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International Journal of Analytical Chemistry
Volume 2012 (2012), Article ID 592650, 7 pages
Application of CZE Method in Routine Analysis for Determination of B-Complex Vitamins in Pharmaceutical and Veterinary Preparations
Dipartimento di Chimica, Sapienza Università, 00185 Roma, Italy
Received 12 July 2011; Revised 28 December 2011; Accepted 9 January 2012
Academic Editor: Mohamed Mohamed
Copyright © 2012 Marina Franco et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
A competitive CZE method for quality control analysis of multivitamin preparations and veterinary products containing B-group vitamins was developed. Vitamins of interest are thiamine hydrochloride (B1), thiamine monophosphate chloride (B1a), riboflavine (B2), riboflavine-5′monophosphate (B2a), nicotinamide (B3), d-pantothenic acid calcium salt (B5), pyridoxine hydrochloride (B6), folic acid (B9), and 4-aminobenzoic acid (B10). These analytes were separated optimizing the experimental conditions in 20 mM tetraborate buffer as a BGE (background electrolyte), on a Beckman P/ACE System MDQ instrument, using uncoated fused silica capillary. The effective capillary length was of 49.5 cm, μm, the applied voltage 20 kV and the temperature 25∘C. Detection was performed by a diode array detector at 214 nm for all vitamins except B5 (190 nm) and B2a (260 nm). Separation time was about 9 min. After experimental conditions optimization, the proposed method was validated. Precision of migration time and corrected peak area, linearity range, LOD and LOQ, accuracy (recovery), robustness, and ruggedness were evaluated for each analyte demonstrating the good reliability of the method. Analyses of the pharmaceutical real samples were performed and confirmed the versatility of this method.
1. Introduction
Quality control (QC) plays an essential role in the pharmaceutical industry. In fact many analytical methods, employing different techniques, are being developed for evaluation of pharmaceutical preparations. Vitamins of B group were well separated by RP-HPLC. A method for the simultaneous determination of taurine and 10 water-soluble vitamins including vitamin B1 (thiamine), B2 (riboflavine), B5 (pantothenic acid), B6 (pyridoxine and pyridoxal), B8 (biotin), B9 (folic acid), C (ascorbic acid), and B3 (nicotinamide and nicotinic acid) in multivitamin tablets was developed and validated. Detection of components was by ESI-MS [1]. Some water-soluble vitamins of our interest (ascorbic acid, thiamine hydrochloride, riboflavine-5′-phosphate sodium, pyridoxine hydrochloride, nicotinamide, and (+)-panthenol) and two preservatives (methylparaben and sodium benzoate) in multivitamin syrup were well-separated on Zorbax SB-Aq (C18) column [2]. A HPLC-UV method was established for the simultaneous determination of eight vitamins, including B1, B2, B3, B6, B9, cyanocobalamin, ascorbic acid in baby milk powder [3]. A validated HPLC-UV method for the determination of seven B-complex vitamins (B1, B2, B3, B6, B9, and cyanocobalamin) in pharmaceuticals and biological fluids after solid-phase extraction was performed [4]. Simultaneous determination of water- and fat-soluble vitamins in pharmaceutical preparations by HPLC was performed in a single run using combined isocratic and linear gradient elution with a mobile phase consisting of trifluoroacetic acid and methanol. The method was applied for real sample. The results were in good agreement with the declared values. Vitamins analyzed were B1, B2, B5, B6, B9, B3, and B12 (cyanocobalamin) [5].
The RP ion-pair HPLC method was applied for determination of some vitamins of our interest in multivitamin with minerals from different authors. For nicotinamide, pyridoxine hydrochloride, thiamine mononitrate and riboflavine a HPLC method was validated using methanol 0.5% acetic acid as the mobile phase [6].
A sensitive RP-HPLC method was developed and validated for the simultaneous determination of B1, B3, B6, and B9 in Pentovit coated tablets. The procedures were carried out on a Supelcosil ABZ column with methanol, heptanesulfonic acid sodium salt, and triethylamine as the mobile phase [7]. For the determination of thiamine and riboflavine in Duoweiyuansu Tablet an HPLC-UV method was established. The mobile phase consisted of ion-pairing reagent (containing 1-hexanesulfonate, glacial acetic acid, and triethylamine)/methanol (80 : 20). The method can be used for the quality control of thiamine and riboflavine in Duoweiyuansu Tablet [8]. There are many papers about vitamins of B group analysed by capillary electrophoresis (CE) and its modifications. Some authors studied determination of vitamins in food based on supercritical fluid extraction prior to micellar electrokinetic capillary chromatographic (MEKC) analyses of individual components. The method was optimized using sodium cholate as the micellar phase for the separation of 11 B-vitamins, ascorbic acid, and 4 impurities in about 25 min [9]. Other authors investigated in capillary zone electrophoresis (CZE) analysis the effect of lower organic alcohols as cosurfactants (methanol, ethanol, n-propanol, isopropanol, propanediol, n-butanol and isoamyl alc.) and n-hexane as an organic modifier in phosphate buffer with varying SDS concentration using a set of vitamins and p-hydroxybenzoic acid as the test mixture. Optimum separations were achieved particularly at high concentrations of the surfactant [10]. The CZE analyses of three vitamins (B1, B2, and B6 in tablets achieved using phosphate-borate buffer pH 9.0 short time of analysis (5 min) [11]. One year later the same authors studied another specific, precise, sensitive, and accurate method for separation of the same vitamins obtaining high separation efficiency and shorter analysis time (3 min) [12]. Four B vitamins, as B1, B2, pyridoxal, pyridoxine, and pyridoxamine (B6) in a pharmaceutical product were determined simultaneously using CZE. An HCl soln. was used for the extraction of the vitamins from a multivitamin-multimineral tablet. BGE employed was sodium phosphate buffer (pH 9.0) [13].
Mixture of four water-soluble B-group vitamins were analysed both by CZE and MECK. The quantitative analyses of different pharmaceutical formulations were compared with the LC method of the US Pharmacopeia obtaining a good correlation [14].
Rapid methods were developed for simultaneously separation of five vitamins: B1, B2, B6, nicotinamide, nicotinic, and ascorbic acid. They were tested on 15 real samples obtaining good resolution by (CZE) and (MECC). CZE was performed with 0.02 M borate buffer, while MECC in 0.02 M borate/phosphate buffer with 4% acetonitrile containing. 0.1 M sodium dodecyl sulfate [15].
Some authors studied a method for the analysis of six water-soluble vitamins (thiamine, nicotinamide, riboflavin, pyridoxine, pantothenic, and ascorbic acid) in a pharmaceutical formulation, by CZE. A good compromise between resolution, analysis time, and analyte stability was obtained by use of a 50 mM borax buffer of pH 8.5. This CZE method was very useful for the separation of more complex samples, but cyanocobalamin could not be separated from nicotinamide in this CZE system. In fact the 2 compounds were in uncharged form the pH used. Instead, they were resolved by MECC using SDS in BGE. Good results with respect to linearity, precision, and accuracy were obtained in the concentration range studied for the 6 vitamins [16].
There are some studies about B-complex by spectrophotometric methods.
Spectrophotometric determination of ternary mixtures of thiamine, riboflavin, and pyridoxal in pharmaceutical and human plasma by least-squares support vector machines were performed. The partial least squares (PLS) modelling and least-squares support vector machines were used for the multivariate calibration of the spectrophotometric data [17]. The same procedure was applied successfully for determination of B1, B2, B3, and B6 in pharmaceuticals by other authors [18].
Simultaneous determination of fourteen water-soluble vitamins (13 of B-group and vitamin C) in selected food matrices by LC/MS/MS technique is described in a recent paper [19]. Analytes were separated in less than 10 min with recoveries between 30% and 70%.
The QC process in pharmaceutical industry needs methods that are able to determine, in a single run, the majority of components. In many cases, to determine all components of a multivitamin pharmaceutical preparation, it is necessary to perform different analyses applying different techniques.
Capillary electrophoresis (CE) is a powerful analytical technique that is widely used in research, and in quality control of pharmaceuticals. As demonstrated exploring the literature data, the MEKC was the only method [9] able to separate up to 11 B-group vitamins. Other CE methods offer the possibility to separate only a few (max 5) molecules of this class. There are no publications about simultaneous determination of nine B-group vitamins by CZE, the simplest in CE system, which offers several advantages over HPLC such as rapid analysis, lower solvent consumption, then lower costs and minor environmental impact, and higher efficiency.
For this purpose, the aim of this work is to develop a validated CZE method for assay of a multicomponent pharmaceutical and veterinary formulations in routine analysis.
2. Experimental
2.1. Apparatus
The analyses were carried out on a P/ACE system from Beckman Instrument Fullerton, CA (USA), with a UV-DAD detector. For ruggedness evaluation, electrophoretic separations were carried out on the SpectraPhoresis 1000 instrument from Thermo-Quest Corporation, CA (USA).
The uncoated fused silica capillary ID = 50 μm, 59.5 cm total length and 49.5 cm effective length was supplied by SGE (Melbourne, Australia). Detection wavelength was set at 214 nm. The sample injections were performed in a hydrodynamic mode (5 s under 0.5 psi).
2.2. Chemicals and Materials
All reagents were of analytical grade purity.
Borax, disodium hydrogen phosphate dihydrate, sodium dihydrogen phosphate monohydrate, potassium chloride, and CTAB (Cetyl trimethylammonium bromide) were from FLUKA (Buchs, Switzerland). Phosphoric acid, sodium hydroxide, chloric acid, and acetonitrile were supplied by Carlo Erba (Milan, Italy). Trizma base (Tris [hydroxymethyl]aminomethane), EDTA (ethylenediaminetetraacetic acid). Sodium bicarbonate, citric acid, oxalic acid, and sodium bitartrate monohydrate were from Sigma-Aldrich (Steinheim, Germany).
The real samples were commercially available pharmaceutical products: Berocca Plus (Bayer S.p.A), Gabbrovital B forte (CEVA VETEM SpA), Trinidex (LDB LAB.DIACO BIOMEDICALI SpA), and Biochetasi (Sigma-Tau SpA). For solution filtering the syringe filters 0.45 μm (Millex HV, Millipore, MA, USA) were used.
2.2.1. The Standards of Vitamins
thiamine hydrochloride (B1), thiamine pyrophosphate chloride (B1a), riboflavine (B2), riboflavine-5′monophosphate (B2a), nicotinamide (B3), d-pantothenic acid calcium salt (B5), pyridoxine hydrochloride (B6), biotin (B8), folic acid (B9), B10 (4-aminobenzoic acid), cyanocobalamin (B12), hydroxocobalamin (B12a), and 2-3 dihydroxybenzoic acid were purchased from Fluka (Buchs, Switzerland).
2.3. Standard, Buffer, and Real Sample Preparation
Standard stock solutions of studied analytes (at 1 mg/mL concentration) were prepared in distilled water, riboflavine and folic acid were dissolved in HCl, respectively, 3 M and 2 M.
The calibration solutions were obtained by dilution of the stock solution with distilled water to give a desired analyte concentration. The real samples preparation was different for each product.
For Berocca Plus preparation, twenty tablets were weighted and grounded in a mortar. The quantity of powder equivalent at one tablet was weighted and dissolved in a 50 mL volumetric flask with distilled water. After sonication for 10 min in an ultrasonic bath, the supernatant solution was centrifuged for 5 min and then filtered through the 0.45 μm syringe filter. Finally the solution was diluted with distilled water to reach a concentration order inside the calibration range.
For Trinidex sample, the intravenous injection solution was filtered through the 0.45 μm syringe filter without dilution and injected.
For Gabbrovital preparation, the veterinary intramuscular injection solution was diluted 1 : 1000 because of its high concentration, then filtered and analysed.
For Biochetasi sample, the powder contained in the vial for the intramuscular injection, was diluted with distilled water to reach a desired concentration and then filtered through the 0.45 μm syringe filter.
3. Results and Discussion
3.1. Method Development and Optimization
In order to propose a suitable method for routine analysis, it was necessary to evaluate the experimental conditions for the best resolution of studied analytes.
First, because of different solubility and stability for each vitamin, many conditions for their dissolution were tested. Several parameters for the CZE analysis, such as BGE composition and concentration, pH, injection conditions, wavelengths, applied voltage, and temperature were explored.
3.1.1. Effect of BGE Composition, Concentration, and pH
The BGE buffer composition is one of the most important parameters in capillary electrophoresis.
In order to obtain maximum precision level, it is necessary to choose the buffer very carefully.
Most of vitamins are nitrogen-containing, protonable molecules, so starting point of this work was to explore the low range of pH values for their separation.
In the preliminary step of study, the BGEs tested pH ranging between 1.5–4.2 and concentration ranging between 20 mM to 50 mM, are HCl/KCl, phosphate, phosphate-oxalate, phosphate with 5% acetonitrile, phosphate with CTAB, phosphate-tartrate, and tartrate.
Only in 20 mM phosphate buffer at pH = 2.3 good separation of eleven analytes was realised in about 23 minutes. In Figure 1, analytes from 1 to 7 are cations, the others (8–10) are in anionic form. In these operating conditions, riboflavine (B2) and cyanocobalamin (B12) are overlaid. Since these compounds are often contained in the same pharmaceutical preparation, it is impossible to determinate both of them. Long analysis time, high intensity of current, and low repeatability of migration time (RSD% ~ 10%) did not allow to propose this procedure for routinely analyses.
Consequently the possibility of separation of studied vitamins in alkaline buffers were evaluated.
BGE buffers at pH between 8.5 and 9.3 into the range of concentration 20 mM to 80 mM were explored: tris/HCl, bicarbonate/carbonate, tris/borate, borate, borate with EDTA, and borate with CTAB.
Best separation of nine vitamins was realized in 20 mM borate buffer at pH 9.2 in about 9 minutes (Figure 2).
The peaks are symmetric and baseline resolved for individual B vitamins with exception of d-pantothenic acid calcium salt (B5) and riboflavine-5′monophosphate (B2a), that are coeluted. Since a good compromise between peak symmetry, resolution, and analysis time resulted in 20 mM borate buffer at pH = 9.2, these experimental conditions were chosen as optimal.
3.1.2. Effect of Wavelength
Primarily it was necessary to select the most suitable wavelength for the simultaneous detection of vitamins, since spectral properties of each one differs enough. The UV spectra obtained by UV-DAD show three suitable wavelengths for quantitative analysis. 214 nm for all the vitamins, at exception of d-pantothenic acid calcium salt (B5) and riboflavine-5′monophosphate (B2a), that are overlaid. Then the quantitative analysis of these two analytes was realized at the wavelengths of 190 and 260 nm, because the considered compounds do not interfere themselves. In fact vitamin B5 has only maximum of absorbance at 190 nm, while vitamin B2a presents two maximums at 214 and 260 nm.
3.1.3. Effect of Applied Voltage
For the optimization of separation voltage the analyses ranging the applied voltage between 10 and 30 kV were carried out. At low voltage the separation of all the analytes was reached but the analysis time increased to 20 min with the broadening of peaks. Increasing the voltage (max 30 kV) the optimal value results in 20 kV producing the current intensity of 25 uA and good repeatability. At 30 kV the separation of analytes was incomplete.
3.1.4. Effect of Temperature
The increase of temperature (30°C) produced the shortening of analysis time (the viscosity of the BGE decrease). It should be advantageous setting high temperature of cartridge but B-complex is thermolabile. So the suitable temperature for analyses of these compounds resulted in 25°C.
3.2. Method Validation
The method was validated following the ICH guideline [20].
3.2.1. Precision
The precision was evaluated in terms of RSD% of migration time () and corrected peak area () for intraday and interday analyses. For the intra-day precision evaluation the standard solutions at three concentrations levels (low, intermediate, and high) were injected in the same day. To estimate the interday precision, the standard solutions were analysed for five consecutive days performing five consecutive injections every day. The calculated RSD% values are reported in Table 1.
3.2.2. Calibration Range
The linearity of detector response was tested in different ranges as reported in Table 2. For the quantitative analysis the Internal Standard method was applied. For its property, was choosen Internal Standard 3,4 dihydroxy-benzoic acid.
Six standard solutions, containing nine analytes of interest and the Internal Standard, were injected in triplicate. The calibration lines were obtained plotting R (corrected areas ratio) versus the standard solutions concentration using Microsoft EXCEL.
3.2.3. LOD and LOQ
LOD, the lowest concentration of analytes that can be distinguished from the noise, defined as signal to noise ratio S/N of 3 : 1 was ranging between 0.9 μg/mL to 9.0 μg/mL.
LOQ, the lowest concentration of analytes that can be quantified with good precision, defined as signal to noise ratio S/N of 10 : 1 was ranging between 3.0 μg/mL to 30.0 μg/mL.
3.2.4. Analysis of Real Samples
Four pharmaceutical formulation containing B-complex vitamins were analyzed. The experimental results are given in Table 3. No interference was observed in pharmaceutical solutions. RSD% of migration time and corrected peak area values were lower, respectively, than 0.5% and 3.0%. A typical electropherogram of commercial pharmaceutical preparation (Berocca Plus) is shown in Figure 3.
3.2.5. Accuracy
Accuracy was evaluated by recovery assays on the commercial product. After fortification, the real sample undergo the analysis and the resulted concentration were compared with the data obtained without fortification. The resulting recoveries data are ranging from 97.0 to 101.4%.
3.2.6. Ruggedness
For this purpose, measurements on the SpectraPhoresis 1000 apparatus in the optimal experimental conditions were performed. In this instrument the cartridge form is different and the capillary total length is 44 cm, the effective length 36 cm (shorter than optimal length of capillary utilized on the Beckman instrument). Consequently, on this instrument, it was necessary to apply lower voltage (10 kV). The electropherogram, obtained on this apparatus, injecting the standard mixture in hydrodynamic mode for 1 sec, is shown in Figure 4. Repeatability of migration time is ranging from 0.32% to 0.52%.
4. Conclusion
Proposed method was developed for the simultaneous determination of nine water-soluble vitamins (B1, B1a, B2, B2a, B3, B5, B6, B9, and B10) in the multivitamin pharmaceutical formulations by CZE. The best resolution was obtained in about 9 min using a simple tetraborate buffer 20 mM, pH = 9.2 at 25°C, and constant voltage of 20 kV in uncoated fused silica capillary. The method is suitable for the vitamins B analysis as the validation confirmed: it is precise, accurate, and rugged. The analyses of real samples proved its applicability. Since no expensive reagent and no pretreatment of samples are required in this procedure, it offers a valid alternative for quality control analysis in the pharmaceutical industry.
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function | court building, office |
contributed by | rgctobin |
The architects were presented with the challenging context of Trim Castle, Europe's largest Norman fortress (completed 1204) in which to refurbish and extend an existing courthouse building, dating from the 1810s. The refurbished courthouse gains breathing space from its new neighbour which accommodates office space. The new wing reacts to the context in which the building is placed - the limestone wall which wraps around the ground floor complements the adjacent castle's rampart, and the circular tower takes its form from the fortifications along the castle's curtain wall. Four courtrooms are available for sittings of the High, Circuit and District Courts.


text:
"...all my days were written in Your book and planned before a single one of them began."
Psalm 139:16
Wednesday, April 2, 2008
1 comment:
- Hillary said...
Oh Bless! I love that too! Thanks for sharing! I needed that!
- April 2, 2008 at 8:20 AM
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text:
97545 Secure Login/XML feed renderin
This project is now closed with a project budget of N/A.
Get free quotes for a project like thisProject Budget
N/AProject Description
I am building a person search site. I am looking to hire someone to help me build the secure login and the xml feed part.
Part 1. Designing and building a secure login to my web site. Once logged in user has the ability to do searches by entering pre-determined criteria.
Part 2 is the XML feed part. Entered search criteria will be send to a 3rd party website and the contents of the XML feed rendered to a report shown on the users browser.
When replying please include areas you think need to be addressed.
I'm looking for a secure log in mechanism with all the associated features (similar to what Banks do for online banking):
User portal is based on PHP that will tie into a mysql database.
Users should be able to register with name/password and an activation email should be sent which will include users agreement and triggered before the account is ready to be activated for use.
Users should be able to Log in, change password and be able to provide "Security question" to answer if they forget their password. If user answers security question correctly then the users password will be emailed to the registered email address.
a. There would be Inactivity sign out set at 10 minutes.
b. The user's IP address must be stored in the user profile for each use.
c. The web page will have an interface to the amount of successful submissions made and deleted from number of searches available.
d. Last 3 searches and results are stored in the mysql database for view later if user requested.
Only way to activate account for use is through Admin panel. An admin user id could look at the data entered and activate the user if needed.
Also will want a deployment document to tell me how to integrate into secure area of the website and mysql table structure and create sql's.
- Secure Login
- Activate members
- Set add, delete total number of searches.
- Can add/edit/delete members
- View all members
- Edit members
- Secure Login
- Change password
- Change personal information
- View last 3 searches (History)
Part 2.
I am looking to render the contents of a third party hosted xml feed on secure part of my web site.
Require a small search/results page where user will enter name, and other basic Search criteria and submit to a web site using GET or POST methods.
firstName � required
middleName � optional
lastName � required
city � optional
state � optional
DOB � optional (must be a proper date format mm/dd/yyyy)
I will provide a detailed document with all the required information and the example of xml file and example of output (please note this file is hosted elsewhere and I have no control over its structure).
This is a part of a big project and successes of this project could lead to other projects. There could be a bonus. I need a working demo of the work before payment made to the winning bidder.
Please, along with your bid, please detail how you would render the attached XML file.
Skills Required
Looking to make some money?
- Set your budget and the timeframe
- Outline your proposal
- Get paid for your work
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text:
Sin Without
$ 90.00
Adjustable 18-Karat Gold plated ring inscribed with the word "Cunt" on the inside. The outside of the band is blank and finished with a subtle insignia on the right corner.
- 2mm thick x 9.8mm tall (width / height)
- Brass plated 18-Karat Gold.
- Adjustable Band for Fit and Comfort.
- Handmade in Downtown Los Angeles.
- For sizing details and care instructions visit www.sinwithout.com


text:
IUD with progestogen
IUD with progestogen | |
Correctly inserted IUD
Background | |
Type | Intrauterine |
First use |
1990 (Mirena—currently available) |
Synonyms | intrauterine system (IUS), levonorgestrel intrauterine system |
Trade names | Kyleena, Liletta, Mirena, Skyla, others |
AHFS/Drugs.com | Multum Consumer Information |
Failure rates (first year) | |
Perfect use | 0.2%[1] |
Typical use | 0.2%[1] |
Usage | |
Duration effect | 5 years (Mirena) 3 years (Skyla) |
Reversibility | 2–6 months |
User reminders | Check thread position monthly |
Advantages and disadvantages | |
STI protection | No |
Periods | Menstrual irregularity, periods usually lighter or none at all |
Weight | Potential side effect |
Benefits | No need to remember to take daily action |
Risks | benign ovarian cysts, transient risk of PID, uterine perforation (rare) |
Intrauterine device (IUD) with progestogen, sold under the brand name Mirena among others, is a intrauterine device that releases the hormone levonorgestrel.[2] It is used for birth control, heavy menstrual periods, and to prevent excessive build of the lining of the uterus in those on estrogen replacement therapy.[2] It is one of the most effective forms of birth control with a one-year failure rate around 0.2%.[1] The device is placed in the uterus and lasts three to five years.[3] Following removal fertility returns quickly.[2]
Side effects include irregular periods, benign ovarian cysts, pelvic pain, and depression.[2] Rarely uterine perforation may occur.[2] Use is not recommended during pregnancy but is safe with breastfeeding.[2] The IUD with progestogen is a type of long-acting reversible birth control.[4] It works by making the mucous at the opening to the cervix thick, stopping the buildup of the lining of the uterus, and occasionally preventing ovulation.[2]
The IUD with levonorgestrel was first approved for medical use in 1990 in Finland and in the United States in 2000.[5] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[6] The wholesale cost in the developing world is about US$122.46 each.[7] In the United Kingdom they cost the NHS about £88 pounds.[2] In the United States they cost around US$844.00.[8] More than 120 countries have approved the device and it is used by more than 10 million women.[5][9]
Medical uses[edit]
In addition to birth control, hormonal IUD are used for prevention and treatment of:
- heavy menstrual periods[10]
- Endometriosis and chronic pelvic pain[10][11]
- Adenomyosis and dysmenorrhea[10][12]
- Anemia[13]
- In some cases, use of a hormonal IUD may prevent a need for a hysterectomy.[14][needs update]
- Considered one of the most effective forms of reversible birth control[15]
- Can be used while breastfeeding[16] (see also nursing mothers)
- No preparations needed before sex,[17] though routine checking of the device strings by patient and physician is advised to ensure proper placement remains intact[18]
- 90% of users who wish to become pregnant do so within 24 months of removal.[19]
- May experience lighter periods (some women stop having periods completely, see also amenorrhea)[20]
- Effective for up to three to five years (depending on the IUD)[21]
- Irregular periods and spotting between periods often occurs after insertion[20]
- Mild to moderate discomfort experienced during insertion procedure, including cramping or backache
- Other potential adverse effects and risks
After insertion, Mirena is officially sold as effective for up to five years, although several studies have shown that it remains effective through seven years.[22][23] Skyla is effective for 3 years.[24]
The hormonal IUD is a long-acting reversible contraceptive, and is considered one of the most effective forms of birth control. The first year failure rate for the hormonal IUD is 0.2% and the five year failure rate is 0.7%.[25] These rates are comparable to tubal sterilization, but unlike sterilization the effects of the hormonal IUD are reversible.
The hormonal IUD is considered to be more effective than other common forms of reversible contraception, such as the birth control pill, because it requires little action by the user after insertion.[15] The effectiveness of other forms of birth control is mitigated (decreased) by the users themselves. If medication regimens for contraception are not followed precisely, the method becomes less effective. IUDs require no daily, weekly, or monthly regimen, so their typical use failure rate is therefore the same as their perfect use failure rate.[15]
In women with bicornuate uterus and in need of contraception, two IUDs are generally applied (one in each horn) due to lack of evidence of efficacy with only one IUD.[26] Evidence is lacking regarding progestogen IUD usage for menorrhagia in bicornuate uterus, but a case report showed good effect with a single IUD for this purpose.[27]
Progestogen-only contraceptives such as an IUD are not believed to affect milk supply or infant growth.[28] However, a study in the Mirena application for FDA approval found a lower continuation of breastfeeding at 75 days in hormonal IUD users (44%) versus copper IUD users (79%).[29]
When using Mirena, about 0.1% of the maternal dose of levonorgestrel can be transferred via milk to the nursed infant.[30] A six-year study of breastfed infants whose mothers used a levonorgestrel-only method of birth control found the infants had increased risk of respiratory infections and eye infections, though a lower risk of neurological conditions, compared to infants whose mothers used a copper IUD.[31] No longer-term studies have been performed to assess the long-term effects on infants of levonorgestrel in breast milk.
There are conflicting recommendations about use of Mirena while breastfeeding. The U.S. FDA does not recommend any hormonal method, including Mirena, as a first choice of contraceptive for nursing mothers.[citation needed] The World Health Organization recommends against immediate postpartum insertion, citing increased expulsion rates. It also reports concerns about potential effects on the infant's liver and brain development in the first six weeks postpartum. However, it recommends offering Mirena as a contraceptive option beginning at six weeks postpartum even to nursing women.[32] Planned Parenthood offers Mirena as a contraceptive option for breastfeeding women beginning at four weeks postpartum.[33]
A hormonal IUD should not be used by women who:
- Are, or think they may be, pregnant[16]
- Have abnormal vaginal bleeding that has not been explained[16]
- Have untreated cervical or uterine cancer[16]
- Have, or may have, breast cancer[16]
- Have abnormalities of the cervix or uterus[34]
- Have had pelvic inflammatory disease within the past 3 months[16]
- Have had an STI such as chlamydia or gonorrhea within the past 3 months[16]
- Have liver disease or tumor[34]
- Have an allergy to levonorgestrel or any of the inactive ingredients included in the device[34]
Insertion of an IUD is not recommended for women having had a D&E abortion (second-trimester abortion) within the past four weeks.[33] To reduce the risk of infection, insertion of an IUS is not recommended for women that have had a medical abortion but have not yet had an ultrasound to confirm that the abortion was complete, or that have not yet had their first menstruation following the medical abortion.[33]
A full list of contraindications can be found in the WHO Medical Eligibility Criteria for Contraceptive Use and the CDCUnited States Medical Eligibility Criteria for Contraceptive Use.[16][35]
Side effects[edit]
- Irregular menstrual pattern: irregular bleeding and spotting is common in the first 3 to 6 months of use. After that time periods become shorter and lighter, and 20% of women stop having periods after 1 year of use.[36] The average user reports 16 days of bleeding or spotting in the first month of use, but this diminishes to about four days at 12 months.[37][38]
- Cramping and Pain: many women feel discomfort or pain during and immediately after insertion. Some women may have cramping for the first 1–2 weeks after insertion.[39]
- Expulsion: Sometimes the IUD can slip out of the uterus. This is termed expulsion. Around 5% of IUD users experience expulsion. If this happens a woman is not protected from pregnancy.[39][40] Expulsion is more common in younger women, women who have not had children, and when an IUD is inserted immediately after childbirth or abortion.[41][42][43]
- Perforation: Very rarely, the IUD can be pushed through the wall of the uterus during insertion. Risk of perforation is mostly determined by the skill of the practitioner performing the insertion. For experienced medical practitioners, the risk of perforation is 1 per 1,000 insertions or less.[44] With postpartum insertions, perforation of the uterus is more likely to occur when uterine involution is incomplete; involution usually completes by 4–6 weeks postpartum.[42] Special considerations apply to women who plan to breastfeed. If perforation does occur it can damage the internal organs, and in some cases surgery is needed to remove the IUD.
- Pregnancy complications: Although the risk of pregnancy with an IUD is very small, if one does occur there is an increased risk of serious problems. These include ectopic pregnancy, infection, miscarriage, and early labor and delivery. As many as half the pregnancies that occur in Mirena users may be ectopic. The incidence rate of ectopic pregnancies is approximately 1 per 1000 users per year.[45] Immediate removal the IUD is recommended in the case of pregnancy.[39][40] No pattern of birth defects was found in the 35 babies for whom birth outcomes were available at the time of FDA approval.[46]
- Infection: The insertion of the IUD does have a small risk of pelvic inflammatory disease (PID). Concurrent infection with gonorrhea or chlamydia at the time of insertion increases the risk of pelvic inflammatory disease.[47] If PID does occur, it will most likely happen within 21 days of insertion. The device itself does not increase the risk of infection.[39]
- Ovarian Cysts: Enlarged follicles (ovarian cysts) have been diagnosed in about 12% of the subjects using a hormonal IUD. Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain or dyspareunia. In most cases the enlarged follicles disappear spontaneously after two to three months. Surgical intervention is not usually required.[48]
- Mental health changes including: nervousness, depressed mood, mood swings[34]
- Weight gain[34]
- Headache, migraine[34]
- Nausea[34]
- Acne[34]
- Excessive hairiness[34]
- Lower abdominal or back pain[34]
- Decreased libido[34]
- Itching, redness or swelling of the vagina[34]
- Vaginal discharge[49]
- Breast pain, tenderness[49]
- Edema[49]
- Abdominal distension[49]
- Cervicitis [49]
- May affect glucose tolerance [49]
- May experience a change in vision or contact lens tolerance [19]
- May deplete Vitamin B1 which can affect energy, mood, and nervous system functioning [19]
- A "lost coil" occurs when the thread cannot be felt by a woman on routine checking and is not seen on speculum examination.[50] Various thread collector devices or simple forceps may then be used to try to grasp the device through the cervix.[51] In the rare cases when this is unsuccessful, an ultrasound scan may be arranged to check the position of the coil and exclude its perforation through into the abdominal cavity or its unrecognised previous expulsion.
According to a 1999 evaluation of the studies performed on progestin-only birth control by the International Agency for Research on Cancer, there is some evidence that progestin-only birth control reduces the risk of endometrial cancer. The IARC concluded that there is no evidence progestin-only birth control increases the risk of any cancer, though the available studies were too small to be definitively conclusive.[52]
Progesterone is a hormone in the endometrium that counteracts estrogen driven growth.[53] Very low levels of progesterone will cause estrogen to act more, leading to endometrial hyperplasia and adenocarcinoma.[53] These effects can be minimized if treated with progestin, but not in very many cases.
Estrogen and progesterone have an antagonistic relationship. Estrogen promotes the growing of endometrial lining, while progesterone limits it.[53] In the case of endometrial cancer, progesterone can negatively regulate estrogen driven growth. Tumors formed are correlated with insufficient progesterone and excess estrogen.[53] In patients with endometrial cancer who use progestin releasing IUDs concluded mixed results.
Bone density[edit]
No evidence has been identified to suggest Mirena affects bone mineral density (BMD).[54] Two small studies, limited to studying BMD in the forearm, show no decrease in BMD.[55][56] One of the studies showed at 7 years of use, similar BMD at the midshaft of the ulna and at the distal radius as nonusers matched by age and BMI.[55] In addition, BMD measurements were similar to the expected values for women in the same age group as the participants. The authors of the study said their results were predictable, since it is well established that the main factor responsible for bone loss in women is hypoestrogenism, and, in agreement with previous reports, they found estradiol levels in Mirena users to be normal.[55]
Composition and hormonal release[edit]
The hormonal IUD is a small 'T'-shaped piece of plastic, which contains levonorgestrel, a type of progestin.[25] The cylinder of the device is coated with a membrane that regulates the release of the drug.[57] Mirena releases the drug at an initial rate of 20 micrograms per day. This declines to a rate of 14 micrograms per day after 5 years, which is still in the range of clinical effectiveness. Skyla releases 14 micrograms per day and declines to 5 micrograms per day after 3 years.[24] Bayer markets Skyla as Jaydess in the United Kingdom.[58] Jaydess releases 6 micrograms per day and lasts for 3 years.[59] In comparison, oral contraceptives can contain 150 micrograms of levonorgestrel.[39] The hormonal IUD releases the levonorgestrel directly into the uterus, as such its effects are mostly paracrine rather than systemic. Most of the drug stays inside the uterus, and only a small amount is absorbed into the rest of the body.[39] Blood levels of levonorgestrel in Mirena users are half those found in Norplant users and one-tenth those found in users of levonorgestrel-only pills).[60]
Insertion and removal[edit]
The hormonal IUD is inserted in a similar procedure to the nonhormonal copper IUD, and can only be inserted by a qualified medical practitioner.[39] Before insertion, a pelvic exam is performed to examine the shape and position of the uterus. It is also recommended that patients be tested for gonorrhea and chlamydia prior to insertion, as a current STI at the time of insertion can increase the risk of pelvic infection.[61] During the insertion, the vagina is held open with a speculum, the same device used during a pap smear.[39] A grasping instrument is used to steady the cervix, the length of the uterus is measured for proper insertion, and the IUD is placed using a narrow tube through the opening of the cervix into the uterus.[39] A short length of monofilament plastic/nylon string hangs down from the cervix into the vagina. The string allows physicians and patients to check to ensure the IUD is still in place and enables easy removal of the device.[39] Mild to moderate cramping can occur during the procedure, which generally takes five minutes or less. Insertion can be performed immediately postpartum and post-abortion if no infection has occurred.[16] Misoprostol is not effective in reducing pain in IUD insertion.[62]
Removal of the device should also be performed by a qualified medical practitioner. After removal, fertility will return to previous levels relatively quickly.[63] One study found that the majority of participants returned to fertility within three months.[64]
Mechanisms of action[edit]
The hormonal IUD's primary mechanism of action is to prevent fertilization.[39][65][66][67][68] The levonorgestrel intrauterine system has several contraceptive effects:
- The inside of the uterus becomes fatal to sperm[67][69]
- Cervical mucus thickens[22]
- Ovulation is not inhibited[70]
- They can also thin the endometrial lining and potentially impair implantation but this is not the usual function.[71][72]
Numerous studies have demonstrated that IUDs primarily prevent fertilization, not implantation.[39] In one experiment involving tubal flushing, fertilized eggs were found in half of women not using contraception, but no fertilized eggs were found in women using IUDs.[73] IUDs also decrease the risk of ectopic pregnancy, which further implies that IUDs prevent fertilization.[39]
Hormonal IUDs were developed in the 1970s following the development of the copper IUD in the 1960s and 1970s.[74] Dr. Antonio Scommenga, working at the Michael Reese Hospital in Chicago, discovered that administering progesterone inside the uterus could have contraceptive benefits.[74] With knowledge of Scommegna's work, a Finnish doctor, Jouni Valtteri Tapani Luukkainen, created the 'T'-shaped IUD that released progesterone, marketed as the Progestasert System in 1976. This IUD had a short, 1-year lifespan and never achieved widespread popularity. Following this relative lack of success, Dr. Luukkainen replaced the progesterone with the hormone levonorgestrel to be released over a 5-year period, creating what is now Mirena.[75]
The Mirena IUD was studied for safety and efficacy in two clinical trials in Finland and Sweden involving 1,169 women who were all between 18 and 35 years of age at the beginning of the trials. The trials included predominantly Caucasian women who had been previously pregnant with no history of ectopic pregnancy or pelvic inflammatory disease within the previous year. Over 70% of the participants had previously used IUDs.[76]
In 2013 Skyla, a lower dose levonorgestrel IUD effective for up to 3 years, was approved by the FDA.[77] Skyla has a different bleeding pattern than Mirena, with only 6% of women in clinical trials becoming amenorrheic (compared to approximately 20% with Mirena). In 2015, Liletta was approved by the FDA. Liletta has a similar size and levonorgestrel release characteristics as Mirena, and is FDA-approved for 3 years of use following a study in which 6 women out of 1,751 conceived while using Liletta.[78]
In 2009, Bayer, the maker of Mirena, was issued an FDA Warning Letter by the United States Food and Drug Administration for overstating the efficacy, minimizing the risks of use, and making "false or misleading presentations" about the device.[79][80] From 2000 to 2013, the federal agency received over 70,072 complaints about the device and related adverse effects.[81][82] As of April 2014, over 1,200 lawsuits have been filed in the United States.[80][83][84][85][86]
- ^ a b c Trussell, James (2011). "Contraceptive efficacy". In Hatcher, Robert A.; Trussell, James; Nelson, Anita L.; Cates, Willard Jr.; Kowal, Deborah; Policar, Michael S. (eds.). Contraceptive technology (20th revised ed.). New York: Ardent Media. pp. 779–863. ISBN 978-1-59708-004-0. ISSN 0091-9721. OCLC 781956734. Table 26–1 = Table 3–2 Percentage of women experiencing an unintended pregnancy during the first year of typical use and the first year of perfect use of contraception, and the percentage continuing use at the end of the first year. United States.
- ^ a b c d e f g h British national formulary: BNF 69 (69th ed.). British Medical Association. 2015. p. 556. ISBN 9780857111562.
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- ^ a b Bradley, Linda D.; Falcone, Tommaso (2008). Hysteroscopy: Office Evaluation and Management of the Uterine Cavity. Elsevier Health Sciences. p. 171. ISBN 0323041019.
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- ^ Sheng, J; Zhang, WY; Zhang, JP; Lu, D. (2009). "The LNG-IUS study on adenomyosis: a 3-year follow-up on the efficacy and side effects of the use of levonorgestrel intrauterine system for the treatment of dysmenorrheal associated with adenomyosis". Contraception. 79 (3): 189–193. doi:10.1016/j.contraception.2008.11.004. PMID 19185671.
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- ^ Rowe, Patrick; Farley, Tim; Peregoudov, Alexandre; Piaggio, Gilda; Boccard, Simone; Landoulsi, Sihem; Meirik, Olav. "Safety and efficacy in parous women of a 52-mg levonorgestrel-medicated intrauterine device: a 7-year randomized comparative study with the TCu380A". Contraception. 93 (6): 498–506. doi:10.1016/j.contraception.2016.02.024.
- ^ a b Highlights of Prescribing Information (Report). 9 January 2013.
- ^ a b [1], Bayer Pharmaceuticals.
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- ^ Acharya GP, Mills AM (July 1998). "Successful management of intractable menorrhagia with a levonorgestrel-releasing intrauterine device, in a woman with a bicornuate uterus". J Obstet Gynaecol. 18 (4): 392–3. doi:10.1080/01443619867263. PMID 15512123.
- ^ Truitt S, Fraser A, Grimes D, Gallo M, Schulz K (2003). Lopez, Laureen M, ed. "Combined hormonal versus nonhormonal versus progestin-only contraception in lactation". Cochrane Database Syst Rev (2): CD003988. doi:10.1002/14651858.CD003988. PMID 12804497.
- ^ FDA Medical Review p. 37.
- ^ MIRENA® Data Sheet, Bayer NZ, 11 December 2009http://www.bayerresources.com.au/resources/uploads/DataSheet/file9503.pdf Retrieved 2011-02-10
- ^ Schiappacasse V, Díaz S, Zepeda A, Alvarado R, Herreros C (2002). "Health and growth of infants breastfed by Norplant contraceptive implants users: a six-year follow-up study". Contraception. 66 (1): 57–65. doi:10.1016/S0010-7824(02)00319-0. PMID 12169382.
- ^ "Medical Eligibility Criteria for Contraceptive Use" (PDF). Third Edition. World Health Organization. 2004: 101, 113. Retrieved 16 August 2006. pp.101, 113.
- ^ a b c "Understanding IUDs". Planned Parenthood. July 2005. Archived from the original on 12 October 2006. Retrieved 8 October 2006.
- ^ a b c d e f g h i j k l "Mirena: Consumer Medicine Information" (PDF). Bayer. March 2014. Retrieved 27 April 2014.
- ^ WHO (2010). "Intrauterine devices (IUDs)". Medical Eligibility Criteria for Contraceptive Use (4th ed.). Geneva: Reproductive Health and Research, WHO. ISBN 978 92 4 1563888.
- ^ Hidalgo, M; Bahomondes, L; Perrottie, M; Diaz, J; Dantas-Monterio, C; Petta, CA. (2002). "Bleeding Patterns and clinical performance of the levonorgestrel-releasing intrauterine device (Mirena) up to two years". Contraception. 65 (2): 129–132. doi:10.1016/S0010-7824(01)00302-X. PMID 11927115.
- ^ McCarthy L (2006). "Levonorgestrel-Releasing Intrauterine System (Mirena) for Contraception". Am Fam Physician. 73 (10): 1799–. Retrieved 4 May 2007.
- ^ Rönnerdag M, Odlind V (1999). "Health effects of long-term use of the intrauterine levonorgestrel-releasing system. A follow-up study over 12 years of continuous use". Acta Obstet Gynecol Scand. 78 (8): 716–21. doi:10.1034/j.1600-0412.1999.780810.x. PMID 10468065.
- ^ a b c d e f g h i j k l m Dean, Gillian; Schwarz, Eleanor Bimla (2011). "Intrauterine contraceptives (IUCs)". In Hatcher, Robert A.; Trussell, James; Nelson, Anita L.; Cates, Willard Jr.; Kowal, Deborah; Policar, Michael S. Contraceptive technology (20th revised ed.). New York: Ardent Media. pp. 147–191. ISBN 978-1-59708-004-0. ISSN 0091-9721. OCLC 781956734. p.150:
Mechanism of action
Although the precise mechanism of action is not known, currently available IUCs work primarily by preventing sperm from fertilizing ova.26 IUCs are not abortifacients: they do not interrupt an implanted pregnancy.27 Pregnancy is prevented by a combination of the "foreign body effect" of the plastic or metal frame and the specific action of the medication (copper or levonorgestrel) that is released. Exposure to a foreign body causes a sterile inflammatory reaction in the intrauterine environment that is toxic to sperm and ova and impairs implantation.28,29 The production of cytotoxic peptides and activation of enzymes lead to inhibition of sperm motility, reduced sperm capacite journal and survival, and increased phagocytosis of sperm.30,31… The progestin in the LNg IUC enhances the contraceptive action of the device by thickening cervical mucus, suppressing the endometrium, and impairing sperm function. In addition, ovulation is often impaired as a result of systemic absorption of levonorgestrel.23
p. 162:
Table 7-1. Myths and misconceptions about IUCs
Myth: IUCs are abortifacients. Fact: IUCs prevent fertilization and are true contraceptives. - ^ a b Population Information Program, Johns Hopkins School of Public Health (1995). "IUDs—An Update". Population Reports. XXII (5).
- ^ IUDs—An Update. "Chapter 2.7:Expulsion".
- ^ a b IUDs—An Update. "Chapter 3.3 Postpartum Insertion".
- ^ IUDs—An Update. "Chapter 3.4 Postabortion Insertion".
- ^ World Health Organization (1987). "Mechanisms of action, safety and efficacy of intrauterine devices: technical report series 753.". Geneva.
- ^ FDA Medical Review pp. 3-4
- ^ FDA Medical Review p. 5,41
- ^ Grimes, DA (2000). "Intrauterine Device and upper-genital-tract infection". The Lancet. 356: 1013–1019. doi:10.1016/S0140-6736(00)02699-4. PMID 11041414.
- ^ Bahamondes L; Hidalgo M; Petta CA; Diaz J; Espejo-Arce X; Monteiro-Dantas C. (2003). "Enlarged ovarian follicles in users of a levonorgestrel-releasing intrauterine system and contraceptive implant". J. Reproduc. Med. 48 (8): 637–640. PMID 12971147.
- ^ a b c d e f "Mirena". BayerUK. 11 June 2013. Retrieved 18 June 2015.
- ^ Nijhuis J, Schijf C, Eskes T (1985). "The lost IUD: don't look too far for it". Ned Tijdschr Geneeskd. 129 (30): 1409–10. PMID 3900746.
- ^ Kaplan N (1976). "Letter: Lost IUD". Obstet Gynecol. 47 (4): 508–9. PMID 1256735.
- ^ "Hormonal Contraceptives, Progestogens Only". International Agency for Research on Cancer. 1999. Retrieved 8 October 2006.
- ^ a b c d Kim, Julie; Chapman-Davis, Eloise (26 January 2010). "Role of Progesterone in Endometrial Cancer". Semin Reprod Med. 28: 81–90. doi:10.1055/s-0029-1242998. PMC 4767501. PMID 20104432.
- ^ Faculty of Family Planning and Reproductive Health Care Clinical Effectiveness Unit (2004). "FFPRHC Guidance (April 2004). The levonorgestrel-releasing intrauterine system (LNG-IUS) in contraception and reproductive health" (PDF). J Fam Plann Reprod Health Care. 30 (2): 99–109. doi:10.1783/147118904322995474. PMID 15086994.
- ^ a b c Wong AY, Tang LC, Chin RK (2010). "Levonorgestrel-releasing intrauterine system (Mirena) and Depot medroxyprogesterone acetate (Depoprovera) as long-term maintenance therapy for patients with moderate and severe endometriosis: a randomised controlled trial.". Aust N Z J Obstet Gynaecol. 50 (3): 273–9. doi:10.1111/j.1479-828X.2010.01152.x. PMID 20618247.
- ^ Bahamondes MV, Monteiro I, Castro S, Espejo-Arce X, Bahamondes L (2010). "Prospective study of the forearm bone mineral density of long-term users of the levonorgestrel-releasing intrauterine system.". Hum Reprod. 25 (5): 1158–64. doi:10.1093/humrep/deq043. PMID 20185512.
- ^ Luukkainen, T. (1991). "Levonorgestrel-Releasing Intrauterine Device". Annals of the New York Academy of Sciences. 626: 43–49. doi:10.1111/j.1749-6632.1991.tb37898.x.
- ^ Bayer Group. "What is Jaydess®?". Jaydess. Bayer PLC. Retrieved 16 November 2016.
- ^ Römer, T.; Bühling, K. J. (2013). "Intrauterine hormonelle Kontrazeption". Gynäkologische Endokrinologie. 11 (3): 188–196. doi:10.1007/s10304-012-0532-4.
- ^ "Mirena Medical Review" (PDF). FDA. Center for Drug Evaluation and Research: 6. 2000-12-05.
- ^ Mohllajee, AP; Curtis, KM; Herbert, PB. (2006). "Does insertion and use of an intrauterine device increase the risk of pelvic inflammatory disease among women with sexually transmitted infection? A systematic review". Contraception. 73 (2): 145–153. doi:10.1016/j.contraception.2005.08.007.
- ^ Lopez, LM; Bernholc, A; Zeng, Y; Allen, RH; Bartz, D; O'Brien, PA; Hubacher, D (29 July 2015). "Interventions for pain with intrauterine device insertion.". The Cochrane database of systematic reviews. 7: CD007373. doi:10.1002/14651858.CD007373.pub3. PMID 26222246.
- ^ Mansour, D; Gemzell-Danielsson, K; Inki, Pirjo; Jensen, JT. (2011). "Fertility after discontinuation of contraception: a comprehensive review of the literature". Contraception. 84 (5): 465–477. doi:10.1016/j.contraception.2011.04.002. PMID 22018120.
- ^ Randic, L; Vlasic, S; Matrljan, I; Waszak, C (1985). "Return to fertility after IUD removal for planned pregnancy". Contraception. 32 (3): 253–259. doi:10.1016/0010-7824(85)90048-4.
- ^ Ortiz, María Elena; Croxatto, Horacio B. (June 2007). "Copper-T intrauterine device and levonorgestrel intrauterine system: biological bases of their mechanism of action". Contraception. 75 (6 Suppl): S16‒S30. doi:10.1016/j.contraception.2007.01.020. PMID 17531610. p. S28:
Active substances released from the IUD or IUS, together with products derived from the inflammatory reaction present in the luminal fluids of the genital tract, are toxic for spermatozoa and oocytes, preventing the encounter of healthy gametes and the formation of viable embryos. The current data do not indicate that embryos are formed in IUD users at a rate comparable to that of nonusers. The common belief that the usual mechanism of action of IUDs in women is destruction of embryos in the uterus is not supported by empirical evidence. The bulk of the data indicate that interference with the reproductive process after fertilization has taken place is exceptional in the presence of a T-Cu or LNG-IUD and that the usual mechanism by which they prevent pregnancy in women is by preventing fertilization. - ^ ESHRE Capri Workshop Group (May–June 2008). "Intrauterine devices and intrauterine systems". Human Reproduction Update. 14 (3): 197‒208. doi:10.1093/humupd/dmn003. PMID 18400840. p. 199:
Mechanisms of action
Thus, both clinical and experimental evidence suggests that IUDs can prevent and disrupt implantation. It is unlikely, however, that this is the main IUD mode of action, … The best evidence indicates that in IUD users it is unusual for embryos to reach the uterus.
In conclusion, IUDs may exert their contraceptive action at different levels. Potentially, they interfere with sperm function and transport within the uterus and tubes. It is difficult to determine whether fertilization of the oocyte is impaired by these compromised sperm. There is sufficient evidence to suggest that IUDs can prevent and disrupt implantation. The extent to which this interference contributes to its contraceptive action is unknown. The data are scanty and the political consequences of resolving this issue interfere with comprehensive research.
p. 205:
IUDs that release copper or levonorgestrel are extremely effective contraceptives... Both copper IUDs and levonorgestrel releasing IUSs may interfere with implantation, although this may not be the primary mechanism of action. The devices also create barriers to sperm transport and fertilization, and sensitive assays detect hCG in less than 1% of cycles, indicating that significant prevention must occur before the stage of implantation. - ^ a b Speroff, Leon; Darney, Philip D. (2011). "Intrauterine contraception". A clinical guide for contraception (5th ed.). Philadelphia: Lippincott Williams & Wilkins. pp. 239–280. ISBN 978-1-60831-610-6. pp. 246–247:
Mechanism of action
The contraceptive action of all IUDs is mainly in the intrauterine cavity. Ovulation is not affected, and the IUD is not an abortifacient.58–60 It is currently believed that the mechanism of action for IUDs is the production of an intrauterine environment that is spermicidal.
Nonmedicated IUDs depend for contraception on the general reaction of the uterus to a foreign body. It is believed that this reaction, a sterile inflammatory response, produces tissue injury of a minor degree but sufficient enough to be spermicidal. Very few, if any, sperm reach the ovum in the fallopian tube.
The progestin-releasing IUD adds the endometrial action of the progestin to the foreign body reaction. The endometrium becomes decidualized with atrophy of the glands.65 The progestin IUD probably has two mechanisms of action: inhibition of implantation and inhibition of sperm capacite journal, penetration, and survival. - ^ Jensen, Jeffrey T.; Mishell, Daniel R. Jr. (2012). "Family planning: contraception, sterilization, and pregnancy termination". In Lentz, Gretchen M.; Lobo, Rogerio A.; Gershenson, David M.; Katz, Vern L. Comprehensive gynecology. Philadelphia: Mosby Elsevier. pp. 215–272. ISBN 978-0-323-06986-1. p. 259:
Intrauterine devices
Mechanisms of action
The common belief that the usual mechanism of action of IUDs in women is destruction of embryos in the uterus is not supported by empirical evidence... Because concern over mechanism of action represents a barrier to acceptance of this important and highly effective method for some women and some clinicians, it is important to point out that there is no evidence to suggest that the mechanism of action of IUDs is abortifacient.
The LNG-IUS, like the copper device, has a very low ectopic pregnancy rate. Therefore, fertilization does not occur and its main mechanism of action is also preconceptual. Less inflammation occurs within the uterus of LNG-IUS users, but the potent progestin effect thickens cervical mucus to impede sperm penetration and access to the upper genital track. Although the LNG-IUS also produces a thin, inactive endometrium, there is no evidence to suggest that this will prevent implantation, and the device should not be used for emergency contraception. - ^ Guttinger, A; Critchley, HO (2007). "Endometrial effects of intrauterine levonorgestrel". Contraception. 75 (6 Suppl.): S93–S98. doi:10.1016/j.contraception.2007.01.015. PMID 17531624.
- ^ Malik, S (January 2013). "Levonorgestrel-IUS system and endometrial manipulation.". Journal of mid-life health. 4 (1): 6–7. doi:10.4103/0976-7800.109625. PMC 3702070. PMID 23833526.
- ^ ESHRE Capri Workshop, Group (2008). "Intrauterine devices and intrauterine systems.". Human Reproduction Update. 14 (3): 197–208. doi:10.1093/humupd/dmn003. PMID 18400840.
Both copper IUDs and levonorgestrel releasing IUSs may interfere with implantation
- ^ Hatcher, Robert A. (2011). Contraceptive technology (20th rev. ed.). [New York, N.Y.]: Ardent Media. p. 162. ISBN 978-1-59708-004-0.
Although the precise mechanism of action is not known, currently available IUCs work primarily by preventing sperm from fertilizing ova.26 IUCs are not abortifacients: they do not interrupt an implanted pregnancy.27 Pregnancy is prevented by a combination of the "foreign body effect" of the plastic or metal frame and the specific action of the medication (copper or levonorgestrel) that is released. Exposure to a foreign body causes a sterile inflammatory reaction in the intrauterine environment that is toxic to sperm and ova and impairs implantation.28,29 The production of cytotoxic peptides and activation of enzymes lead to inhibition of sperm motility, reduced sperm capacite journal and survival, and increased phagocytosis of sperm.30,31… The progestin in the LNg IUC enhances the contraceptive action of the device by thickening cervical mucus, suppressing the endometrium, and impairing sperm function. In addition, ovulation is often impaired as a result of systemic absorption of levonorgestrel
- ^ Alvarez, F; Brache, V.; Fernandez, E; Guerrero, B; Guiloff, E; Hess, R; et al. (1988). "New insights on the mode of action of intrauterine contraceptive devices in women". Fertil Steril. 49: 768–773. PMID 3360166.
- ^ a b Thiery, M (1997). "Pioneers of the intrauterine device". The European Journal of Contraception & Reproductive Health Care. 2 (1): 15–23. doi:10.1080/13625189709049930. PMID 9678105.
- ^ Thiery, M (2000). "Intrauterine contraception: from silver ring to intrauterine implant". European Journal of Obstetrics & Gynecology and Reproductive Biology. 90: 145–152. doi:10.1016/s0301-2115(00)00262-1. PMID 10825633.
- ^ "MIRENA - levonorgestrel intrauterine device". Bayer Health Pharmaceuticals. May 2009. Archived from the original on 18 June 2015. Retrieved 18 June 2015.
- ^ FDA drug approval for Skyla
- ^ Eisenberg, DL; Schreiber, CA; Turok, DK; Teal, SB; Westhoff, CL; Creinin, MD; ACCESS IUS, Investigators (July 2015). "Three-year efficacy and safety of a new 52-mg levonorgestrel-releasing intrauterine system.". Contraception. 92 (1): 10–6. doi:10.1016/j.contraception.2015.04.006. PMID 25934164.
- ^ "2009 Warning Letters and Untitled Letters to Pharmaceutical Companies". U.S. Food and Drug Administration. Retrieved 18 June 2015.
- ^ a b Bekiempis, Victoria (24 April 2014). "The Courtroom Controversy Behind Popular Contraceptive Mirena". Newsweek. Retrieved 18 June 2015.
- ^ Budusun, Sarah. "Thousands of women complain about dangerous complications from Mirena IUD birth control". ABC Cleveland. Retrieved 18 June 2015.
- ^ Colla, Connie (21 May 2013). "Mirena birth control may be causing complications in women". ABC 15 Arizona. Retrieved 18 June 2015.
- ^ Mosher, Steven (20 November 2012). "The Mirena IUD is Becoming More Popular - and the Lawsuits are Piling Up". Population Research Institute. Retrieved 18 June 2015.
- ^ Bekiempis, Victoria (24 April 2014). "The Courtroom Controversy Behind Popular Contraceptive Mirena". Newsweek. Retrieved 16 November 2016.
- ^ "Popular contraceptive device Mirena target of lawsuits in Canada, U.S". CTV. May 21, 2014. Retrieved 16 November 2016.
- ^ Blackstone, Helena (31 May 2016). "When IUDs Go Terribly Wrong". Vice. Retrieved 16 November 2016.
External links[edit]
- FDA (2000). "Medical review" (PDF scanned image). - on Berlex Laboratories' Mirena application
- Physician Fact Sheet (2008 U.S. version)
- Physician Fact Sheet (2013 U.K. version)
- Mirena drug description/side effects
- Video showing the insertion procedure for a Mirena IUD


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Live Music Pubs, Bars and Inns in Chester Cheshire, Pubsulike has 4 Live Music Pubs, Bars and Inns in our Chester Cheshire Live Music Pub Guide, located in Chester, and it's localities. Why not review a Pub that is known to you? Tell us what you think. Our researchers are constantly checking and updating the information. If you think we have missed a Live Music Pub in Cheshire please Nominate the Pub, Bar or Inn and we will include it in our Live Music Pub Guide free of charge.
Add/View Reviews | Cherry Orchard Inn |
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Cherry Orchard Inn |
Pub's own Website | Add/View Reviews | Telfords Warehouse |
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The Ship Victory |
Add/View Reviews | Union Vaults |
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Union Vaults |


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MLB Net Sets Non-Playoff Record With WBC Game NBC Sports Rebranding California RSNs NCAA Settlement Gets Preliminary Approval Citi, AT&T Execs On Not Renewing USOC Deals ESPN Responds To Cowherd Comments Budweiser Rolling Out MLB Team Cans Fox Sports Radio Adds Doug Gottlieb NFL's Leiweke: Raiders Vote Likely Next Week WME Plans To Keep Miami Open In Key Biscayne Former Bulls GM Krause Passes Away At 77
SBD/April 27, 2012/People and Pop Culture
Print All-
Jimmie Johnson Repeats Atop Forbes List Of Most Influential Athletes In America
NASCAR driver JIMMIE JOHNSON for the second consecutive year tops Forbes' list of "America's Most Influential Athletes," according to Tom Van Riper of FORBES. Jets QB TIM TEBOW is listed second, up from No. 10 last year. This year, six of the 10 most influential athletes are NFL QBs, with both the Broncos' PEYTON MANNING and the Giants' ELI MANNING "in the fold." The list was created using results from Nielsen and E-Poll poll that "surveyed over 1,100 adults about dozens of well-known athletes to measure their likeability and whether they're considered 'influential,' an important quality for marketers." Candidates were limited to "pro athletes who are currently active and who score at least 20% 'awareness' with the general public." Dropping off the list from '11 are driver JEFF GORDON, U.S. Olympic Gold Medalist swimmer MICHAEL PHELPS, Steelers S TROY POLAMALU, Heat F LEBRON JAMES and TNT analyst SHAQUILLE O'NEAL, who is no longer eligible after retiring from the NBA last year. Their replacements on the list: Eli Manning, Knicks G JEREMY LIN, boxer MANNY PACQUIAO, Saints QB DREW BREES and Packers QB AARON RODGERS. Below is the complete Forbes list (FORBES.com, 4/23).
RKNAME % INFLUENTIALLIKE/LIKE A LOT1NASCAR driver Jimmie Johnson 25%40%2Jets QB Tim Tebow 24%50%3Broncos QB Peyton Manning 21%52%4Boxer Manny Pacquiao 20%59%5Patriots QB Tom Brady 19%38%6Packers QB Aaron Rodgers 19%62%7NASCAR driver Dale Earnhardt Jr. 19%41%8Saints QB Drew Brees 19%63%9Giants QB Eli Manning 18%57%10Knicks G Jeremy Lin 18%66% -
Executive Transactions
CBS Sports named MARK WOLFF Coordinating Producer of College Basketball. Wolff will be responsible for the day-to-day planning of the net's NCAA basketball coverage. Wolff joins BOB FISHMAN on the lead basketball production team working the regular season and NCAA Tournament, including the Final Four. Wolff will also continue to serve as a producer for the NFL (CBS Sports)....Univ. of California-Riverside named ERIC BUSKIRK Senior AD/Development (UC-Riverside)....Mandalay Baseball Properties Exec VP & CMO STEVE DELAY has left the company after more than 12 years (Eric Fisher, SportsBusiness Journal).
Do you have an executive announcement? If so, please send to firstname.lastname@example.com. -
Names In The News
Prior to Thursday night's first round of the NFL Draft, Saints Owner TOM BENSON told reporters that his granddaughter, co-Owner & Exec VP RITA BENSON LEBLANC, "is hospitalized at Oschner Hospital" in New Orleans. USA TODAY's Glenn Guilbeau notes LeBlanc "has been on leave from work for several weeks." Benson said, "Unfortunately Rita's in the hospital. She's OK. Oschner's taking good care of her" (USA TODAY, 4/27). In New Orleans, WVUE-Fox reporter Jennifer Hale wrote on Twitter Friday, "Rita Benson LeBlanc released from hospital" (TWITTER.com, 4/27).
NEW ROLE: Israeli basketball club Maccabi Bazan Haifa hired former Syracuse Univ. associate head coach BERNIE FINE as a basketball consultant to the team, which is owned by Florida-based businessman JEFFREY ROSEN. After 36 seasons at Syracuse, Fine was "fired in November, amid allegations that he sexually molested two former ball boys" (ESPN.com, 4/26).
NAMES: ESPN's CHRIS BERMAN this week appeared at his alma mater, Brown Univ., to honor outgoing AD MICHAEL GOLDBERGER, who is leaving the school after nearly 40 years (GOLOCALPROV.com, 4/25)....After the Knicks Tuesday announced GLEN GRUNWALD as the team's permanent Exec VP & GM, interim head coach MIKE WOODSON and former President of Basketball Operations ISIAH THOMAS, along with their wives, met for dinner at Serafina in White Plains, N.Y. (N.Y. POST, 4/26)....RIHANNA and JAY-Z will headline the BBC Radio 1 Hackney Weekend 2012, on June 23-24, a month before the London Games (BLOOMBERG.com, 4/26)....Wells Fargo has made a $100,000 donation to The First Tee of Charlotte, part of the bank's celebration of the 10th anniversary of the PGA Tour's Wells Fargo Championship next week (CHARLOTTE OBSERVER, 4/27)....The D'Backs will receive the '12 Arizona Business Leadership Award. Team President & CEO DERRICK HALL will accept the award on behalf of the organization (D'Backs)....U.S. Treasury Secretary TIM GEITHNER questioned several CEOs Wednesday "about business trends" during a closed-door meeting at Nike HQs in Portland, Ore. Participants at the meeting included Nike President & CEO MARK PARKER and Columbia Sportswear President & CEO TIM BOYLE (BIZJOURNALS.com, 4/26). -
The most valuable rolodex ever, updated every day


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PECH Haiti by Julie Peters Akey
Sunday, March 3, 2013
New Playground Equipment in Haiti!
Thank you to those who donated toward the new playground equipment for the children at Gentille Hirondelle elementary school. The children finally have a place to play!
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A loose sequel of the 1987 film, this movie turns the tables by offering the travails of a good Munchie (voice by Dom DeLuise). Found in an abandoned mine by a young boy (Jaime McEnnan), the creature offers to make all of his dreams come true, including help with bullies and bad grades. ~ John Bush, Rovi
All Munchie cast + crew photos


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I'm not immune to confirmation bias. And if someone suspects that I'm perpetuating an opinion that might not be the whole story, I'd like for them to stop me and remind me of confirmation bias as a starting point for debate.
Present me some conflicting data.
I've spent a great deal of time lately looking at fitness, nutrition and psychological research. I try to read with an open mind, but alas, I often stumble across information that confirms my beliefs rather than opposes my beliefs.
When I do stumble across information that opposes me beliefs, I am probably far more likely to be critical of it as well.
It's important to be skeptical, even of information that supports your beliefs. Continue reading Confirmation Bias


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Thread: Bullshido Artist Ralph Severe
3/26/2010 5:35pm, #1721
3/26/2010 6:42pm, #1722
- Join Date
- Feb 2008
- Posts
- 674
- Style
- bagua
I think it likely that a lawyer might consider the site in that link to be an example of http://en.wikipedia.org/wiki/Passing_off
3/26/2010 11:05pm, #1723
- Join Date
- Jul 2009
- Location
- Pori, Finland
- Posts
- 351
- Style
- Hokutoryu Ju-jutsu
--J Herrington... Awesome.
Think about it, a Red Herring who is also an investigative reporter. There's a hit TV-series to be found in this!
Who's the red private dick
that's a sex machine to all the chicks?
You're damn right
Who is the man
that would risk his scales for his brother man?
Can ya dig it?
Who's the carp that won't cop out
when there's danger all about
Right on
You see this carp Herrington is a bad mother--
(Shut your mouth)
But I'm talkin' about Herrington
(Then we can dig it)
He's a complicated man
but no one understands him but his woman
(J Herrington)
(Sorry if I insult any Shaft fans.)
3/28/2010 7:29pm, #1724--
My sincerest apologies for tacking on to this thread, but this is what Mr. Severe keeps PMing me.
I have told him that I would make these public if he did not stop sending me messages, but he apparently doesn't care. If he doesn't care then neither do I. Mr. Severe, I'm not playing your game of charades.
Please note, I have separated out the quotes, since Mr. Severe did not in his response to me:
Originally Posted by Sri Hanuman
Originally Posted by Sri Hanuman
Originally Posted by Sri Hanuman
Originally Posted by Sri Hanuman
Mark Tripp, never heard of him. He is a forum groupie from what I know of him. Get it? I do not need a judo guy to test me for some type of ranking. If I did I sure would ask a nobody like Marl Tripp for any testing. Why should I? Mark Tripp hasn't been worthy enough for even any personal communication with me so why ask him to test me in something I did when I was in my teens? Hello.. are you really that nutty? Why not get him to test you if you feel he is so worthy?
Originally Posted by Sri Hanuman
Originally Posted by Sri Hanuman
Originally Posted by Sri Hanuman
Originally Posted by Sri Hanuman
Like I said.. what you or the other weak minded groupies say over a hidden forum playing want to be martial artist is a joke at best.
Originally Posted by Sri Hanuman
Originally Posted by Sri Hanuman
Originally Posted by Sri Hanuman
Originally Posted by Sri Hanuman
3/28/2010 7:41pm, #1725--
This was preceded by:
Originally Posted by Sri Hanuman
Originally Posted by Sri Hanuman
Originally Posted by Sri Hanuman
All of the above tells me that you, Mr. Severe are unable to address the issues in a public manner, and wish to clutch at straws. There is nothing you can say to me that you should not be able to say in public.
Please stop making claims which you can not, and will not back up in a public manner. THIS, is why you have no credibility with me, or any member on this board.
Again, I apologize for posting this block of text, but I felt that it should be known that Mr. Severe is still making claims of shodan in Judo, and keeps trying to cling to some image of credibility, when he clearly has none.
3/28/2010 7:46pm, #1726--
I bet if you just added him to your ignore list it would piss him off to no end.
3/29/2010 3:18am, #1727
- Join Date
- Feb 2009
- Posts
- 52
- Style
- jiu jitsu, kyokushin
3/29/2010 5:51am, #1728--
Thing is, you can't get a shodan in judo until you're a minimum of eighteen if I remember correctly.
By that time Ralphie was already immersed in his ninjer training.
Yet another snag in his roster of lies.
Sri Hanuman - you need to quit dignifying Ralph with the Mr. title. Who the hell approaching 50 calls someone else "dude"?
Mega will be in Dallas. Has there been any progress on finding Ralph's cave location?
3/29/2010 6:30am, #1729--
Lowest age would be 16, but again, there would be a record of major shiai wins, which of course Ralph lacks.
He has no legitimate rank in Judo.
He has no skills, knowledge, or training in Judo.
All else is Ralph shooting himself in the eye...."Out of every hundred men, ten shouldn't even be there, eighty are just targets, nine are the real fighters, and we are lucky to have them, for they make the battle. Ah, but the one, one is a warrior, and he will bring the others back." -- Hericletus, circa 500 BC
3/29/2010 9:34am, #1730
- Join Date
- Dec 2008
- Location
- Dallas, Tx
- Posts
- 703
- Style
--The police report may have it, quite frankly mega or no mega he's just a fucking troll. He tries to play cute word games and pretend that you need an AK-47 to drive to Carrolton, **** him. I hang my head in shame that this douche is living in the Metroplex......it would be worst if he was a native.
I think if we all ignore his ass and let the write up stand then eventually he'll go away because you are not going to get any answers in the mean time.


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Tofu Recipes
Category Archives: Aburage Large (Triangle)
Aburage No Nimono
Ingredients: 4 Aloha Tofu Triangle aburage 1/2 cup sugar 1/4 cup shoyu 1/4 cup sake 1 teaspoon instant dashi 1 cup of water Directions: In a pot, boil aburage for 1 to 2 minutes, place it in cold water and squeeze out excess water. In another pot, combine water & instant dashi and boil. Add sugar, [...]
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Aburage Salad
Recipe courtesy of a loyal Aloha Tofu customer Ingredients: 1 package Aloha Tofu Aburage (4 pieces in a package), rinse with hot water and squeeze, slice 1 package tempura fish cake, slice 1 package chikuwa, slice 1 package kamaboko, slice 2 packages bean sprout, rinse Green onion 2 teaspoons garlic powder 4 tablespoons sugar 4 [...]
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Aburage Kim Chee
INGREDIENTS: 1 package Aloha Tofu Aburage (4 or 8 pieces, depending on size), sliced thin Green onions, minced Sesame seeds, roasted Chili pepper, minced SAUCE: 2 tablespoons sesame oil 1-1/2 tablespoons white vinegar 2 cloves garlic, grated 3 tablespoons shoyu 2 tablespoons sugar PREPARATION: Combine first 4 ingredients. Set aside. Mix sauce ingredients. Gradually pour [...]
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diaochan21 |
Subject: Posted: October 5, 2012 07:22 pm
good deck overall but i dont think that there is really much of a point if you just put in a pearl sister perle because her skill will only work if there is a pearl sister pearla on the field.
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Among upcoming video game releases: StarCraft II for PC and Mac is one of the most important releases of 2010 thanks to the genre-defining impact of the original StarCraft in 1998; the praised game BlazBlue gets a sequel in the form of Continuum Shift; and Ace Combat: Joint Assault on PSP marks a rare foray into real-world locations for the jetfighter series.
StarCraft II (PC, Mac)
Release: Worldwide, July 27
Age Rating: Teen / 16+
The followup to 1998's
StarCraft, the real-time strategy par excellence, has been in development since 2003 and comes from Blizzard, which is behind
World of Warcraft's success. StarCraft II builds on the success of the first in both single and multiplayer modes. Blizzard have learned a thing or two from the
WoW experience: Russian, Mexican, Chilean and Argentinian gamers can buy cut-price retail copies and then top up online play with a subscription service - or buy direct from Blizzard's Battle.net for infinite credits.
Price: $59.99 / €59.99
Collectors Edition (DVD, CD, comic etc.): $99.99 / €89.99
BlazBlue: Continuum Shift (360, PS3)
Release: North America, July 27. Europe, October.
Age rating: Teen
Quickly establishing itself as an essential entry in any fighting game fan's library,
BlazBlue: Calamity Trigger took many by surprise with a style and flair that proved robust under scrutiny.
Continuum Shift was bestowed with a good score from Famitsu's four reviewers (9/8/9/8) though Europeans will have to wait a little longer -
Calamity Trigger didn't come out there until April of this year so it's a bit early yet for the sequel.
Price: $39.99
BlazBlue: Continuum Shift Fightstick arcade style controller: $199.99
Ace Combat: Joint Assault (PSP)
Release: Europe, July 30. North America, August 31.
Age Rating: 12+ / Teen
The larger-than-life
Ace Combat dogfighting series debuted in 1995 as
Air Combat on the PlayStation One and has been on PlayStation 2, Xbox 360, and even Apple's iOS.
Joint Assault will be the second PSP title but diverges from the series formula in that it uses real-world locations - London, Egypt, San Francisco and Tokyo among them - alongside the overblown storylines and gigantic airplanes on world-ending bombing runs.
Joint Assault also allows up to four players to play missions co-operatively over the internet, in addition to the standard versus mode.
Price: $39.99 / €39.99
Harvest Moon DS: Grand Bazaar (DS)
Release: North America, July 27
Age Rating: Everyone
It's been around since 1996 and the
Harvest Moon series doesn't look like it's going away anytime soon - the cute crop-tending farm simulations should strike a chord with anyone exposed to
FarmVille or
Happy Farm, though
Harvest Moon fleshes out the farming with pets, family life, and a new story for each game.
Grand Bazaar is not considered to be the pinnacle of perfection among series fans, but its cut-down nature could still prove less daunting for newcomers than the full-fledged (and very much admired)
Rune Factory spin-offs, for example.
Price: $29.99
Castlevania: Harmony of Despair (360)
Release: August 8 via Xbox Live Arcade
Age Rating: Teen / 12+
Resurrecting the legendary
Castlevania series for Xbox 360 is old hand Koji Igarashi, who has worked on a vast number of
Castlevania games. True to its heritage,
Harmony of Despair is a side-scrolling 2D action adventure, modernized with room for up to six players co-operating online.
Price: 1200 Microsoft Points ($15 / €14)
Madden NFL 11 (360 iPhone PS2 PS3 PSP Wii)
Release: North America, August 10. Europe, August 13.
This year,
Madden NFL claims to be simpler, quicker, and deeper than before, compressing a full hour-long game into 30 minutes of playtime and making it easier to instruct teams. Drew Brees of the New Orleans Saints became the latest Madden cover athlete after pulling in the most fan votes. 360 and PS3 trial demos are scheduled for release July 27.
Price: Price: $59.99 / €59.99 (360 PS3), $49.99 / €49.99 (Wii), $39.99 / €39.99 (PS2 PSP)