The Importance Of Bioequivalence

The Importance Of Bioequivalence Bioequivalence is defined as the absence of a significant difference in the rate extent to which the active ingredient or active moiety in pharmaceutical equivalent or pharmaceutical alternative become available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study (Huixiao et al., 2009). The importance of bioequivalence studies is increasing due to the large growth of the production and consumption of generic product (Vetchà ½ et al., 2007). Bioequivalence also assess the relative bioavailability of two drug products thus focuses on comparative drug product performance (Mei-Ling et al., 2001). The rationale of bioequivalence study is the monitoring of pharmacokinetic and pharmacodynamic parameters after the administration of tested drugs (Vetchà ½ et al., 2007). A standard pharmacokinetic study is the conventional method for evaluating the pharmacokinetics of a drug in human subjects. Deferiprone (DFP, Ferriproxà ¢Ã¢â‚¬Å¾Ã‚ ¢, Kelferà ¢Ã¢â‚¬Å¾Ã‚ ¢, L1, CP20) was synthetic hydroxypyridinone iron chelator isolated from legume Mimosa paduca (Clarke and Martell 1992) to be taken orally, and bind iron in conditions of iron overload (Kontoghiorghes, G.J, 1985). Iron was essential to all species and there was no physiologic excretory pathway for this essential element (Andrews, 1999). In conditions of primary iron overload (eg, hemochromatosis) or secondary iron overload (eg, transfusion-dependant thalassemia), accumulation of this potentially toxic element results in massive iron accumulation and lead to generation of toxic free radical damage (Rund and Rachmilewitz 2005). DFP was used in the treatment of Thalassemia Major and was also used worldwide to treat cancer, leukemia, hemodialysis and other diseases like detoxification metals, such as aluminum in hemodialysis patients (Paschalidis et al., 1999; Di-Ji et al., 2004). Deferiprone was the worlds first and only or ally active iron chelating drug, which was effective and inexpensive to synthesize thus increasing the prospects of making it available to most thalassemia patients in third world countries who are not currently receiving any form of chelation therapy (Kontoghiorghes et al., 2004). DFP is a bidentate chelator and has a two pka of 3.6 and 9.9 (Hider and Liu 2003) with strong iron binding properties of pFe3+ 19.6 and pFe2+ 5.6 thus binding it in 3:1 complex indicating a high degree of relative specificity for trivalent iron (Clarke and Martell 1992; Tam et al 2003). It was a water soluble compound with partition coefficient of 0.11 and has a molecular weight of 139 Da which made them move freely through cell membranes of the body. DFP absorbed rapidly and completely after oral administration. . Deferiprone appears in plasma within 5 to 10 minutes of ingestion and Peak plasma levels achieved within 1 hour after administration. Food reduces the rate of absorption but not the extent of absorption thus reducing the peak concentration with Cmax of about 100 µmol/L in fasting state and about 85 µmol/L (Matsui et al 1991; Al-Refaie et al 1995a). Deferiprone is metabolized to the inactive glucuronide that is the predominant form recovered in the urine (James et al., 2001). The drug was eliminated rapidly with a half-life of about 2 hours due to hepatic biotransformation. It was metabolized by glucuronidation and about 90% of the drug excreted in urine as glucuronide. Half-life was shorter in healthy subjects of about 1.3 hours than that of thalassemia subjects having 2.3 hours (Stobie et al 1993). Most frequently occurring side effects are transient gastrointestinal symptoms (GI) such as nausea, vomiting, and abdominal pain (Cohen et al 2003). OBJECTIVE The purpose of this study was to evaluate bioequivalence of new tablet formulation of Deferiprone with Ferriprox ® (Apotex, Canada). MATERIALS AND METHODS Materials Two drug products of deferiprone 500 mg tablet were used for invivo bioequivalence study. One was the test product (Test) manufactured locally and another was the Reference or innovators products. Deferiprone standard was supplied by Assistant Drug Controller, Ministry of Health, Islamabad. Acetonitrile and methanol HPLC grade were purchased from MERCK. Study products The test formulations were Ferrinil 500 mg tablet Batch Noà ¢Ã¢â€š ¬Ã‚ ¦Ãƒ ¢Ã¢â€š ¬Ã‚ ¦. , expiry à ¢Ã¢â€š ¬Ã‚ ¦Ãƒ ¢Ã¢â€š ¬Ã‚ ¦, and the reference product Ferriprox ® 500 mg tablet Batch Noà ¢Ã¢â€š ¬Ã‚ ¦Ãƒ ¢Ã¢â€š ¬Ã‚ ¦ expiryà ¢Ã¢â€š ¬Ã‚ ¦Ãƒ ¢Ã¢â€š ¬Ã‚ ¦ (Apotex INC., Canada). Human subjects The study was approved by the Ethics Committee of BeSt Center, Faculty of Biosciences, University of Veterinary and Animal Sciences, Lahore. Twelve healthy Pakistani male volunteers aged between 18-55 years were included in the study. All volunteers were in good health confirmed by physical and clinical laboratory examination including serology, hematology and biochemical test. All volunteers were abstained from other drug intake and alcoholic preparations three weeks prior to and throughout the study. Those volunteers who had chronic smoking history, alcoholic intake and caffeine intake were excluded. Study design The study carried out was randomized, two-treatment, two-period, two-sequence, single dose crossover study with two weeks wash-out period. Each volunteer was in fasted state approximately 10 hours prior to the study. Each volunteer received a single dose of 1000 mg deferiprone with 240 ml of water. Blood samples were collected immediately before and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 hours after drug intake. A standardized lunch is consumed after blood sampling at 4 hours. The plasma were separated by centrifugation and stored at -80 °C. ANALYTICAL METHOD The analytical method was modified by the method of Goddard et al.1990 using validated HPL method DATA ANALYSIS The pharmacokinetic parameters of both test and reference drug were compared and was determined by taking Cmax and Tmax directly from the individual concentration versus time data. Elimination rate constant was determined from log-linear least squared regression of the terminal part of the plasma concentration versus time curve. Half-life was estimated from equation 0.693/Kel. The area under the concentration versus time curve was calculated by linear trapezoidal rule. The comparison of generic product of deferiprone 500 mg with innovators product was assessed using relevant pharmacokinetic parameters, Cmax, Tmax, AUC (0-t) and AUC (0-à ¢Ã‹â€ Ã… ¾) and was transformed to logarithmic scale before statistical analysis. The difference of the mean corresponding log Cmax, log AUC(0-t) and log AUC(0-à ¢Ã‹â€ Ã… ¾) between the two products will be determined by 2-way analysis of variance (ANOVA) for a crossover design at the significant level of ÃŽÂ ± = 0.05. The 90% confidence interval (CI) (two-one sided test) for the differences of the mean log Cmax, log AUC(0-t) and log AUC(0-à ¢Ã‹â€ Ã… ¾) between the two products were calculated. The two products are considered to be bioequivalent when 90% CI of the differences of all parameters were within WHO accepted range of 80%-125%.

Reflection on Judaism

Judaism is considered by religious Jews to be the expire soon of the covenant relationship that God established with the Children of Israel. Judaism includes a wide corpus of texts, practices, theological positions, and forms of organization. Within Judaism there are a variety of movements, most of which emerge d from Rabbinic Judaism, which holds that God revealed his laws and commandments to Mo season Mount Sinai In the form of both the Written and Oral Torah. 6] Historically, this assertion was challenged by various groups such as the Caduceus and Hellenic Judaism during t he Second Temple period; the Karate and Sebastian during the early and later media al period; [7] and among segments of the modern reform movements. Liberal movements in modern times such as Humanistic Judaism may be monotheistic. 8] Today, the largest Jewish religious movements are Orthodox Judaism (Harder Judaism and Modern Orthodox Juju Dadaism), Conservative Judaism and Reform Judaism. Major sources of diffe rence between these e groups are their approaches dishtowels law, the authority of the Rabbinic tradition, and the SSL influence of the State of Israel. [9] Orthodox Judaism maintains that the Torah and Jewish law are divine in origin, eternal and unalterable, and that they should be strictly followed.Conservative e and Reform Judaism are more liberal, with Conservative Judaism generally promoting a m ore â€Å"traditional† interpretation of Judaism requirements than Reform Judaism. A typical Reform position Is that Jewish law should be viewed as a set of general guidelines rather that n as a setoffs restrictions and obligations whose observance Is required of all Jews. [10][11] Historically, special courts enforced Jewish law; today, these courts still exist but the practice of Judaism I s mostly voluntary.

GRAHAM Surname Meaning and Origin

The Graham surname is believed to be derived from an English place name which meant either gravelly homestead from the Old English grand, meaning gravel, or grey home from the Old English grasgham.  Most  of the original bearers of this surname came from Grantham in Lincolnshire, England. Graham is the 20th most common Scottish surname, and  first came into use in Scotland in the 12th century. Surname Origin: English, Scottish Alternate Surname Spellings: GRAEME, GRAHAME, GRAYHAM Where in the World is the GRAHAM Surname Found? According to WorldNames PublicProfiler, the Graham surname is most common in Northern Ireland and Scotland. There are also many individuals named Graham living in Australia, New Zealand, and Canada. Forebears puts the Graham surname as the 12th most popular surname on Norfolk Island. Other countries with high density of individuals named Graham include Northern Ireland, Scotland, Jamaica, Canada, Australia and New Zealand. Within Scotland, Graham is most common in  Dumfriesshire, followed by Peebleshire and Kinross-shire. Most of the Irish with the Graham surname live in Antrim, Northern Ireland. Famous People with the Last Name GRAHAM Alexander Graham Bell - inventor of the telephoneElizabeth Jennings Graham -  challenged segregation on public transportation in 1854, 100 years before Rosa ParksBill Graham -  legendary rock concert promoter  Billy Graham - television and radio evangelistSylvester Graham -  19th-century Presbyterian minister and inventor of the graham crackerMartha Graham - mother of modern danceKatherine Graham -  America’s first female Fortune 500 CEOBette Nesmith Graham - inventor of liquid paper/white out Genealogy Resources for the Surname GRAHAM Clan Graham Society: Theories on the Origins of the GrahamsNellie Graham Lowry, society genealogist for Club Graham Society, examines a variety of theories on the origins of the Graham surname. Graham Family DNA ProjectJoin over 370 researchers with the Graham surname or its variants interested in working together to combine Y-DNA testing with traditional genealogy research to sort out Graham ancestors around the world. Graham Family Genealogy ForumSearch this popular genealogy forum for the Graham surname to find others who might be researching your ancestors, or post your own Graham query. FamilySearch - GRAHAM GenealogyExplore over 4 million historical records and lineage-linked family trees posted for the Graham surname and its variations on the free FamilySearch website, hosted by the Church of Jesus Christ of Latter-day Saints. GRAHAM Surname Family Mailing ListsRootsWeb hosts a free mailing list for researchers of the Graham surname around the world. DistantCousin.com - GRAHAM Genealogy Family HistoryExplore free databases and genealogy links for the last name Graham. The Graham Genealogy and Family Tree PageBrowse genealogy records and links to genealogical and historical records for individuals with the Graham last name from the website of Genealogy Today. -- Looking for the meaning of a given name? Check out First Name Meanings -- Cant find your last name listed? Suggest a surname to be added to the Glossary of Surname Meanings Origins. ----------------------- References: Surname Meanings Origins Cottle, Basil. Penguin Dictionary of Surnames. Baltimore, MD: Penguin Books, 1967. Menk, Lars. A Dictionary of German Jewish Surnames. Avotaynu, 2005. Beider, Alexander. A Dictionary of Jewish Surnames from Galicia. Avotaynu, 2004. Hanks, Patrick and Flavia Hodges. A Dictionary of Surnames. Oxford University Press, 1989. Hanks, Patrick. Dictionary of American Family Names. Oxford University Press, 2003. Smith, Elsdon C. American Surnames. Genealogical Publishing Company, 1997. Back to Glossary of Surname Meanings Origins