Assessment of porphyrogenicity of drugs and chemicals in selected hepatic cell culture models through a fluorescence-based screening assay.

Compounds that induce 5-aminolevulinic acid [ALA] synthase-1 and/or cytochromes P-450 may induce acute porphyric attacks in patients with the acute hepatic porphyrias [AHPs]. Currently, there is no simple, robust model used to assess and predict the porphyrogenicity of drugs and chemicals. Our aim was to develop a fluorescence-based in vitro assay for this purpose. We studied four different hepatic cell culture models: HepG2 cells, LMH cells, 3D HepG2 organoids, and 3D organoids of primary liver cells from people without known disease [normal human controls]. We took advantage of the fluorescent properties of protoporphyrin IX [PP], the last intermediate of the heme biosynthesis pathway, performing fluorescence spectrometry to measure the intensity of fluorescence emitted by these cells treated with selected compounds of importance to patients with AHPs. Among the four cell culture models, the LMH cells produced the highest fluorescence readings, suggesting that these cells retain more robust heme biosynthesis enzymes or that the other cell models may have lost their inducibility of ALA synthase-1 [ALAS-1]. Allyl isopropyl acetamide [AIA], a known potent porphyrogen and inducer of ALAS-1, was used as a positive control to help predict porphyrogenicity for tested compounds. Among the tested compounds (acetaminophen, acetylsalicylic acid, ß-estradiol, hydroxychloroquine sulfate, alpha-methyldopa, D (-) norgestrel, phenobarbital, phenytoin, sulfamethoxazole, sulfisoxazole, sodium valproate, and valsartan), concentrations greater than 0.314 mM for norgestrel, phenobarbital, phenytoin, and sodium valproate produced fluorescence readings higher than the reading produced by the positive AIA control. Porphyrin accumulation was also measured by HPLC to confirm the validity of the assay. We conclude that LMH cell cultures in multi-well plates are an inexpensive, robust, and simple system to predict the porphyrogenicity of existing or novel compounds that may exacerbate the AHPs.

Interventions for hidradenitis suppurativa: a Cochrane systematic review incorporating GRADE assessment of evidence quality.

More than 50 interventions have been used to treat hidradenitis suppurativa (HS), and so therapy decisions can be challenging. Our objective was to summarize and appraise randomized controlled trial (RCT) evidence for HS interventions in adults. Searches were conducted in Medline, Embase, CENTRAL, LILACS, five trials registers and abstracts from eight dermatology conferences until 13 August 2015. Two review authors independently assessed study eligibility, extracted data and assessed methodological quality. Primary outcomes were quality of life and adverse effects of the interventions. Twelve trials, from 1983 to 2015, investigating 15 different interventions met our inclusion criteria. The median trial duration was 16 weeks and the median number of participants was 27. Adalimumab 40 mg weekly improved the Dermatology Life Quality Index (DLQI) by 4·0 points, which equates to the minimal clinically important difference for the scale, compared with placebo (95% confidence interval -6·5 to -1·5 points). Evidence quality was reduced to 'moderate' because the results are based on only a single study. Adalimumab 40 mg every other week was ineffective in a meta-analysis of two studies comprising 124 participants. Infliximab 5 mg kg(-1) improved the DLQI score by 8·4 points after 8 weeks in a moderate-quality study completed by 33 of 38 participants. Etanercept 50 mg twice weekly was ineffective. Inclusion of a gentamicin sponge prior to primary closure did not improve outcomes. Other interventions, including topical and oral antibiotics, were investigated by relatively small studies, preventing treatment recommendations due to imprecision. More, larger RCTs are required to investigate most HS interventions, particularly oral treatments and surgical therapy. Moderate-quality evidence suggests that adalimumab given weekly and infliximab are effective, whereas adalimumab every other week is ineffective.

Further results on the risk of nonfatal venous thromboembolism in users of the contraceptive transdermal patch compared to users of oral contraceptives containing norgestimate and 35 microg of ethinyl estradiol.

CONTEXT: In 2006, we published a study that indicated that the new transdermal contraceptive patch containing ethinyl estradiol (EE) and the progestin norelgestromin did not increase the risk for venous thromboembolism (VTE) compared to oral contraceptive containing norgestimate and 35 microg of EE. OBJECTIVE: This report updates information on the risk of nonfatal VTE in women using the contraceptive patch in comparison to women using oral contraceptives containing norgestimate (either monophasic or triphasic) and 35 microg of EE (norgestimate-35) using an additional 17 months of data. DESIGN, SETTING AND PARTICIPANTS: Nested case-control design based on information from PharMetrics, a US-based company that collects and organizes information on claims paid by managed care plans. The study was nested among all women, aged 15 to 44 years, who started either the contraceptive patch or norgestimate-35 after April 1, 2002. Cases were women with current use of one of these two study drugs and a documented diagnosis of VTE in the absence of identifiable clinical risk factors (idiopathic VTE) who were not in the earlier study. Up to four controls were matched to each case by age and calendar time. MAIN OUTCOME MEASURES: Odds ratios (ORs) comparing the risk of nonfatal VTE in new users of the two contraceptives. RESULTS: We identified 56 new cases of newly diagnosed, idiopathic VTE in the updated study population. The OR comparing the contraceptive patch to norgestimate-35 was 1.1 (95% CI 0.6-2.1). CONCLUSIONS: After evaluating an additional 17 months of data, the results indicate that the risk of nonfatal VTE for the contraceptive patch is closely similar to the risk for oral contraceptives containing 35 mug of EE and norgestimate.

Authorized generic drugs, price competition, and consumers' welfare.

The growing frequency of authorized generics has important implications for the welfare of prescription drug consumers. Authorized generic entry could affect the timing of generic entry, brand-name and generic prices, and generic penetration. We reviewed 1999-2003 data and found that generic entry in the absence of short-run exclusivity restrictions benefits consumers through lower short-run prices. We suggest that these benefits likely also result from authorized generics. We posit that long-run prices and shares are likely essentially unaffected by authorized generics and that potential costs to consumers from any delayed generic entry are likely small.

Modelling costs and outcomes of expanded availability of emergency contraceptive use in British Columbia.

BACKGROUND: Emergency contraception (EC) can potentially reduce unwanted pregnancies and abortions. However, these agents are underused due to lack of awareness and barriers to utilization. While earlier economic evaluations have indicated that use of EC is potentially cost-effective, recent evidence of a lower risk of pregnancy following unprotected intercourse than previously reported suggest prior studies may have over-estimated cost savings. OBJECTIVES: To model cost savings and pregnancy-related outcomes associated with the policy change authorizing pharmacist provision of EC in British Columbia, and to estimate the costs of initiatives to further women's awareness and utilization of EC that would result. METHODS: Three decision analytic models were developed evaluating current EC utilization (physician-only), EC utilization following pharmacist provision and potential expanded EC awareness and utilization following a public awareness initiative. Models were developed from the Ministry of Health perspective for 2001 using cost and event data from the Ministry supplemented by data from the literature. RESULTS: Current EC utilization saved the Ministry $2.20 million (95% CR: $0.15 million, $4.90 million) in medical costs the first year, and incremental savings from pharmacist provision was $0.64 million (95% CR: $0.24 million, $1.28 million). A public awareness initiative costing less than $2.57 million (95% CR: $0.22 million, $5.75 million) annually is potentially cost saving. CONCLUSIONS: Pharmacist provision of EC was cost saving to the Ministry, even when the estimated risk of pregnancy in the population is less than assumed in previous studies. Increasing EC availability directly from pharmacists and increasing EC awareness have the potential to reduce health care costs.

Cost savings from use of emergency contraceptive pills in Australia.

BACKGROUND: Emergency contraception, which prevents pregnancy after unprotected sexual intercourse, has the potential to reduce significantly the incidence of unintended pregnancy and the consequent need for abortion and to reduce medical care costs. AIM: To determine the savings generated by use of Postinor-2, the levonorgestrel regimen of emergency hormonal contraception, in Australia. METHODS: We modelled the cost savings when women obtain Postinor-2 directly from a pharmacist where cost savings are measured as the cost of pregnancies averted by use of Postinor-2 per dollar spent on Postinor-2. RESULTS: Each dollar spent on a single treatment with Postinor-2 saves A$2.27-A$3.81 in direct medical care expenditures on unintended pregnancy depending on assumptions about savings from costs avoided by preventing mistimed births. Postinor-2 is cost-saving even under the least favourable assumption that mistimed births when prevented today occur 2 years later. Results are robust even to large changes in model input parameters. CONCLUSION: Emergency contraception is cost saving. More extensive use of emergency contraception could save considerable medical and social costs by reducing unintended pregnancies, which are expensive.

Clinical assessment and quality of life of postmenopausal women treated with a new intermittent progestogen combination hormone replacement therapy: a placebo-controlled study.

OBJECTIVE: The aim of this study was to evaluate the effects of a constant-estrogen, intermittent-progestogen hormone replacement regimen (Ortho-Prefest, Ortho-McNeil Pharmaceutical, Raritan, NJ, USA) on menopausal symptoms measured by the Kupperman Index and on quality of life measured by the Menopause Quality of Life-Intervention questionnaire. DESIGN: This was a randomized, double-blind, placebo-controlled multicenter study of 90 days' duration. Nonhysterectomized, postmenopausal women with vasomotor symptoms and at least 6 months' amenorrhea were eligible. On completion of the placebo-controlled portion of the study, participants could elect to receive active treatment for an additional 90 days. RESULTS: The study enrolled 119 participants, 59 and 60 in the Prefest and placebo groups, respectively. A marked reduction of menopausal symptoms, as measured by the Kupperman Index, was observed in the active treatment group compared with the placebo group after 45 days' treatment (mean reduction, 14.8 v 7.2 points, respectively), which was sustained to day 90 (16.8 v 7.8 points; < 0.001). Similarly, greater improvement in quality of life, as measured by the Menopause Quality of Life summary score, was also observed in the active treatment group for the same period (improvement of up to 1.6 points v 0.7 points; < 0.001). The adverse event profile was unremarkable. Of the 114 participants who received the active treatment, 6 withdrew because of adverse events. CONCLUSIONS: The constant-estrogen, intermittent-progestogen regimen was highly effective in relieving menopausal symptoms and in improving quality of life and was well received by the study participants.

[Assessment of selected neoplastic markers in women receiving hormone replacement therapy]. / Ocena wybranych markerów nowotworowych u kobiet stosujacych hormonalna terapie zastepcza.

The study was performed in order to assess the serum levels of proteins believed to be the markers of neoplastic differentiation (CEA and CA 15.3) and proliferation (TPS) in women receiving hormone replacement therapy. 190 women were included into the study. Women were classified into one of four groups: healthy women receiving hormone replacement therapy (n = 76), women with diagnosed benign breast disease (BBD) receiving HRT (n = 26), women with diagnosed BBD without HRT (n = 48), and control group--age matched, regularly menstruating women without HRT (n = 40). Measurements of serum concentrations of neoplastic markers were performed using radioimmunological method. The results indicate that hormone replacement therapy does not provoke a rise in neoplastic markers concentrations above normal levels in any of assessed groups. Women with BBD using HRT were found to have the lowest TPS and CA 15.3 values and the highest CEA values. The long-term usage of HRT was found to cause a gradual rise of average concentrations of all measured markers in BBD group and in healthy women.

Evra--a patch on oral contraception?

Evra (Janssen-Cilag) is the first contraceptive to be available as a skin patch. In promotional material aimed at healthcare professionals, the company claims that Evra offers a "once-weekly method of contraception" with "more than 99% effectiveness and excellent compliance". The company's website for women using Evra carries the slogan "Evra The Right Contraceptive Choice" and claims that the patch is "just as effective as the contraceptive pill". Each patch is intended to be worn for 7 days, in contrast to combined oral contraceptives (COCs), which need to be taken daily. Here we assess whether Evra offers real advantages over COCs and consider its place as a contraceptive option.

Assessment of the metabolic tolerance in postmenopausal women over a 1-year period of two hormone replacement therapies containing estradiol in combination with either norgestrel or trimegestone.

This double-blind, randomized, multi-center study compared the metabolic tolerance of a combined formulation containing estradiol (E2) and trimegestone (TMG) with a standard hormone replacement therapy (HRT) containing estradiol valerate (EV) and norgestrel (NG). Blood lipids, glucose and fibrinogen concentrations were measured in the study which was conducted over 13 cycles, each of 28 days, and included 634 subjects in two randomized groups. A total of 481 subjects completed the study. The circulating concentrations of high density lipoprotein (HDL), HDL2, HDL3 cholesterol and apolipoprotein A1 were increased in the E2 + TMG group and reduced in the EV + NG group. Total cholesterol, low density lipoprotein (LDL) cholesterol, apolipoprotein B and lipoprotein(a) concentrations were decreased in both treatment groups; however, the reduction in LDL cholesterol was greater in the E2 + TMG group. Similar lipid findings were found in a subgroup that excluded subjects who had less than 3 months washout from a previous HRT, who provided a blood sample outside the day 17-28 window, or who were taking beta-blockers or thiazide diuretics. Blood glucose concentrations were reduced slightly in both treatment groups. A significant reduction in fibrinogen was also seen in both groups over the course of the study. The changes in lipid profile, especially HDL cholesterol, were more beneficial in the E2 + TMG group in comparison with the EV + NG group. This reflects the lack of androgenic action of trimegestone in comparison with norgestrel, which exhibits an androgenic effect and prevents the estrogen-induced increase in HDL cholesterol. The results of the study suggest that the use of trimegestone in combination with E2 may be preferable to norgestrel because of the more favorable lipid profile.

Assessment of compliance with a weekly contraceptive patch (Ortho Evra/Evra) among North American women.

OBJECTIVE: To determine compliance with the contraceptive patch (Ortho Evra/Evra) overall and by age among women in North America and to compare rates of perfect use with those of an established oral contraceptive. DESIGN: Data were pooled for three contraceptive studies in which women participated for up to 13 cycles; the subset of centers in North America was used in this analysis. SETTING: 76 North American centers. PATIENT(S): Healthy women 18-45 years of age. INTERVENTION(S): In all studies, the patch regimen was three consecutive 7-day patches (21 days) followed by 1 patch-free week per cycle. MAIN OUTCOME MEASURE(S): Perfect use for the patch or oral contraceptive, defined as 21 consecutive days of drug-taking followed by a 7-day drug-free period; for contraceptive patch users, no patch could be worn for more than 7 days. Oral contraceptives were used according to package labeling. RESULTS: For all contraceptive patch users in North America (n = 1,785), perfect use was consistent across age groups. The percentage of cycles with perfect use of the patch ranged within age groups from 88.1% to 91.0%. In the comparative study conducted only in North America, perfect use was also consistent across age groups for the patch (n = 812), but rates of perfect use for the oral contraceptive (n = 605) differed significantly by age. CONCLUSION(S): Age did not affect compliance with the patch among all North American women studied. In a comparative study of women at North American centers, compliance with the weekly contraceptive patch was significantly better than with an established oral contraceptive. The contraceptive patch is uniformly easy to use across all ages.

[Emergency contraception: a simple, safe, effective and economical method for preventing undesired pregnancy]. / Anticoncepción de emergencia: un método simple, seguro, efectivo y económico para prevenir embarazos no deseados.

In the following article, the most recent knowledge on emergency contraception (EC) is reviewed. EC is defined as those contraceptive methods that may be used to prevent an unwanted pregnancy up to 3 days after unprotected intercourse, contraceptive failure or rape. In case of non-hormonal methods (IUD), the time window for pregnancy prevention goes up to 5 days after intercourse. The different regimens now available, hormonal and non-hormonal methods, indications, contraceptive effectiveness, side effects and safety profile, possible mechanisms of action and counseling strategies will be reviewed. The potential benefits on reproductive health of wide-spread knowledge and easy, non-restrictive access to this methodology are emphasized. An extensive list of recent references is enclosed.

Collaboration with academia in the development of post ovulatory methods.

The 0.75-mg levonorgestrel-containing 'morning after' contraceptive tablet Postinor was developed by Gedeon Richter Ltd., Hungary. The product was first launched in 1979 and registered later in approximately 40 countries. In 1994, the World Health Organization offered the company participation in a multinational clinical trial to prove the superiority of the product over existing (Yuzpe-type) emergency contraceptive products. Based on these data the company was able to redesign the 'morning after' type Postinor into an 'emergency' pill, Postinor-2. During further clinical trials a close working relationship was formed between the Department of Obstetrics and Gynaecology at the Albert Szent-Györgyi Medical University in Szeged, Hungary, and Gedeon Richter. The advantages and challenges of cooperation between public- and private-sector institutions are analyzed in the paper.

Comparative assessment of two low-dose oral contraceptives, Lo-Femenal and Lo-Estrin, in Mexican women.

This trial was designed to determine the differences in effectiveness, clinical acceptability, and one-year discontinuation rates of two low-dose oral contraceptives: Lo-Estrin (norethindrone acetate 1.5 mg plus ethinyl estradiol 0.030 mg) and Lo-Femenal (norgestrel 0.30 mg plus ethinyl estradiol 0.030 mg) in 148 Mexican women. In addition, the effects of both oral contraceptive preparations on blood lipids were prospectively evaluated in a subgroup of 41 women. The results indicated that there were no differences in pregnancy rates, discontinuation or clinical acceptability between the two groups. The lipid changes observed were minimal for the Lo-Femenal subgroup and somewhat greater for the Lo-Estrin group, mainly an increase in serum triglycerides. These changes were interpreted as estrogen induced effects of norethindrone-containing oral contraceptives. Overall, the data indicate that both Lo-Femenal and Lo-Estrin are effective and safe combined oral contraceptives.

Avaliaçäo da exposiçäo ocupacional a hormônios sexuais / Occupational exposure evaluation the sex hormones

O objetivo desse artigo é revisar os principais efeitos sobre a saúde do trabahador, em indústrias formuladoras de contraceptivos orais, que utilizam como matéria-prima ativa uma estrogênio(etinil estradio), associado a um progestogênio (norgestrel e levonorgestrel), visando ao estabelecimento de um programa básico de controle.

[Levonorgestrel releasing subcutaneous implants. 1st year's experience]. / Implantes subdérmicos liberadores de levonorgestrel. Primer año de experiencia.

This multicentric study was done in order to know the contraceptive efficacy and side effects of subdermal implants liberating levonorgestrel, in Mexican women. Results analysis, at one year, of 246 women, at four medical centers of Mexican Institute of Social Security (IMSS), showed that this contraceptive is highly efficacious, as there were no pregnancies in 2326 months of observation. The main side effects were: menstrual disorders in 34.8% of women; soreness in implantation site in 3.6%; headache in 13.4% and nausea, dizziness and vomiting in 11.6%. The most frequent causes for implant retirement were menstrual cycle alterations, and soreness at implantation site, with 7.3 and 3.5 respectively. The continuity rate at one year was 84.3, which was higher to what has been seen at the Institution with other temporal contraceptive methods, so the implants may be considered as one more alternative in family planning methods.

Factors associated with the acceptance of Norplant or IUD among women with similar socio-demographic characteristics.

The purpose of this study was to identify factors that explain why women who consulted at the same clinic, went through the same counseling procedure and who had no contraindications for using Norplant decided to use another long-acting method, the IUD. Subjects were women who consulted at the Family Planning Clinic, State University of Campinas Hospital. One hundred Norplant acceptors and 100 IUD acceptors were interviewed at home, by trained interviewers who were not related to the clinic. Four out of five Norplant acceptors and all IUD acceptors had learned about the method chosen before attending the clinic. Results suggest that among IUD users there were more women who did not like the idea of taking a hormone or medicine to prevent pregnancy, while Norplant acceptors were more willing to try new experiences. Half the Norplant acceptors had learned about the method through TV, compared to 12% of IUD acceptors. Counseling at the clinic was not a determining factor, though it is important to clarify clients' doubts.

Association between contraceptive method accepted and perception of information received: a comparison of Norplant and IUD acceptors.

In the present study Norplant(R) and IUD acceptors who attended the same counseling sessions have been compared on their perception of the information received at the family planning clinic. The study covered 100 acceptors of each method quota matched by parity and years of schooling. Data were obtained through home interviews. The two groups presented no significant differences when selected socio-demographic characteristics were analyzed. Norplant users recalled more information on this method than did IUD acceptors, and the content of what they remembered was different. This included concepts as important as risk of pregnancy, menstrual and health effects, and method of removal. The results suggest that the intrinsic qualities of the new method and the presence of a group of women motivated to use one with its general characteristics, are not sufficient conditions for its acceptance.

PIP: In this study, Norplant (R) and IUD acceptors who attended the same counselling sessions have been compared on their perceptions of the information received at the family planning clinic. The study included 100 acceptors of each method quota matched by parity and years of schooling. Data were obtained through home interviews. The 2 groups presented no significant differences when selected sociodemographic characteristics were analyzed. R users recalled more information on this method than did IUD acceptors, and the content of what they remembered was different. This included concepts as important as risk of pregnancy, menstrual and health effects, and method of removal. Results suggest that the intrinsic qualities of the new method and the presence of a group of women motivated to use 1 with its general characteristics are not sufficient conditions for its acceptance.

[Levonorgestrel-releasing subcutaneous implants. First year's experience]. / Implantes subdérmicos liberadores de levonorgestrel. Primer año de experiencia.

This multicentric study was done in order to know the anticonceptive efficacy and side effects of subdermic implants liberating levonorgestrel, in Mexican women. Results analysis, at one year, of 246 women, at four medical centers of Mexican Institute of Social Security (IMSS), showed that this anticonceptive is highly efficacious, as there were no pregnancies in 2326 months of observation. The main side effects were: menstrual disorders in 34.8% of women; soreness in implantation site in 3.6%; headache in 13.4% and nausea, dizziness and vomiting in 11.6%. The most frequent causes for implant retirement were menstrual cycle alterations, and soreness at implantation site, with 7.3 and 3.5 respectively. The continuity rate at one year was 84.3, which was higher to what has been seen at the Institution with other temporal anticonceptive methods, so the implants may be considered as one more alternative in family planning methods.