Extended regimen of a levonorgestrel/ethinyl estradiol transdermal delivery system: Predicted serum hormone levels using a population pharmacokinetic model.

OBJECTIVE: This study employed population pharmacokinetic (popPK) models to predict levonorgestrel (LNG) and ethinyl estradiol (EE) exposure after dosing with the transdermal contraceptive TWIRLA® (LNG/EE TDS) as a 12-week extended regimen in a healthy female population. METHODS: PopPK models were developed using data from a previously published phase 1, open-label, randomized clinical trial, ATI-CL14 (NCT01243580), in 36 healthy individuals. Models used cycle 2 data from 18 individuals who received the LNG/EE TDS, delivering LNG 120 µg/day and EE 30 µg/day, followed by a 1-week TDS-free period. Noncompartmental PK analyses were performed on simulated concentration-time profiles of 12 consecutive weeks of LNG/EE TDS use. RESULTS: The simulated concentration-time profiles and PK parameters for the simulated extended regimen indicated that predicted LNG and EE exposures at week 12 were similar to week 3 (predicted geometric mean EE area under the concentration-time curve from time 0 to 168 h [AUC0-168] on week 3 was 0.2% lower than week 12 and LNG AUC0-168 on week 3 was 0.9% lower than week 12), suggesting both were at steady state by week 3. Therefore, no notable accumulation beyond that at week 3 is predicted for LNG and EE following a 12-week extended regimen. The results are supported by the accumulation ratios based on maximum concentration and the area under the curve being similar at weeks 3 and 12 for LNG and EE. CONCLUSION: These results indicate that a 12-week extended LNG/EE regimen would provide similar systemic hormonal exposure as that seen by week 3 in a standard 28-day regimen, without further hormonal accumulation. The data support the safe use of a non-daily, low-dose hormonal contraceptive in an extended regimen but should be confirmed in a clinical PK study.

Hydrothermal Degradation of Amino Acids.

Within the past years, hydrothermal processes have gathered much attention as promising conversion technologies for especially wet biomass. Amino acids are an integral component of biomass, zoo biomass in particular. However, what happens to them during hydrothermal treatment? Reviewing the available literature going back to the mid of the 20th century revealed an astonishing, but still fragmentary view. In fact, two universal degradation reactions could be identified (i. e., deamination and decarboxylation), competing with each other. Thereby, small structural differences may obviously have huge impacts on the fate of individual amino acids. Nevertheless, the amount of available experimental data is relatively scarce in many cases. In this work, the available knowledge about the degradation of 20 proteinogenic amino acids under hydrothermal conditions was presented and discussed critically. The hydrothermal conversion of proteinaceus biomass as well as the Maillard reaction, both extensively reviewed elsewhere, were only touched on.

Nitrogen-Containing Hydrochar: The Influence of Nitrogen-Containing Compounds on the Hydrochar Formation.

Hydrothermal carbonization (HTC) of fructose and urea containing solutions was conducted at 180 °C to study the influence of nitrogen-containing compounds on conversion and product properties. The concentration of fructose was fixed, while the concentration of urea was gradually increased to study its influence on the formation of nitrogen-containing hydrochar (N-HC). The degradation of urea has an important influence on the HTC of fructose. The Maillard reaction (MR) promotes the formation of N-HC in acidic conditions. However, in alkaline conditions, MR promotes the formation of bio-oil at the expense of N-HC. Alkaline conditions reduce N-HC yield by catalyzing fragmentation reactions of fructose and by promoting the isomerization of fructose to glucose. The results showed that adjusting the concentration of nitrogen-containing compounds or the pH value of the reaction environment is important to force the reaction toward the formation of N-HC or N-bio-oil.

The natural history of Type 1 infantile GM1 gangliosidosis: A literature-based meta-analysis.

INTRODUCTION: Type 1 GM1 gangliosidosis is an ultra-rare, rapidly fatal lysosomal storage disorder, with life expectancy of <3 years of age. To date, only one prospective natural history study of limited size has been reported. Thus, there is a need for additional research to provide a better understanding of the progression of this disease. We have leveraged the past two decades of medical literature to conduct the first comprehensive retrospective study characterizing the natural history of Type 1 GM1 gangliosidosis. OBJECTIVES: The objectives of this study were to establish a large sample of patients from the literature in order to identify: 1) clinically distinguishing factors between Type 1 and Type 2 GM1 gangliosidosis, 2) age at first symptom onset, first hospital admission, diagnosis, and death, 3) time to onset of common clinical findings, and 4) timing of developmental milestone loss. METHODS: PubMed was searched with the keyword "GM1 Gangliosidosis" and for articles from the year 2000 onwards. A preliminary review of these results was conducted to establish subtype classification criteria for inclusion of only Type 1 patients, resulting in 44 articles being selected to generate the literature dataset of 154 Type 1 GM1 gangliosidosis patients. Key clinical events of these patient cases were recorded from the articles. RESULTS: Comprehensive subtyping criteria for Type 1 GM1 gangliosidosis were created, and clinical events, including onset, diagnosis, death, and symptomology, were mapped over time. In this dataset, average age of diagnosis was 8.7 months, and average age of death was 18.9 months. DISCUSSION: This analysis demonstrates the predictable clinical course of this disease, as almost all patients experienced significant multi-organ system dysfunction and neurodevelopmental regression, particularly in the 6- to 18-month age range. Patients were diagnosed at a late age relative to disease progression, indicating the need for improved public awareness and screening. CONCLUSION: This study highlights the significant burden of illness in this disease and provides critical natural history data to drive earlier diagnosis, inform clinical trial design, and facilitate family counseling.

Influence of the pH Value on the Hydrothermal Degradation of Fructose.

The hydrothermal treatment of sugars features a promising technology for the production of fine and platform chemicals from renewable resources. In this work the hydrothermal decomposition of fructose was studied in a buffered medium at a pH range between 2.2 and 8.0. It is demonstrated that at lower pH values mainly 5-hydroxymethylfurfural (HMF), levulinic acid and humin are generated, while lactic acid and acetic acid are produced at higher pH values. The work shows that the use of moderate acidic conditions may have advantages for the hydrothermal HMF production over the use of strongly acidic conditions, as especially the degradation into levulinic acid is suppressed. Besides, this study deals with a rather complex reaction network, hence limitations and need for adaption of the kinetic model are discussed.

Intranasal carbetocin reduces hyperphagia in individuals with Prader-Willi syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) is a genetic neurodevelopmental disorder of life-threatening hyperphagia, obesity, intellectual deficits, compulsivity, and other behavioral problems. The efficacy and safety of i.n. carbetocin, an oxytocin analog, was evaluated in a prospective, randomized, double-blinded trial in adolescents with PWS. METHODS: Eligible patients aged 10-18 years with genetically confirmed PWS were randomized (1:1) to i.n. carbetocin or placebo 3 times daily for 14 days. The primary efficacy endpoint was change in parent/caregiver-rated Hyperphagia in PWS Questionnaire-Responsiveness (HPWSQ-R) total score. Secondary efficacy endpoints included HPWSQ-R behavior, drive, and severity domains; clinician-rated HPWSQ; Children's Yale-Brown Obsessive-Compulsive Severity Scale; food domain of the Reiss Profile; and Clinical Global Impression-Improvement scale. Endpoints were assessed using analysis of covariance. Relationship between primary and secondary endpoints was assessed using Pearson correlation coefficients. Safety was assessed throughout the study. RESULTS: Demographics and clinical characteristics were similar between treatment groups (carbetocin, n = 17; placebo, n = 20). Patients receiving carbetocin had statistically significant reductions in HPWSQ-R total score at study end (-15.6) versus patients receiving placebo (-8.9; P = 0.029); several secondary efficacy endpoints also demonstrated significant differences (P < 0.05). Treatment effects for the primary and secondary endpoints were highly correlated (P ≤ 0.0001). Incidence of adverse events (AEs) was similar between treatment groups. CONCLUSION: I.n. carbetocin was well tolerated and improved hyperphagia and behavioral symptoms of PWS. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01968187FUNDING. The study was funded by Ferring Pharmaceuticals. Recruitment was aided by ongoing work in PWS performed through Eunice Kennedy Shriver National Institute of Child Health and Human Development grant U54 HD083211.

An Evaluation of the Pharmacodynamics, Safety, and Tolerability of the Potassium Binder RDX7675.

Hyperkalemia is common in patients with heart failure or chronic kidney disease, particularly those taking renin-angiotensin-aldosterone system inhibitors, and can cause arrhythmias and sudden cardiac death. The most widely used treatment, sodium polystyrene sulfonate (SPS), limits gastrointestinal potassium absorption, but has poor palatability. RDX7675 (RDX227675) is the calcium salt of a reengineered polystyrene sulfonate-based resin with improved palatability over SPS. The pharmacodynamic effects and safety of RDX7675 were assessed in a phase 1, single-center, randomized, active-controlled study. Healthy volunteers received nominal active doses of RDX7675 4.6 g twice a day (BID), 4.6 g 3 times a day (TID), 6.9 g BID, 13.7 g daily (QD), 9.2 g TID, or 13.7 g BID (n = 12 each), or equivalent doses of SPS (n = 3 each), for 4 days. RDX7675 dosing increased stool potassium excretion and decreased urinary potassium excretion from baseline. Stool potassium excretion increased by up to 1481 mg/day with RDX7675 (6.9 g BID), and urinary potassium excretion decreased by up to 939 mg/day (13.7 g BID). Similar levels of potassium excretion were observed using QD, BID, or TID dosing of a 13.7 g total daily RDX7675 dose. Few adverse events were reported. In conclusion, repeated oral dosing with RDX7675 over 4 days reduced potassium absorption in healthy volunteers; the results support QD dosing of RDX7675 in future clinical studies.

Evaluation of the Pharmacodynamic Effects of the Potassium Binder RDX7675 in Mice.

INTRODUCTION: Hyperkalemia is a common complication in patients with heart failure or chronic kidney disease, particularly those who are taking inhibitors of the renin-angiotensin-aldosterone system. RDX7675, the calcium salt of a reengineered polystyrene sulfonate-based resin, is a potassium binder that is being investigated as a novel treatment for hyperkalemia. This study evaluated the pharmacodynamic effects of RDX7675 in mice, compared to 2 current treatments, sodium polystyrene sulfonate (SPS) and patiromer. METHODS: Seven groups of 8 male CD-1 mice were given either standard chow (controls) or standard chow containing 4.0% or 6.6% active moiety of RDX7675, patiromer, or SPS for 72 hours. Stool and urine were collected over the final 24 hours of treatment for ion excretion analyses. RESULTS: RDX7675 increased stool potassium (mean 24-hour excretion: 4.0%, 9.19 mg; 6.6%, 18.11 mg; both P < .0001) compared with controls (4.47 mg) and decreased urinary potassium (mean 24-hour excretion: 4.0%, 12.05 mg, P < .001; 6.6%, 6.68 mg, P < .0001; vs controls, 20.38 mg). The potassium-binding capacity of RDX7675 (stool potassium/gram of resin: 4.0%, 1.14 mEq/g; 6.6%, 1.32 mEq/g) was greater (all P < .0001) than for patiromer (4.0%, 0.63 mEq/g; 6.6%, 0.48 mEq/g) or SPS (4.0%, 0.73 mEq/g; 6.6% 0.55 mEq/g). RDX7675 and patiromer decreased urinary sodium (mean 24-hour excretion: 0.07-1.38 mg; all P < .001) compared to controls (5.01 mg). In contrast, SPS increased urinary sodium excretion (4.0%, 13.31 mg; 6.6%, 17.60 mg; both P < .0001) compared to controls. CONCLUSIONS: RDX7675 reduced intestinal potassium absorption and had a greater potassium-binding capacity than patiromer or SPS in mice. The calcium-based resins RDX7675 and patiromer reduced intestinal sodium absorption, unlike sodium-based SPS. These results support further studies in humans to confirm the potential of RDX7675 for the treatment of patients with hyperkalemia.

Palatability and physical properties of potassium-binding resin RDX7675: comparison with sodium polystyrene sulfonate.

BACKGROUND: Hyperkalemia is a potentially life-threatening condition that patients with heart failure or chronic kidney disease, especially those taking renin-angiotensin-aldosterone system inhibitors, are at high risk of developing. Sodium polystyrene sulfonate (SPS), a current treatment, binds potassium within the gastrointestinal tract to reduce potassium absorption. However, poor palatability limits its long-term use. RDX7675, a novel potassium binder in development for the treatment of hyperkalemia, is a calcium salt of a reengineered polystyrene sulfonate-based resin designed to have enhanced palatability. Here, the physical properties and palatability of RDX7675 and SPS are compared. METHODS: RDX7675 and SPS particle sizes were measured using wet dispersion laser diffraction. Palatability was assessed in a randomized, crossover, healthy volunteer study with two visits. At visit 1 (open label), volunteers evaluated high-viscosity, intermediate-viscosity, and water-reconstituted formulations of RDX7675 (all vanilla flavor), and an equivalent reconstituted SPS (Resonium A®). At visit 2 (single-blind), volunteers evaluated RDX7675 as a high-viscosity formulation in vanilla, citrus, and mint flavors, and as intermediate-viscosity, low-viscosity, and reconstituted formulations in citrus flavor. Volunteers used a "sip and spit" technique to rate overall acceptability and seven individual characteristics from 1 ("dislike everything") to 9 ("like extremely"). RESULTS: RDX7675 particles were smaller than SPS particles, with a narrower size range (RDX7675, 80%, 14-52 µm; SPS, 11.3-124.2 µm), and had a smooth, spherical shape, in contrast to the shard-like SPS particles. Reconstituted RDX7675 was considered superior to SPS for five of the seven palatability characteristics and for overall acceptability (median, visit 1: reconstituted RDX7675, 5.0; SPS, 4.0). High-viscosity vanilla was the most highly rated RDX7675 formulation (median overall acceptability, visit 2: 7.0). CONCLUSION: The smaller, more uniformly shaped, spherical particles of RDX7675 resulted in improved palatability over SPS when reconstituted in water. The overall results are promising for future patient acceptability of RDX7675 treatment.

Analytical pharmacology and the elucidation of function.

James Black believed that analysis of biological assays provides insights into the operation of physiological control systems. In this paper, we illustrate this point in three 'cardiovascular' assays. The first determined the half-life (t½) of 'endothelium-derived relaxing factor' (EDRF), using bradykinin to release EDRF, which produced concentration-related relaxations of a precontracted artery. With the introduction of time delays between the source of EDRF and the assay artery, there were rightward shifts in dose-response curves, which provided the basis of calculating t½. The second assay determined the roles of noradrenaline reuptake and prejunctional α(2)-adrenoceptor activity on transmitter concentration at sympathetic synapses with atria and resistance vessels. In the former, the reuptake role was paramount, whilst prejunctional receptor activity was dominant at vascular synapses, owing to anatomical differences. The third assay provided in vivo estimates of the enhancement of the total peripheral resistance responses to constrictor and dilator stimuli owing to the structural changes in hypertension. Major nonlinearities in the dose-response curve obscured this enhancement. Their effect was avoided by deriving extended dose-response curves from combined constrictor and dilator data, permitting calculation of the enhancement over the range between the nonlinearities.

A new approach to assessing the structural total peripheral resistance amplifier in renal (Page) hypertension in conscious rabbits.

BACKGROUND AND AIM: Structural changes in the large resistance vessels in hypertension amplify resistance responses in vitro, but their role in vivo has been controversial. To resolve this matter, we re-examined earlier data in Page hypertension. METHODS: Total peripheral resistance (TPR) and total peripheral conductance (TPC) responsiveness were compared in hypertensive and normotensive rabbits, 5 weeks after bilateral renal cellophane wrapping or sham operation. The rabbits were studied with effectors intact; during ganglionic blockade; during neurohumoral blockade (NHB). For each condition extended scaled dose (ScD)-TPC and TPR curves were derived from individual dose-response curves to two constrictors and two dilators. RESULTS: The ScD-response curves had two major nonlinearities: at high constrictor doses, due to functional (reversible) rarefaction (reduction in microcirculatory density); at high dilator doses, due to impaired autoregulation. The amplifier is best assessed during NHB over the intervening ScD range, by determining the TPR and TPC ratios from hypertensive and normotensive rabbits. Over this range the hypertensive: normotensive (H: N) ratio averaged 1.88 +/- 0.03 TPR units and was the same for constrictor and dilator responses, suggesting a structural basis; the resting H: N TPR ratio was also closely similar. At higher ScDs functional rarefaction developed initially at a greater rate in normotensive than in hypertensive rabbits. We conjecture that this was because some permanent rarefaction had already developed in hypertensive rabbits since the onset of hypertension. CONCLUSION: The systemic structural TPR amplifier is haemodynamically important in vivo and contributes to hypertension.

A randomized controlled trial of a low-dose combined oral contraceptive containing 3 mg drospirenone plus 20 microg ethinylestradiol in the treatment of acne vulgaris: lesion counts, investigator ratings and subject self-assessment.

OBJECTIVE: To assess the efficacy of a combined oral contraceptive (COC) containing 3 mg drospirenone (drsp) plus 20 microg ethinylestradiol (EE) administered in 24 days of active treatment followed by a four-day hormone-free interval (24/4 regimen) compared with placebo for the treatment of moderate acne vulgaris. METHODS: Healthy females (14-45 years old) with moderate facial acne were randomized to 3 mg drsp/20 microg EE 24/4 (n = 270) or placebo (n = 268) for six cycles. The secondary efficacy variables measured included change from baseline to endpoint (cycle 6) in individual lesion count for nodules, papules, pustules, open and closed comedones. RESULTS: There were significantly greater reductions in individual lesion counts from baseline to endpoint in the 3 mg drsp/20 microg EE group than in the placebo group (P < 0.05 from parametric model). CONCLUSION: The 3 mg drsp/20 microg EE COC administered in a 24/4 regimen significantly reduced acne lesions.

A double-blind, randomized, saline-controlled study of the efficacy and safety of EUFLEXXA for treatment of painful osteoarthritis of the knee, with an open-label safety extension (the FLEXX trial).

OBJECTIVE: To report the FLEXX trial, the first well-controlled study assessing the safety and efficacy of Euflexxa (1% sodium hyaluronate; IA-BioHA) therapy for knee osteoarthritis (OA) at 26 weeks. METHODS: This was a randomized, double-blind, multicenter, saline-controlled study. Subjects with chronic knee OA were randomized to 3 weekly intra-articular (IA) injections of either buffered saline (IA-SA) or IA-BioHA (20 mg/2 ml). The primary efficacy outcome was subject recorded difference in least-squares means between IA-BioHA and IA-SA in subjects' change from baseline to week 26 following a 50-foot walk test, measured via 100-mm visual analog scale (VAS). Secondary outcome measures included Osteoarthritis Research Society International responder index, Western Ontario McMaster University Osteoarthritis Index VA 3.1 subscales, patient global assessment, rescue medication, and health-related quality of life (HRQoL) by the SF-36. Safety was assessed by monitoring and reporting vital signs, physical examination of the target knee following injection, adverse events, and concomitant medications. RESULTS: Five hundred eighty-eight subjects were randomized to either IA-BioHA (n = 293) or IA-SA (n = 295), with an 88% 26 week completion rate. No statistical differences were noted between the treatment groups at baseline. In the IA-BioHA group, mean VAS scores decreased by 25.7 mm, compared with 18.5 mm in the IA-SA group. This corresponded to a median reduction of 53% from baseline for IA-BioHA and a 38% reduction for IA-SA. The difference in least-squares means was -6.6 mm (P = 0.002). Secondary outcome measures were consistent with significant improvement in Osteoarthritis Research Society International responder index, HRQoL, and function. Both IA-SA and IA-BioHA injections were well tolerated, with a low incidence of adverse events that were equally distributed between groups. Injection-site reactions were reported by 1 (<1%) subject in the IA-SA group and 2 (1%) in the IA-BioHA group. CONCLUSIONS: IA-BioHA therapy resulted in significant OA knee pain relief at 26 weeks compared with IA-SA. Subjects treated with IA-BioHA also experienced significant improvements in joint function, treatment satisfaction, and HRQoL.

Bleeding patterns associated with non-oral hormonal contraceptives: a review of the literature.

It is generally accepted that poor tolerance to changes in vaginal bleeding associated with hormonal contraceptive use may influence compliance and continuation with the chosen method. However, disparities in the collation and reporting of bleeding data hamper comparison among studies and products. In this review, we systematically assessed MEDLINE and EMBASE for articles assessing parenteral hormonal contraceptives that reported bleeding data based on reference periods as recommended by the World Health Organization (WHO). Overall, 31 studies published between 1986 and October 2007 were included in this review. The use of parenteral hormonal contraception was in general associated with a decrease in bleeding with continued use from Reference Period 1 to 4. However, this decrease was less marked with the combined hormonal depots and both progestin-only and combined hormonal vaginal rings than with progestin-only implants, depots and the levonorgestrel intrauterine system. Overall, reporting vaginal bleeding by 90-day reference periods as recommended by the WHO allows straightforward comparison of bleeding patterns between studies.

Treatment of acne using a 3-milligram drospirenone/20-microgram ethinyl estradiol oral contraceptive administered in a 24/4 regimen: a randomized controlled trial.

OBJECTIVE: To assess the efficacy of the combined oral contraceptive containing 3-mg drospirenone/20-microgram ethinyl estradiol (3-mg drospirenone/20-microgram ethinyl estradiol) administered as 24 consecutive days of active treatment after a 4-day hormone-free interval (24/4 regimen) compared with placebo for the treatment of moderate acne vulgaris. METHODS: Healthy females aged 14-45 years with moderate acne were randomized in this double-blind study to 3-mg drospirenone/20-microgram ethinyl estradiol (n=270) or placebo (n=268) for six cycles of 28 days. The primary outcome measures of acne lesion counts and Investigator Static Global Assessment scale ratings were assessed at baseline and during cycles 1, 3, and 6. RESULTS: The percentage reduction from baseline to endpoint for total lesions is 46.3% for 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 combination oral contraceptive group and 30.6% for placebo group (P<.001). The likelihood of participants in the 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen group having "clear" or "almost clear" skin as rated by the investigators at endpoint was about threefold (odds ratio 3.13, 95% confidence interval 1.69-5.81; P=.001) greater than in the placebo group. The 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen was well tolerated. CONCLUSION: The low-dose combined oral contraceptive containing 3-mg drospirenone/20-microgram ethinyl estradiol administered in a 24/4 regimen significantly reduced acne lesion counts more effectively than placebo and demonstrated greater improvement in the Investigator Static Global Assessment rating of acne. The safety profile was consistent with low-dose combined oral contraceptive use.

A combined oral contraceptive containing 3-mg drospirenone/ 20-microg ethinyl estradiol in the treatment of acne vulgaris: a randomized, double-blind, placebo-controlled study evaluating lesion counts and participant self-assessment.

This study compared the efficacy of a low-dose combined oral contraceptive (COC) containing 3-mg drospirenone and 20-microg ethinyl estradiol (3-mg DRSP/20-microg EE) administered in a 24-day active pill/4-day inert pill (24/4) regimen and placebo in women with moderate acne vulgaris during 6 treatment cycles. A total of 534 participants were randomized and dispensed study medication (n = 266 [3-mg DRSP/20-microg EE 24/4 regimen COC group]; n = 268 [placebo group]). Women of reproductive age were eligible for inclusion in the study. Treatment with the 3-mg DRSP/20-microg EE 24/4 regimen COC was associated with a greater reduction from baseline to end point in individual lesion counts (papules, pustules, open and closed comedones) compared with placebo. The mean nodule count remained essentially constant throughout the study and was low in both treatment groups. There was a significantly higher probability that a participant had an improved assessment on the investigator's overall improvement rating scale (odds ratio [OR], 4.02; 95% CI [confidence interval], 2.29-7.31; P < .0001) and participant's overall self-assessment rating scale (OR, 2.82; 95% CI, 1.60-5.13; P = .0005) in the 3-mg DRSP/20-microg EE 24/4 regimen COC group than in the placebo group. The COC 3-mg DRSP/20-microg EE 24/4 regimen is a suitable option for women with moderate acne vulgaris who require contraception.

Efficacy and safety of 3 mg drospirenone/20 mcg ethinylestradiol oral contraceptive administered in 24/4 regimen in the treatment of acne vulgaris: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: A randomized, double-blind, parallel-group study to investigate the efficacy and safety of the 3 mg drospirenone (drsp)/20 mcg ethinylestradiol (EE) combined oral contraceptive (COC) administered in a 24/4 regimen (24 active tablets and 4 inert tablets per cycle) for the treatment of moderate acne vulgaris. STUDY DESIGN: Healthy females (aged 14-45 years old) with moderate facial acne were randomized to 3 mg drsp/20 mcg (n=266) or placebo (n=268) for six cycles of 28 days. RESULTS: Women who received the 3 mg drsp/20 mcg EE 24/4 COC had greater reductions from baseline in inflammatory, noninflammatory and total lesion counts. The odds of women in the 3 mg drsp/20 mcg EE 24/4 regimen COC group having 'clear' or 'almost clear' skin as rated by the investigators at end point was about fourfold greater than that in the placebo group (odds ratio 4.31; 95% CI: 2.11-9.60; p=.001). The 3 mg drsp/20 mcg EE 24/4 regimen COC was well tolerated and had a safety profile consistent with low-dose COC use. CONCLUSION: The 3 mg drsp/20 mcg EE 24/4 regimen COC was significantly more effective than placebo in treating moderate acne vulgaris.

Differences in symptom scores and health outcomes in premenstrual syndrome.

BACKGROUND: In studies of premenstrual syndrome (PMS), a significant response to treatment is commonly defined as a 50% reduction in symptom scores, but empirical support for this definition is lacking. We compared healthcare utilization in women with and without PMS according to the Daily Record of Severity of Problems (DRSP) scores in order to determine the degree of symptomatic variation in premenstrual symptoms associated with differences in the burden of illness. METHODS: Participants were women aged 18-45 years enrolled in a medical group in southern California. Respondents completed the Medical Outcomes Study Short Form-36 (SF-36) at baseline and the DRSP symptom and occupational productivity items daily. Luteal phase DRSP scores were averaged over two consecutive cycles. Respondents were categorized as having mild/no and moderate/severe PMS or premenstrual dysphoric disorder (PMDD) using a previously published, validated algorithm. Medical costs were estimated from medical claims data over the 2 years prior to study entry. RESULTS: Compared with women with moderate/severe PMS/PMDD (n = 117), those with mild/no PMS/PMDD (n = 271) had 43% lower DRSP scores (29.7 and 52.4, p < 0.05), higher SF-36 mental component summary (49.9 and 40.5, p < 0.0001) and physical component summary (52.6 and 50.8, p = 0.04) scores, and fewer workdays per month with reduced productivity (13.3 and 22.0, p < 0.0001) and workdays missed due to health reasons (1.2 and 2.7, p = 0.001). Women with moderate/severe PMS/PMDD had greater odds of having >10 office visits (OR = 1.80, 95% CI 1.01, 3.22) and of accumulating >$500 in medical charges (OR = 1.9, 95% CI 1.2, 3.0). CONCLUSIONS: A 43% difference in premenstrual vs. postmenstrual symptom scores is associated with a significant difference in healthcare burden. These data support the use of a 50% reduction in symptom ratings as a clinically relevant improvement in PMS/PMDD treatment trials, although smaller differences may also be meaningful.

Bleeding patterns associated with oral contraceptive use: a review of the literature.

The regulation of vaginal bleeding is an important effect impacting the choice of contraceptive methods. However, comparing vaginal bleeding control and disturbance between various contraceptive studies is often limited by the lack of uniformity in the analysis and reporting of the bleeding patterns. In 1986, the World Health Organization (WHO) issued recommendations for the standardized collection, analysis and reporting of bleeding associated with contraceptives based on 90-day reference periods. We systematically reviewed MEDLINE and EMBASE for all articles reporting bleeding data by reference periods in healthy women using oral contraception. Overall, 17 publications between 1986 and September 2006 were included for review. There was marked variability in the reporting of bleeding data with most studies reporting a few selected bleeding parameters. However, these studies showed, in general, that oral contraceptive users have the greatest bleeding (i.e., results in the highest number of bleeding/spotting days) during the first reference period which decreases by Reference Period 4. Reporting of the bleeding/spotting data using the WHO recommendations may be useful in objectively comparing vaginal bleeding patterns among different oral contraceptive products.