However, human as well as animal studies have clearly showed that the hearts of type 2 diabetic humans and animals may exhibit increased signaling through PI3K-Akt but yet are resistant to cardioprotection by IPC or ischemic post-conditioning. Therefore, this study was designed to determine whether activation of insulin signaling prior to IPC is detrimental for cardioprotection and to assess the role of insulin receptors (IRs) and Akt in mediating this effect. Wild-type (WT) hearts, hearts lacking IRs or hearts expressing an active form of Akt (myrAkt1) were perfused ex vivo using a Langendorff preparation and were subjected to IPC (3cycles of 5min ischemia followed by 5min reflow before 30min no flow ischemia and then by 45min reperfusion) in the presence or absence of 1nmol/L insulin. Interestingly, whereas insulin was protective against I/R (30min no flow ischemia and 45min reperfusion), it completely abolished cardioprotection by IPC in WT hearts but not in mice lacking insulin receptors (IRs) in cardiomyocytes (CIRKO) or in all cardiac cells (TIRKO). The suppression of IPC-mediated cardioprotection was mediated through downstream signaling to Akt and Gsk3ß. In addition, transgenic induction of Akt in the heart was sufficient to abrogate IPC even when insulin was absent, further confirming the involvement of Akt in insulin's suppression of cardioprotection by IPC. These data provide evidence that excessive insulin signaling to Akt is detrimental for cardioprotection by IPC and could explain the failure of the diabetic myocardium to precondition.

UCP3 regulates cardiac efficiency and mitochondrial coupling in high fat-fed mice but not in leptin-deficient mice.

These studies investigate the role of uncoupling protein 3 (UCP3) in cardiac energy metabolism, cardiac O(2) consumption (MVO(2)), cardiac efficiency (CE), and mitochondrial uncoupling in high fat (HF)-fed or leptin-deficient mice. UCP3KO and wild-type (WT) mice were fed normal chow or HF diets for 10 weeks. Substrate utilization rates, MVO(2), CE, and mitochondrial uncoupling were measured in perfused working hearts and saponin-permeabilized cardiac fibers, respectively. Similar analyses were performed in hearts of ob/ob mice lacking UCP3 (U3OB mice). HF increased cardiac UCP3 protein. However, fatty acid (FA) oxidation rates were similarly increased by HF diet in WT and UCP3KO mice. By contrast, MVO(2) increased in WT, but not in UCP3KO with HF, leading to increased CE in UCP3KO mice. Consistent with increased CE, mitochondrial coupling was increased in the hearts of HF-fed UCP3KO mice. Unexpectedly, UCP3 deletion in ob/ob mice reduced FA oxidation but had no effect on MVO(2) or CE. In addition, FA-induced mitochondrial uncoupling was similarly enhanced in U3OB compared with ob/ob hearts and was associated with elevated mitochondrial thioesterase-1 protein content. These studies show that although UCP3 may mediate mitochondrial uncoupling and reduced CE after HF feeding, it does not mediate uncoupling in leptin-deficient states.