Evaluation of the food effect on a drospirenone only contraceptive containing 4 mg administered with and without high-fat breakfast in a randomised trial.

BACKGROUND: The objective of the present trial was to assess the difference in pharmacokinetics (PK) of an oral test preparation containing 4 mg drospirenone (DRSP) under fasting conditions compared to PK upon food intake after single dose administration. METHODS: Open label, single centre, two-treatment, two-sequence, crossover study in 24 healthy female volunteers, with duration of 1 day per sequence and with a real wash-out period of 14 days to investigate the relative bioavailability of DRSP with both forms of administration. The 90% confidence intervals (CI) were calculated for the intra-individual ratio (test with food vs. without food) of the PK endpoints Area under the curve; 0-72 h [AUC(0-72 h)] and maximal plasma concentration [Cmax] of DRSP. RESULTS: The 90% CI calculated by analysis of variance using logistic transformation (ANOVA-log) for the endpoint, intra-individual ratio (Test 'A' = with food intake) vs. Test 'B' = without food intake) of AUC(0-72 h) of drospirenone was between 104.72 and 111.36%. The 90% CI calculated by means of ANOVA- log for the endpoint intra-individual ratio (Test 'A' vs. Test 'B') of Cmax of DRSP was between 118.58 and 141.10%. The mean relative bioavailability of the test with food 'A' compared to the Test without food 'B' after single dose administration based on the endpoints AUC(0-72 h) was 107.99%; for the endpoint Cmax it was 129.35%. CONCLUSIONS: The rate of absorption, based on the endpoint Cmax of DRSP was increased by about 30% under fed conditions. With respect to consumer habits, this may represent a relevant benefit for contraceptive safety, as the time span between food consumption and pill intake does not play a role. IMPLICATIONS: Our results suggest that the food intake has no impact on the absorption of 4 mg DRSP in the management of contraception. This increases the contraceptive efficacy as no interference with food is expected when consuming the oral formulation under real life conditions. TRAIL REGISTRATION: Trial registration number: EudraCT-No: 2012-004,309-28.

Pharmacokinetics, metabolism and serum concentrations of progestins used in contraception.

Many different forms of hormonal contraception are used by millions of women worldwide. These contraceptives differ in the dose and type of synthetic progestogenic compound (progestin) used, as well as the route of administration and whether or not they contain estrogenic compounds. There is an increasing awareness that different forms of contraception and different progestins have different side-effect profiles, in particular their cardiovascular effects, effects on reproductive cancers and susceptibility to infectious diseases. There is a need to develop new methods to suit different needs and with minimal risks, especially in under-resourced areas. This requires a better understanding of the pharmacokinetics, metabolism, serum and tissue concentrations of progestins used in contraception as well as the biological activities of progestins and their metabolites via steroid receptors. Here we review the current knowledge on these topics and identify the research gaps. We show that there is a paucity of research on most of these topics for most progestins. We find that major impediments to clear conclusions on these topics include a lack of standardized methodologies, comparisons between non-parallel clinical studies and variability of data on serum concentrations between and within studies. The latter is most likely due, at least in part, to differences in intrinsic characteristics of participants. The review highlights the importance of insight on these topics in order to provide the best contraceptive options to women with minimal risks.

Antiretroviral therapy and vaginally administered contraceptive hormones: a three-arm, pharmacokinetic study.

BACKGROUND: Drug-drug interactions between orally administered antiretroviral therapy (ART) and hormones released from an intravaginal ring are not known. We hypothesised that ART containing either efavirenz or ritonavir-boosted atazanavir would alter plasma concentrations of vaginally administered etonogestrel and ethinylestradiol but that ART concentrations would be unchanged during use of an intravaginal ring. METHODS: We did a parallel, three-group, pharmacokinetic evaluation at HIV clinics in Asia (two sites), South America (five), sub-Saharan Africa (three), and the USA (11) between Dec 30, 2014, and Sept 12, 2016. We enrolled women with HIV who were either ART-naive (control group; n=25), receiving efavirenz-based ART (n=25), or receiving atazanavir-ritonavir-based ART (n=24). Women receiving ART were required to be on the same regimen for at least 30 days, with 400 copies or less per mL of plasma HIV-1 RNA; women not receiving ART had CD4 counts of 350 cells per µL or less. We excluded participants who had a bilateral oophorectomy or conditions that were contraindicated in the intravaginal ring product labelling. An intravaginal ring releasing etonogestrel and ethinylestradiol was inserted at entry (day 0). Single plasma samples for hormone concentrations were collected on days 7, 14, and 21 after intravaginal ring insertion. The primary outcome was the plasma concentration of etonogestrel and ethinylestradiol on day 21. Etonogestrel and ethinylestradiol concentrations were compared between each ART group and the control group by geometric mean ratio (GMR) with 90% CIs and Wilcoxon rank-sum test. As secondary outcomes, efavirenz or ritonavir-boosted atazanavir concentrations were assessed by 8-h intensive pharmacokinetic sampling at entry before intravaginal ring insertion and before intravaginal ring removal on day 21. Antiretroviral areas under the concentration-time curve (AUC0-8 h) were compared before and after intravaginal ring insertion by GMR (90% CI) and Wilcoxon signed-rank test. This study is registered with ClinicalTrials.gov, number NCT01903031. FINDINGS: Between Dec 30, 2014, and Sept 12, 2016, we enrolled 84 participants in the study; ten participants were excluded from the primary hormone analysis. 74 participants met the primary endpoint: 25 in the control group, 25 in the efavirenz group, and 24 in the atazanavir group. On day 21 of intravaginal ring use, participants receiving efavirenz had 79% lower etonogestrel (GMR 0·21, 90% CI 0·16-0·28; p<0·0001) and 59% lower ethinylestradiol (0·41, 0·32-0·52; p<0·0001) concentrations compared with the control group. By contrast, participants receiving ritonavir-boosted atazanavir had 71% higher etonogestrel (1·71, 1·37-2·14; p<0·0001), yet 38% lower ethinylestradiol (0·62, 0·49-0·79; p=0·0037) compared with the control group. The AUC0-8 h of efavirenz or atazanavir did not differ between the groups. INTERPRETATION: Hormone exposure was significantly lower when an intravaginal ring contraceptive was combined with efavirenz-based ART. Further studies designed to examine pharmacodynamic endpoints, such as ovulation, when intravaginal ring hormones are combined with efavirenz are warranted. FUNDING: National Institutes of Health, through the AIDS Clinical Trials Group and the International Maternal Pediatric Adolescent AIDS Clinical Trials Network, National Institute of Allergy and Infectious Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health.

O uso da pílula anticoncepcional e as alterações das principais vias metabólicas / The use of contraceptive pill and alterations of main metabolic pathways

As pílulas anticoncepcionais são esteroides que visam impedir a gravidez indesejada e regular distúrbios menstruais. Acessíveis em grande variedade no mercado e no SUS, são o método contraceptivo mais aceito pelas mulheres, entretanto trazem diversos efeitos colaterais. O objetivo deste trabalho foi analisar como a pílula anticoncepcional pode alterar as principais vias metabólicas femininas. Trata-se de uma revisão bibliográfica nas bases de dados SciELO, BVS e PubMed, com foco nas correlações entre o uso da pílula anticoncepcional e as alterações metabólicas. Os anticoncepcionais orais atuam na inibição da biossíntese de androgênios e estimulação da SHBG, o que reduz o efeito anabólico proteico. Também promovem o acréscimo dos níveis de LDL-colesterol, colesterol total, PCR-us e dímero D, e alterações na sensibilidade da insulina, no metabolismo do zinco e na hemostasia. Apesar de existirem recomendações que preconizam o uso de outros métodos contraceptivos e estudos que demonstram a satisfação feminina ao trocar os anticoncepcionais orais pelos LARCs, a pílula ainda é a mais utilizada pelas mulheres.(AU)

Contraceptive pills are steroids that prevent unwanted pregnancy and regular menstrual disorders. Accessible in a great variety in market and SUS, they are the contraceptive method most accepted by women, however, they bring several side effects. The objective of this study was analyze how the contraceptive pill can alter the main female metabolic pathways. This is a literature review in the SciELO, BVS and PubMed databases, focusing on the correlations between the use of contraceptive pill and metabolic alterations. Oral contraceptives act to inhibit androgen biosynthesis and stimulate SHBG, which reduces the protein anabolic effect. They also bring about high levels of LDL cholesterol, total cholesterol, CRP, D-dimer, changes in insulin, absence of zinc metabolism and hemostasis. Although there are recommendations that recommend the use of other contraceptive methods and studies that demonstrate the satisfaction of women in exchanging oral contraceptives with LARCs, the pill is still the most used by women.(AU)

Cunninghamella blakesleeana-mediated biotransformation of a contraceptive drug, desogestrel, and anti-MDR-Staphylococcus aureus activity of its metabolites.

Staphylococcus aureus is one of the most infectious agents among staphylococcal bacteria. Currently many strains of S. aureus have developed resistance against available antibiotics. Therefore, the treatment of infections caused by them is a major challenge. During current study, desogestrel (1), a contraceptive drug, was found to be a potent growth inhibitor of drug resistant strains of S. aureus. Therefore, in search of new and effective agents against multi-drug resistant S. aureus strains, whole-cell bio-catalytic conversion of desogestrel (1) by Cunninghamella blakesleeana ATCC 8688A at pH 7.0 and 25 °C was carried out, yielding three new metabolites, 13-ethyl-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-6ß,15ß,17ß-triol (2), 13-ethyl-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-3ß,6ß,17ß-triol (3), and 13-ethyl-11-methylene-18,19-dinor-17α-pregn-20-yn-3α,5α,6ß,17ß-tetraol (4), along with a known metabolite, 13-ethyl-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-6ß,17ß-dihydroxy-3-one (5). Among them, compounds 1-2 showed a potent activity against S. aureus EMRSA-17, S. aureus NCTC 13277 (MRSA-252), and S. aureus NCTC 13143, and clinically isolated Pakistani strain of S. aureus in an in vitro Microplate Alamar Blue Assay (MABA). Vancomycin was used as the standard drug in this assay. In addition, compound 1 also showed a significant activity against vancomycin-resistant S. aureus (VRSA) ATCC 700699. Compounds 1-5 were also evaluated against 3T3 normal cell line (mouse fibroblast) where they all were identified as non-cytotoxic. The present study thus provides new leads for the development of anti-bacterial drugs against MDR S. aureus.

Drospirenone intake alters plasmatic steroid levels and cyp17a1 expression in gonads of juvenile sea bass.

Drospirenone (DRO) is one of the most widely used progestins in contraceptive treatments and hormone replacement therapies. The pharmacokinetics and potential toxicological effects of DRO were investigated in juvenile sea bass (Dicentrarchus labrax) exposed through the diet (0.01-10 µg DRO/g) for up to 31 days. DRO was detected in the blood (4-27 ng/mL) of fish exposed to the highest concentration, with no significant bioaccumulation over time and no alteration of hepatic metabolizing enzymes, namely, CYP1A and CYP3A-catalysed activities and UDP-glucuronyltransferase (UGT). Pregnenolone (P5), progesterone (P4), 17α-hydroxyprogesterone (17P4), 17α-hydroxypregnenolone (17P5), androstenedione (AD) and testosterone (T) were determined in plasma and gene expression of cyp17a1, cyp19a1a and cyp11ß analysed by qRT-PCR in gonads. The significant increase in plasmatic levels of 17P5, 17P4 and AD detected after 31 days exposure to 10 ng DRO/g together with the increased expression of cyp17a1 in females evidence the ability of DRO to alter steroid synthesis at low intake concentrations (7 ng DRO/day). However, the potential consequences of this steroid shift for female reproduction remain to be investigated.

Development and validation of sensitive LC/MS/MS method for quantitative bioanalysis of levonorgestrel in rat plasma and application to pharmacokinetics study.

Rapid, sensitive, selective and accurate LC/MS/MS method was developed for quantitative determination of levonorgestrel (LNG) in rat plasma and further validated for specificity, linearity, accuracy, precision, sensitivity, matrix effect, recovery efficiency and stability. Liquid-liquid extraction procedure using hexane:ethyl acetate mixture at 80:20 v:v ratio was employed to efficiently extract LNG from rat plasma. Reversed phase Luna column C18(2) (50×2.0mm i.d., 3µM) installed on a AB SCIEX Triple Quad™ 4500 LC/MS/MS system was used to perform chromatographic separation. LNG was identified within 2min with high specificity. Linear calibration curve was drawn within 0.5-50ng·mL(-1) concentration range. The developed method was validated for intra-day and inter-day accuracy and precision whose values fell in the acceptable limits. Matrix effect was found to be minimal. Recovery efficiency at three quality control (QC) concentrations 0.5 (low), 5 (medium) and 50 (high) ng·mL(-1) was found to be >90%. Stability of LNG at various stages of experiment including storage, extraction and analysis was evaluated using QC samples, and the results showed that LNG was stable at all the conditions. This validated method was successfully used to study the pharmacokinetics of LNG in rats after SubQ injection, providing its applicability in relevant preclinical studies.

Contraception and sexual health in obese women.

As the proportion of women with obesity increases worldwide, understanding the influence of body weight on sexual behavior, fertility, and contraceptive effectiveness is critical for health-care professionals and patients. Although many have theorized that obese women are different from normal-weight women regarding sexual health and behavior, current evidence for the most part disproves this. The exception is in adolescents where body image may play a role in riskier behavior, placing them at a greater risk of an unintended pregnancy. Given that most modern contraceptives were not originally evaluated in obese women, understanding how weight affects contraceptive pharmacokinetics and efficacy should be a focus of ongoing research. Evidence is reassuring that most modern contraceptive methods are safe and effective in obese women. This paper reviews what is known about sexual and contraceptive behavior, as well as the effectiveness and pharmacokinetics of modern contraceptives, for overweight and obese women.

Ulipristal acetate in emergency contraception.

Despite the widespread availability of highly effective methods of contraception, unintended pregnancy is common. Unplanned pregnancies have been linked to a range of health, social and economic consequences. Emergency contraception reduces risk of pregnancy after unprotected intercourse, and represents an opportunity to decrease number of unplanned pregnancies and abortions. Emergency contraception pills (ECP) prevent pregnancy by delaying or inhibiting ovulation, without interfering with post fertilization events. If pregnancy has already occurred, ECPs will not be effective, therefore ECPs are not abortificants. Ulipristal acetate (17alpha-acetoxy-11beta-(4N-N,N-dymethilaminophenyl)-19-norpregna--4,9-diene-3,20-dione) is the first drug that was specifically developed and licensed for use as an emergency contraceptive. It is an orally active, synthetic, selective progesterone modulator that acts by binding with high affinity to the human progesterone receptor where it has both antagonist and partial agonist effects. It is a new molecular entity and the first compound in a new pharmacological class defined by the pristal stem. Up on the superior clinical efficacy evidence, UPA has been quickly recognized as the most effective emergency contraceptive pill, and recently recommended as the first prescription choice for all women regardless of the age and timing after intercourse. This article provides literature review of UPA and its role in emergency contraception.

Epilepsy in pregnancy - a collaborative team effort of obstetricians, neurologists and primary care physicians for a successful outcome.

BACKGROUND: Epilepsy is the most commonly encountered serious neurological problem in obstetrical practice. The disease and treating medications may have significant impact on contraceptive choice, efficacy and reproduction. OBJECTIVE: This article seeks to inform general practitioners (GPs) about current developments in the field of pregnancy care for women with epilepsy and to foster a collaborative approach in their management. DISCUSSION: The care of a pregnant woman with epilepsy needs to start well before pregnancy occurs, while she is still under the care of a GP, especially if she is on antiepileptic medication. GPs are familiar with the concept of GP management plans and team care arrangements for chronic diseases. This model of team care should be extended to the management of women with epilepsy with regards to reproduction. It is hoped this will enhance perinatal outcomes for women and their infants by encouraging shared communication between the obstetrician, neurologist and GP.

Effects of erythromycin at steady-state concentrations on the pharmacokinetics of ulipristal acetate.

WHAT IS KNOWN AND OBJECTIVE: Ulipristal acetate (UPA) is a novel selective progesterone receptor modulator for the treatment of benign gynaecological conditions such as uterine myoma. In vitro, it is mainly metabolized by the cytochrome P450 isoenzyme CYP3A4 and to a small extent by CYP1A2 and CYP2D6. Erythromycin, a macrolide antibiotic, has been shown to be a moderate CYP3A4 inhibitor. Thus, the aim of this study was to determine the effects of erythromycin at steady-state concentrations on the pharmacokinetics of UPA. Effects on the pharmacokinetics of the mono-demethylated metabolite of UPA (PGL4002) were also evaluated. METHODS: This was a non-randomized, single-sequence, two-period, open, single-dose study in 18 healthy female subjects. Subjects received oral UPA (20 mg) once daily on days 1 and 13 and twice-daily erythromycin propionate administrations (500 mg) from days 9 through 17. RESULTS: Geometric mean Cmax and AUCs of UPA were increased by 24% [geometric mean ratio point estimate (90% CI): 1·24 (1·01-1·52)] and +224% and +227% [geometric mean ratio point estimates (90% CI): AUC0-t 3·24 (2·75-3·83) and AUC0-∞ (3·27 (2·79-3·83)], respectively, with no effect on median tmax or t1/2. Geometric mean Cmax of PGL4002 was decreased by 47% [geometric mean ratio point estimate (90% CI): 0·523 (0·44-0·62)], but AUCs were increased by +62% and +66% [geometric mean ratio point estimates (90% CI): AUC0-t 1·62 (1·43-1·85) and AUC0-∞ by 1·66 (1·47-1·88)], respectively, with no effect on median tmax. However, geometric mean t1/2.doubled from 24 h to 48 h. No subject was discontinued from the study due to adverse events. WHAT IS NEW AND CONCLUSION: Concomitant use of ulipristal acetate with erythromycin at therapeutic concentrations led to a limited increase in Cmax and a 3-fold increase in AUCs for UPA and to a decrease in Cmax and an increase in AUCs and prolonged elimination for PGL4002. This indicates that inhibition of CYP3A4 impacted rate and extent of absorption of UPA and also its metabolism by slowing the elimination of its metabolite PGL4002.

Pharmacokinetics of a multipurpose pod-intravaginal ring simultaneously delivering five drugs in an ovine model.

Multipurpose technologies that simultaneously protect from sexually transmitted infections and unintended pregnancy are urgently needed. Pod-intravaginal rings (IVRs) formulated with the antiretroviral agents (ARVs) tenofovir, nevirapine, and saquinavir and the contraceptives etonogestrel and estradiol were evaluated in sheep. Steady-state concentrations were maintained for 28 days with controlled, sustained delivery. This proof-of-principle study demonstrates that pod IVRs can deliver three ARVs from different mechanistic classes and a progestin-estrogen combination over the wide range needed for putative preventative efficacy.

Changes in gastric pH and in pharmacokinetics of ulipristal acetate - a drug-drug interaction study using the proton pump inhibitor esomeprazole.

OBJECTIVE: Ulipristal acetate is a novel selective progesterone receptor modulator for the treatment of benign gynecological conditions such as uterine myoma. As a Biopharmaceutical Classification System (BCS) II compound, it is highly soluble at low pH but has low solubility at neutral conditions. Esomeprazole, a proton pump inhibitor used widely for treatment of gastric and duodenal ulcers, efficiently increases gastric pH. Thus, the aim of this study was to determine the effects of esomeprazole on the pharmacokinetics of ulipristal acetate. MATERIALS AND METHODS: This was a nonrandomized, single sequence, 2 period, open, study in 18 healthy female subjects. Subjects received oral ulipristal acetate tablets (10 mg) once on Days 1 and 13 and daily esomeprazole administrations (20 mg) from Days 9 through 14. RESULTS: Co-administration of esomeprazole decreased geometric mean Cmax of ulipristal acetate by 65% (geometric mean ratio point estimate (90% CI): 0.35 (0.28 - 0.42)), and delayed median tmax from 0.75 to 1.00 h (Hodges-Lehmann estimate of difference (90% CI): tmax 0.63 (0.25 - 1.25)) but had minor effects on AUCs of +15% and +11% (geometric mean ratio point estimates (90% CI): AUC0-t 1.15 (1.02 - 1.31) and AUC0-∞ (1.11 (0.98 - 1.27)), respectively. A total of 6 adverse events were reported by 4 subjects, none of them being serious. CONCLUSIONS: Concomitant use of ulipristal acetate with esomeprazole at therapeutic concentrations led to a modified absorption rate while exposure in terms of AUC remained close to bioequivalence limits. In the context of chronic administration of ulipristal acetate, no clinically significant effects are expected from co-administration with drugs increasing gastric pH.

The contraceptive vaginal ring, NuvaRing(®), a decade after its introduction.

OBJECTIVES: To review the clinical experience with the contraceptive vaginal ring (CVR, NuvaRing(®)) since its introduction over ten years ago. METHODS: The literature was searched on efficacy, cycle control, safety, user preference and satisfaction of the CVR in comparison with combined oral contraceptives (COCs) and the patch, with special attention to recent developments. RESULTS: The ring has the same working mechanism and contraindications as COCs. Serum levels of steroids are steadier, whereas oestrogenic exposure is lower. Contraceptive efficacy is similar, as are metabolic changes. Cycle control is better, and compliance and continuation rates are equal or higher. Oestrogen-related adverse symptoms appear to be fewer, but reports on the incidence of venous thrombosis are conflicting. Expulsion of the ring is reported by 4% to 20% of women. Local adverse events are the main reason for discontinuation. Acceptability is as high as with COCs and, after structured counselling, the ring is preferred by many women to the pill or the patch. CONCLUSIONS: Efficacy of the CVR, and the metabolic changes and adverse events it elicits, are generally comparable to those of COCs, yet oestrogenic exposure is lower and cycle control superior. After counselling, the ring is preferred to the pill by many women.

Ulipristal acetate: a new emergency contraceptive.

Ulipristal acetate (UPA) is a newly developed emergency contraceptive currently available in the USA and Europe. It is approved as a 30 mg one-time dose taken within 120 h (5 days) of unprotected intercourse or failed contraception. This selective progesterone receptor modulator appears to be more effective than the levonorgestrel-containing emergency contraceptive, which must be taken within 72 h of unprotected intercourse. According to pharmacodynamic trials, UPA delays follicular maturation and ovulation. In addition, UPA may modulate the endometrium. Both Phase III clinical trials found that UPA does not lose efficacy within the 120-h dosing interval. Throughout all phases of clinical studies, UPA was shown to be well tolerated with only minimal adverse drug reactions, all of which are similar to competitor therapies.

Combining prevention of HIV-1, other sexually transmitted infections and unintended pregnancies: Development of dual-protection technologies.

A significant number of women, especially in developing countries, need protection against more than one sexually transmitted infection (STIs), for instance HIV-1 and HSV-2, and family planning methods to prevent unwanted pregnancies. Dual protection technologies (DPTs; also known as multipurpose technologies) are designed to address two different indications with one product. Examples of DPTs are vaginal products capable of preventing transmission of HIV-1 in women while simultaneously providing contraceptive properties and a vaginal product capable of reducing HIV-1 transmission while preventing transmission of a second STI. DPTs can be categorized into three main approaches: 1) physical barriers, 2) chemical barriers, and 3) a combination of physical and chemical barriers. Examples of physical barriers are male and female condoms, diaphragms and cervical caps. Chemical barriers include use of a single drug with two mechanisms of action (viz., dual-activity compounds with microbicidal and contraceptive properties or activity against HIV-1 and a second STI pathogen such as HSV-2) or a combination of two drugs each targeted against separate mechanisms for achieving contraception and inhibition of HIV-1. Combinations of chemical and physical barriers are based on physical barriers such as a diaphragm along with a microbicide. Examples of each approach and current prototypes (such as vaginal gels and intravaginal rings) under development are described in this paper. Challenges facing development and regulatory approval of DPTs are also reviewed. This article forms part of a special supplement on a presentation covering DPTs, based on the symposium "Trends in Microbicide Formulations", held on 25 and 26 January 2010, Arlington, VA.

Interaction of contraceptive antimicrobial peptide nisin with target cell membranes: implications for use as vaginal microbicide.

BACKGROUND: Nisin, a naturally occurring antimicrobial peptide (AMP), is currently the focus of clinical trials as an intravaginal microbicide. Therefore its mechanism of interaction with various cell membranes was studied. STUDY DESIGN: Flow cytometry was used for quantitative estimation of membrane damage by nisin which was further determined by scanning electron microscopy (SEM). Affinity of nisin for different unilamellar liposome vesicles was determined spectroflurometrically and confirmed using laser scanning confocal microscopy (LSCM). RESULTS: Propidium iodide (PI) staining by flow cytometry exhibited selective membrane permeabilizing effect of nisin on sperm and bacterial membranes which correlated with ultrastructural changes. In vitro interaction of nisin with liposome model vesicles revealed significant leakage of calcein from liposomes composed of phosphatidylcholine/phosphatidylglycerol (POPC/POPG) (e.g., bacteria) and phosphatidylcholine/phosphatidylserine (POPC/POPS) (e.g., spermatozoa) as compared to phosphatidylcholine/phosphatidylethanolamine (POPC/POPE) vesicles (e.g., red blood corpuscles). LSCM results were in complete agreement with cell membrane affinity studies. CONCLUSION: This unique property of nisin can be exploited in the development of a safe and effective vaginal microbicide for the prevention of sexually transmitted infections/acquired immunodeficiency syndrome (STIs/AIDS) and unplanned pregnancies.

Pharmacokinetic interactions between contraceptives and antiepileptic drugs.

The occurrence of bi-directional drug interactions between antiepileptic drugs (AEDs) and combined oral contraceptives (OCs) pose potential risks of un-intended pregnancy and as well as seizure deterioration. It is well established that several of the older AEDs (carbamazepine, phenytoin and phenobarbital), are strong inducers of the hepatic cytochrome P450 (CYP) 3A4 enzyme system, and are associated with increased the risk of contraceptive failure. In addition, it is demonstrated that also some of the newer AEDs, oxcarbazepine and topiramate influence on the pharmacokinetics of OCs, which is thought to be due to a more selective induction of subgroups of the hepatic enzyme system. Estrogens containing OCs induce the glucuronosyltransferase and may reduce the plasma levels and the effect of AEDs cleared by glucuronidation. This has been most intensively studied for lamotrigine but also other AEDs, which undergoes glucuronidation processes, such as valproate and oxcarbazepine, may be affected by OCs. The magnitude of the drug-drug interactions show in general wide inter-individual variability and the change in the elimination rate is often unpredictable and can be influenced by a number of co-variants such as co-medication of other drugs, as well as genetic and environmental factors. It is therefore recommended that change in OC use is assisted by AED monitoring whenever possible.

Estradiol valerate and alcohol intake: dose-response assessments.

BACKGROUND: An injection of estradiol valerate (EV) provides estradiol for a prolonged period. Recent research indicates that a single 2.0 mg injection of EV modifies a female rat's appetite for alcoholic beverages. This research extends the initial research by assessing 8 doses of EV (from .001 to 2.0 mg/female rat), as well assessing the effects of 2.0 mg EV in females with ovariectomies. RESULTS: With the administration of EV, there was a dose-related loss of bodyweight reaching the maximum loss, when it occurred, at about 4 days after injections. Subsequently, rats returned to gaining weight regularly. Of the doses tested, only the 2.0 mg dose produced a consistent increase in intake of ethanol during the time previous research indicated that the rats would show enhanced intakes. There was, however, a dose-related trend for smaller doses to enhance intakes. Rats with ovariectomies showed a similar pattern of effects, to intact rats, with the 2 mg dose. After extensive histories of intake of alcohol, both placebo and EV-treated females had estradiol levels below the average measured in females without a history of alcohol-intake. CONCLUSION: The data support the conclusion that pharmacological doses of estradiol can produce enduring changes that are manifest as an enhanced appetite for alcoholic beverages. The effect can occur among females without ovaries.

Delivery of ethinylestradiol from film forming polymeric solutions across human epidermis in vitro and in vivo in pigs.

Film forming polymeric solutions may present an alternative to the common transdermal dosage forms such as patches or gels. To evaluate the potential of these systems for transdermal drug delivery the permeation of ethinylestradiol from four formulations with different polymers was tested across heat separated human epidermis. The formulation with the best results was then modified by incorporating chemical enhancers to further increase the efficiency of the delivery system. Finally, drug delivery from the developed film forming systems was compared to a commercially available transdermal patch in vitro as well as in vivo in pigs. Among the tested preparations the formulation with polyurethane-14-AMP-acrylates copolymer (DynamX) showed the highest ethinylestradiol permeation. The drug transport was further increased with the incorporation of oleic acid as penetration enhancer, especially when used in combination with propylene glycol. The enhancing effect of oleic acid/propylene glycol was concentration-dependent and increased disproportionately with rising enhancer content. The film forming solution showed a higher ethinylestradiol permeation through heat separated human epidermis than the commercial EVRA patch in vitro and achieved measurable plasma concentrations of ethinylestradiol in vivo in pigs. These promising results encourage the further development of film forming polymeric solutions as novel transdermal dosage form.