Of the estimated 8.8 million Jews living in Europe at the beginning of World War II, the majority of whom were Ashkenazi, about 6 million – more than two-thirds – were systematically murdered in the Holocaust. These included 3 million of 3.3 million Polish Jews (91%); 900,000 of 1.5 million in Ukraine (60%); and 50–90% of the Jews of other Slavic nations, Germany, Hungary, and the Baltic states, and over 25% of the Jews in France. Sephardi communities suffered similar depletions in a few countries, including Greece, the Netherlands and the former Yugoslavia. As the large majority of the victims were Ashkenazi Jews, their percentage dropped from nearly 92% of world Jewry in 1931 to nearly 80% of world Jewry today. The Holocaust also effectively put an end to the dynamic development of the Yiddish language in the previous decades, as the vast majority of the Jewish victims of the Holocaust, around 5 million, were Yiddish speakers. Many of the surviving Ashkenazi Jews emigrated to countries such as Israel, Canada, Argentina, Australia, and the United States after the war.


Religious Jews have Minhagim, customs, in addition to Halakha, or religious law, and different interpretations of law. Different groups of religious Jews in different geographic areas historically adopted different customs and interpretations. On certain issues, Orthodox Jews are required to follow the customs of their ancestors, and do not believe they have the option of picking and choosing. For this reason, observant Jews at times find it important for religious reasons to ascertain who their household's religious ancestors are in order to know what customs their household should follow. These times include, for example, when two Jews of different ethnic background marry, when a non-Jew converts to Judaism and determines what customs to follow for the first time, or when a lapsed or less observant Jew returns to traditional Judaism and must determine what was done in his or her family's past. In this sense, "Ashkenazic" refers both to a family ancestry and to a body of customs binding on Jews of that ancestry. Reform Judaism, which does not necessarily follow those minhagim, did nonetheless originate among Ashkenazi Jews.


As Ashkenazi Jews moved away from Europe, mostly in the form of aliyah to Israel, or immigration to North America, and other English-speaking areas; and Europe (particularly France) and Latin America, the geographic isolation that gave rise to Ashkenazim has given way to mixing with other cultures, and with non-Ashkenazi Jews who, similarly, are no longer isolated in distinct geographic locales. Hebrew has replaced Yiddish as the primary Jewish language for many Ashkenazi Jews, although many Hasidic and Hareidi groups continue to use Yiddish in daily life. (There are numerous Ashkenazi Jewish anglophones and Russian-speakers as well, although English and Russian are not originally Jewish languages.)


A 2006 study found Ashkenazi Jews to be a clear, homogeneous genetic subgroup. Strikingly, regardless of the place of origin, Ashkenazi Jews can be grouped in the same genetic cohort – that is, regardless of whether an Ashkenazi Jew's ancestors came from Poland, Russia, Hungary, Lithuania, or any other place with a historical Jewish population, they belong to the same ethnic group. The research demonstrates the endogamy of the Jewish population in Europe and lends further credence to the idea of Ashkenazi Jews as an ethnic group. Moreover, though intermarriage among Jews of Ashkenazi descent has become increasingly common, many Haredi Jews, particularly members of Hasidic or Hareidi sects, continue to marry exclusively fellow Ashkenazi Jews. This trend keeps Ashkenazi genes prevalent and also helps researchers further study the genes of Ashkenazi Jews with relative ease. It is noteworthy that these Haredi Jews often have extremely large families.


Ashkenazi Jews have a noted history of achievement in Western societies in the fields of exact and social sciences, literature, finance, politics, media, and others. In those societies where they have been free to enter any profession, they have a record of high occupational achievement, entering professions and fields of commerce where higher education is required. Ashkenazi Jews have won a large number of the Nobel awards. While they make up about 2% of the U.S. population, 27% of United States Nobel prize winners in the 20th century, a quarter of Fields Medal winners, 25% of ACM Turing Award winners, half the world's chess champions, including 8% of the top 100 world chess players, and a quarter of Westinghouse Science Talent Search winners have Ashkenazi Jewish ancestry.


Although the Jewish people in general were present across a wide geographical area as described, genetic research done by Gil Atzmon of the Longevity Genes Project at Albert Einstein College of Medicine suggests "that Ashkenazim branched off from other Jews around the time of the destruction of the First Temple, 2,500 years ago ... flourished during the Roman Empire but then went through a 'severe bottleneck' as they dispersed, reducing a population of several million to just 400 families who left Northern Italy around the year 1000 for Central and eventually Eastern Europe."


A 2001 study by Nebel et al. showed that both Ashkenazi and Sephardic Jewish populations share the same overall paternal Near Eastern ancestries. In comparison with data available from other relevant populations in the region, Jews were found to be more closely related to groups in the north of the Fertile Crescent. The authors also report on Eu 19 (R1a) chromosomes, which are very frequent in Central and Eastern Europeans (54%–60%) at elevated frequency (12.7%) in Ashkenazi Jews. They hypothesized that the differences among Ashkenazim Jews could reflect low-level gene flow from surrounding European populations and/or genetic drift during isolation. A later 2005 study by Nebel et al., found a similar level of 11.5% of male Ashkenazim belonging to R1a1a (M17+), the dominant Y-chromosome haplogroup in Central and Eastern Europeans.


They established communities throughout Central and Eastern Europe, which had been their primary region of concentration and residence until recent times, evolving their own distinctive characteristics and diasporic identities. In the late Middle Ages the center of gravity of the Ashkenazi population, and its traditional cultural life, shifted steadily eastward, out of the German lands into Poland and Lithuania (including present-day Belarus and Ukraine). In the course of the late 18th and 19th centuries, those Jews who remained in or returned to the German lands experienced a cultural reorientation; under the influence of the Haskalah and the struggle for emancipation, as well the intellectual and cultural ferment in urban centers, they gradually abandoned the use of Yiddish, while developing new forms of Jewish religious life and cultural identity.


The name Ashkenazi derives from the biblical figure of Ashkenaz, the first son of Gomer, son of Khaphet, son of Noah, and a Japhetic patriarch in the Table of Nations (Genesis 10). The name of Gomer has often been linked to the ethnonym Cimmerians. Biblical Ashkenaz is usually derived from Assyrian Aškūza (cuneiform Aškuzai/Iškuzai), a people who expelled the Cimmerians from the Armenian area of the Upper Euphrates, whose name is usually associated with the name of the Scythians. The intrusive n in the Biblical name is likely due to a scribal error confusing a waw ו with a nun נ.


The genome-wide genetic study carried out in 2010 by Behar et al. examined the genetic relationships among all major Jewish groups, including Ashkenazim, as well as the genetic relationship between these Jewish groups and non-Jewish ethnic populations. The study found that contemporary Jews (excluding Indian and Ethiopian Jews) have a close genetic relationship with people from the Levant. The authors explained that "the most parsimonious explanation for these observations is a common genetic origin, which is consistent with an historical formulation of the Jewish people as descending from ancient Hebrew and Israelite residents of the Levant".


The history of Jews in Greece goes back to at least the Archaic Era of Greece, when the classical culture of Greece was undergoing a process of formalization after the Greek Dark Age. The Greek historian Herodotus knew of the Jews, whom he called "Palestinian Syrians", and listed them among the levied naval forces in service of the invading Persians. While Jewish monotheism was not deeply affected by Greek Polytheism, the Greek way of living was attractive for many wealthier Jews. The Synagogue in the Agora of Athens is dated to the period between 267 and 396 CE. The Stobi Synagogue in Macedonia, was built on the ruins of a more ancient synagogue in the 4th century, while later in the 5th century, the synagogue was transformed into Christian basilica.


In an essay on Sephardi Jewry, Daniel Elazar at the Jerusalem Center for Public Affairs summarized the demographic history of Ashkenazi Jews in the last thousand years, noting that at the end of the 11th century, 97% of world Jewry was Sephardic and 3% Ashkenazi; by the end of XVI century, the: 'Treaty on the redemption of captives', by Gracian of the God's Mother, Mercy Priest, who was imprisoned by Turks, cites a Tunisian Hebrew, made captive when arriving to Gaeta, who aided others with money, named: 'Simon Escanasi', in the mid-17th century, "Sephardim still outnumbered Ashkenazim three to two", but by the end of the 18th century, "Ashkenazim outnumbered Sephardim three to two, the result of improved living conditions in Christian Europe versus the Ottoman Muslim world." By 1931, Ashkenazi Jews accounted for nearly 92% of world Jewry. These factors are sheer demography showing the migration patterns of Jews from Southern and Western Europe to Central and Eastern Europe.


In Israel, the term Ashkenazi is now used in a manner unrelated to its original meaning, often applied to all Jews who settled in Europe and sometimes including those whose ethnic background is actually Sephardic. Jews of any non-Ashkenazi background, including Mizrahi, Yemenite, Kurdish and others who have no connection with the Iberian Peninsula, have similarly come to be lumped together as Sephardic. Jews of mixed background are increasingly common, partly because of intermarriage between Ashkenazi and non-Ashkenazi, and partly because many do not see such historic markers as relevant to their life experiences as Jews.


In this respect, the counterpart of Ashkenazi is Sephardic, since most non-Ashkenazi Orthodox Jews follow Sephardic rabbinical authorities, whether or not they are ethnically Sephardic. By tradition, a Sephardic or Mizrahi woman who marries into an Orthodox or Haredi Ashkenazi Jewish family raises her children to be Ashkenazi Jews; conversely an Ashkenazi woman who marries a Sephardi or Mizrahi man is expected to take on Sephardic practice and the children inherit a Sephardic identity, though in practice many families compromise. A convert generally follows the practice of the beth din that converted him or her. With the integration of Jews from around the world in Israel, North America, and other places, the religious definition of an Ashkenazi Jew is blurring, especially outside Orthodox Judaism.


But after emancipation, a sense of a unified French Jewry emerged, especially when France was wracked by the Dreyfus affair in the 1890s. In the 1920s and 1930s, Ashkenazi Jews from Europe arrived in large numbers as refugees from antisemitism, the Russian revolution, and the economic turmoil of the Great Depression. By the 1930s, Paris had a vibrant Yiddish culture, and many Jews were involved in diverse political movements. After the Vichy years and the Holocaust, the French Jewish population was augmented once again, first by Ashkenazi refugees from Central Europe, and later by Sephardi immigrants and refugees from North Africa, many of them francophone.


The term Ashkenazi also refers to the nusach Ashkenaz (Hebrew, "liturgical tradition", or rite) used by Ashkenazi Jews in their Siddur (prayer book). A nusach is defined by a liturgical tradition's choice of prayers, order of prayers, text of prayers and melodies used in the singing of prayers. Two other major forms of nusach among Ashkenazic Jews are Nusach Sefard (not to be confused with the Sephardic ritual), which is the general Polish Hasidic nusach, and Nusach Ari, as used by Lubavitch Hasidim.


Efforts to identify the origins of Ashkenazi Jews through DNA analysis began in the 1990s. Currently, there are three types of genetic origin testing, autosomal DNA (atDNA), mitochondrial DNA (mtDNA), and Y-chromosomal DNA (Y-DNA). Autosomal DNA is a mixture from an individual's entire ancestry, Y-DNA shows a male's lineage only along his strict-paternal line, mtDNA shows any person's lineage only along the strict-maternal line. Genome-wide association studies have also been employed to yield findings relevant to genetic origins.


In 2006, a study by Behar et al., based on what was at that time high-resolution analysis of haplogroup K (mtDNA), suggested that about 40% of the current Ashkenazi population is descended matrilineally from just four women, or "founder lineages", that were "likely from a Hebrew/Levantine mtDNA pool" originating in the Middle East in the 1st and 2nd centuries CE. Additionally, Behar et al. suggested that the rest of Ashkenazi mtDNA is originated from ~150 women, and that most of those were also likely of Middle Eastern origin. In reference specifically to Haplogroup K, they suggested that although it is common throughout western Eurasia, "the observed global pattern of distribution renders very unlikely the possibility that the four aforementioned founder lineages entered the Ashkenazi mtDNA pool via gene flow from a European host population".


Speculation that the Ashkenazi arose from Khazar stock surfaced in the later 19th century and has met with mixed fortunes in the scholarly literature. In late 2012 Eran Elhaik, a research associate studying genetics at the Johns Hopkins University School of Public Health, argued for Khazar descent in his paper The Missing Link of Jewish European Ancestry: Contrasting the Rhineland and the Khazarian Hypotheses. A 2013 study of Ashkenazi mitochondrial DNA found no significant evidence of Khazar contribution to the Ashkenazi Jewish DNA, as would be predicted by the Khazar hypothesis.


Sporadic epigraphic evidence in grave site excavations, particularly in Brigetio (Szőny), Aquincum (Óbuda), Intercisa (Dunaújváros), Triccinae (Sárvár), Savaria (Szombathely), Sopianae (Pécs), and Osijek in Croatia, attest to the presence of Jews after the 2nd and 3rd centuries where Roman garrisons were established, There was a sufficient number of Jews in Pannonia to form communities and build a synagogue. Jewish troops were among the Syrian soldiers transferred there, and replenished from the Middle East, after 175 C.E. Jews and especially Syrians came from Antioch, Tarsus and Cappadocia. Others came from Italy and the Hellenized parts of the Roman empire. The excavations suggest they first lived in isolated enclaves attached to Roman legion camps, and intermarried among other similar oriental families within the military orders of the region.Raphael Patai states that later Roman writers remarked that they differed little in either customs, manner of writing, or names from the people among whom they dwelt; and it was especially difficult to differentiate Jews from the Syrians. After Pannonia was ceded to the Huns in 433, the garrison populations were withdrawn to Italy, and only a few, enigmatic traces remain of a possible Jewish presence in the area some centuries later.


With the onset of the Crusades in 1095, and the expulsions from England (1290), France (1394), and parts of Germany (15th century), Jewish migration pushed eastward into Poland (10th century), Lithuania (10th century), and Russia (12th century). Over this period of several hundred years, some have suggested, Jewish economic activity was focused on trade, business management, and financial services, due to several presumed factors: Christian European prohibitions restricting certain activities by Jews, preventing certain financial activities (such as "usurious" loans) between Christians, high rates of literacy, near universal male education, and ability of merchants to rely upon and trust family members living in different regions and countries.


In the Midrash compilation, Genesis Rabbah, Rabbi Berechiah mentions Ashkenaz, Riphath, and Togarmah as German tribes or as German lands. It may correspond to a Greek word that may have existed in the Greek dialect of the Palestinian Jews, or the text is corrupted from "Germanica." This view of Berechiah is based on the Talmud (Yoma 10a; Jerusalem Talmud Megillah 71b), where Gomer, the father of Ashkenaz, is translated by Germamia, which evidently stands for Germany, and which was suggested by the similarity of the sound.


In the generations after emigration from the west, Jewish communities in places like Poland, Russia, and Belarus enjoyed a comparatively stable socio-political environment. A thriving publishing industry and the printing of hundreds of biblical commentaries precipitated the development of the Hasidic movement as well as major Jewish academic centers. After two centuries of comparative tolerance in the new nations, massive westward emigration occurred in the 19th and 20th centuries in response to pogroms in the east and the economic opportunities offered in other parts of the world. Ashkenazi Jews have made up the majority of the American Jewish community since 1750.


Religious Ashkenazi Jews living in Israel are obliged to follow the authority of the chief Ashkenazi rabbi in halakhic matters. In this respect, a religiously Ashkenazi Jew is an Israeli who is more likely to support certain religious interests in Israel, including certain political parties. These political parties result from the fact that a portion of the Israeli electorate votes for Jewish religious parties; although the electoral map changes from one election to another, there are generally several small parties associated with the interests of religious Ashkenazi Jews. The role of religious parties, including small religious parties that play important roles as coalition members, results in turn from Israel's composition as a complex society in which competing social, economic, and religious interests stand for election to the Knesset, a unicameral legislature with 120 seats.


New developments in Judaism often transcend differences in religious practice between Ashkenazi and Sephardic Jews. In North American cities, social trends such as the chavurah movement, and the emergence of "post-denominational Judaism" often bring together younger Jews of diverse ethnic backgrounds. In recent years, there has been increased interest in Kabbalah, which many Ashkenazi Jews study outside of the Yeshiva framework. Another trend is the new popularity of ecstatic worship in the Jewish Renewal movement and the Carlebach style minyan, both of which are nominally of Ashkenazi origin.


Several famous people have Ashkenazi as a surname, such as Vladimir Ashkenazy. However, most people with this surname hail from within Sephardic communities, particularly from the Syrian Jewish community. The Sephardic carriers of the surname would have some Ashkenazi ancestors since the surname was adopted by families who were initially of Ashkenazic origins who moved to Sephardi countries and joined those communities. Ashkenazi would be formally adopted as the family surname having started off as a nickname imposed by their adopted communities. Some have shortened the name to Ash.


A study of haplotypes of the Y-chromosome, published in 2000, addressed the paternal origins of Ashkenazi Jews. Hammer et al. found that the Y-chromosome of Ashkenazi and Sephardic Jews contained mutations that are also common among Middle Eastern peoples, but uncommon in the general European population. This suggested that the male ancestors of the Ashkenazi Jews could be traced mostly to the Middle East. The proportion of male genetic admixture in Ashkenazi Jews amounts to less than 0.5% per generation over an estimated 80 generations, with "relatively minor contribution of European Y chromosomes to the Ashkenazim," and a total admixture estimate "very similar to Motulsky's average estimate of 12.5%." This supported the finding that "Diaspora Jews from Europe, Northwest Africa, and the Near East resemble each other more closely than they resemble their non-Jewish neighbors." "Past research found that 50–80 percent of DNA from the Ashkenazi Y chromosome, which is used to trace the male lineage, originated in the Near East," Richards said.


In 2013, however, a study of Ashkenazi mitochondrial DNA by a team led by Martin B. Richards of the University of Huddersfield in England reached different conclusions, again corroborating the pre-2006 origin hypothesis. Testing was performed on the full 16,600 DNA units composing mitochondrial DNA (the 2006 Behar study had only tested 1,000 units) in all their subjects, and the study found that the four main female Ashkenazi founders had descent lines that were established in Europe 10,000 to 20,000 years in the past while most of the remaining minor founders also have a deep European ancestry. The study states that the great majority of Ashkenazi maternal lineages were not brought from the Near East (i.e., they were non-Israelite), nor were they recruited in the Caucasus (i.e., they were non-Khazar), but instead they were assimilated within Europe, primarily of Italian and Old French origins. Richards summarized the findings on the female line as such: "[N]one [of the mtDNA] came from the North Caucasus, located along the border between Europe and Asia between the Black and Caspian seas. All of our presently available studies including my own, should thoroughly debunk one of the most questionable, but still tenacious, hypotheses: that most Ashkenazi Jews can trace their roots to the mysterious Khazar Kingdom that flourished during the ninth century in the region between the Byzantine Empire and the Persian Empire." The 2013 study estimated that 80 percent of Ashkenazi maternal ancestry comes from women indigenous to Europe, and only 8 percent from the Near East, while the origin of the remainder is undetermined. According to the study these findings "point to a significant role for the conversion of women in the formation of Ashkenazi communities."


A 2010 study on Jewish ancestry by Atzmon-Ostrer et al. stated "Two major groups were identified by principal component, phylogenetic, and identity by descent (IBD) analysis: Middle Eastern Jews and European/Syrian Jews. The IBD segment sharing and the proximity of European Jews to each other and to southern European populations suggested similar origins for European Jewry and refuted large-scale genetic contributions of Central and Eastern European and Slavic populations to the formation of Ashkenazi Jewry", as both groups – the Middle Eastern Jews and European/Syrian Jews – shared common ancestors in the Middle East about 2500 years ago. The study examines genetic markers spread across the entire genome and shows that the Jewish groups (Ashkenazi and non Ashkenazi) share large swaths of DNA, indicating close relationships and that each of the Jewish groups in the study (Iranian, Iraqi, Syrian, Italian, Turkish, Greek and Ashkenazi) has its own genetic signature but is more closely related to the other Jewish groups than to their fellow non-Jewish countrymen. Atzmon's team found that the SNP markers in genetic segments of 3 million DNA letters or longer were 10 times more likely to be identical among Jews than non-Jews. Results of the analysis also tally with biblical accounts of the fate of the Jews. The study also found that with respect to non-Jewish European groups, the population most closely related to Ashkenazi Jews are modern-day Italians. The study speculated that the genetic-similarity between Ashkenazi Jews and Italians may be due to inter-marriage and conversions in the time of the Roman Empire. It was also found that any two Ashkenazi Jewish participants in the study shared about as much DNA as fourth or fifth cousins.


A 2013 trans-genome study carried out by 30 geneticists, from 13 universities and academies, from 9 countries, assembling the largest data set available to date, for assessment of Ashkenazi Jewish genetic origins found no evidence of Khazar origin among Ashkenazi Jews. "Thus, analysis of Ashkenazi Jews together with a large sample from the region of the Khazar Khaganate corroborates the earlier results that Ashkenazi Jews derive their ancestry primarily from populations of the Middle East and Europe, that they possess considerable shared ancestry with other Jewish populations, and that there is no indication of a significant genetic contribution either from within or from north of the Caucasus region", the authors concluded.


The origins of the Ashkenazim are obscure, and many theories have arisen speculating about their ultimate provenance. The most well supported theory is the one that details a Jewish migration through what is now Italy and other parts of southern Europe. The historical record attests to Jewish communities in southern Europe since pre-Christian times. Many Jews were denied full Roman citizenship until 212 CE, when Emperor Caracalla granted all free peoples this privilege. Jews were required to pay a poll tax until the reign of Emperor Julian in 363. In the late Roman Empire, Jews were free to form networks of cultural and religious ties and enter into various local occupations. But, after Christianity became the official religion of Rome and Constantinople in 380, Jews were increasingly marginalized.


Historical records show evidence of Jewish communities north of the Alps and Pyrenees as early as the 8th and 9th century. By the 11th century Jewish settlers, moving from southern European and Middle Eastern centers, appear to have begun to settle in the north, especially along the Rhine, often in response to new economic opportunities and at the invitation of local Christian rulers. Thus Baldwin V, Count of Flanders, invited Jacob ben Yekutiel and his fellow Jews to settle in his lands; and soon after the Norman Conquest of England, William the Conqueror likewise extended a welcome to continental Jews to take up residence there. Bishop Rüdiger Huzmann called on the Jews of Mainz to relocate to Speyer. In all of these decisions, the idea that Jews had the know-how and capacity to jump-start the economy, improve revenues, and enlarge trade seems to have played a prominent role. Typically Jews relocated close to the markets and churches in town centres, where, though they came under the authority of both royal and ecclesiastical powers, they were accorded administrative autonomy.


In the first half of the 11th century, Hai Gaon refers to questions that had been addressed to him from Ashkenaz, by which he undoubtedly means Germany. Rashi in the latter half of the 11th century refers to both the language of Ashkenaz and the country of Ashkenaz. During the 12th century, the word appears quite frequently. In the Mahzor Vitry, the kingdom of Ashkenaz is referred to chiefly in regard to the ritual of the synagogue there, but occasionally also with regard to certain other observances.


France's blended Jewish community is typical of the cultural recombination that is going on among Jews throughout the world. Although France expelled its original Jewish population in the Middle Ages, by the time of the French Revolution, there were two distinct Jewish populations. One consisted of Sephardic Jews, originally refugees from the Inquisition and concentrated in the southwest, while the other community was Ashkenazi, concentrated in formerly German Alsace, and speaking mainly Yiddish. The two communities were so separate and different that the National Assembly emancipated them separately in 1790 and 1791.


Various studies have arrived at diverging conclusions regarding both the degree and the sources of the non-Levantine admixture in Ashkenazim, particularly in respect to the extent of the non-Levantine genetic origin observed in Ashkenazi maternal lineages, which is in contrast to the predominant Levantine genetic origin observed in Ashkenazi paternal lineages. All studies nevertheless agree that genetic overlap with the Fertile Crescent exists in both lineages, albeit at differing rates. Collectively, Ashkenazi Jews are less genetically diverse than other Jewish ethnic divisions.


Before 2006, geneticists had largely attributed the ethnogenesis of most of the world's Jewish populations, including Ashkenazi Jews, to Israelite Jewish male migrants from the Middle East and "the women from each local population whom they took as wives and converted to Judaism." Thus, in 2002, in line with this model of origin, David Goldstein, now of Duke University, reported that unlike male Ashkenazi lineages, the female lineages in Ashkenazi Jewish communities "did not seem to be Middle Eastern", and that each community had its own genetic pattern and even that "in some cases the mitochondrial DNA was closely related to that of the host community." In his view this suggested "that Jewish men had arrived from the Middle East, taken wives from the host population and converted them to Judaism, after which there was no further intermarriage with non-Jews."


A 2006 study by Seldin et al. used over five thousand autosomal SNPs to demonstrate European genetic substructure. The results showed "a consistent and reproducible distinction between 'northern' and 'southern' European population groups". Most northern, central, and eastern Europeans (Finns, Swedes, English, Irish, Germans, and Ukrainians) showed >90% in the "northern" population group, while most individual participants with southern European ancestry (Italians, Greeks, Portuguese, Spaniards) showed >85% in the "southern" group. Both Ashkenazi Jews as well as Sephardic Jews showed >85% membership in the "southern" group. Referring to the Jews clustering with southern Europeans, the authors state the results were "consistent with a later Mediterranean origin of these ethnic groups".


By the 1890s the profound effect of adrenal extracts on many different tissue types had been discovered, setting off a search both for the mechanism of chemical signalling and efforts to exploit these observations for the development of new drugs. The blood pressure raising and vasoconstrictive effects of adrenal extracts were of particular interest to surgeons as hemostatic agents and as treatment for shock, and a number of companies developed products based on adrenal extracts containing varying purities of the active substance. In 1897 John Abel of Johns Hopkins University identified the active principle as epinephrine, which he isolated in an impure state as the sulfate salt. Industrial chemist Jokichi Takamine later developed a method for obtaining epinephrine in a pure state, and licensed the technology to Parke Davis. Parke Davis marketed epinephrine under the trade name Adrenalin. Injected epinephrine proved to be especially efficacious for the acute treatment of asthma attacks, and an inhaled version was sold in the United States until 2011 (Primatene Mist). By 1929 epinephrine had been formulated into an inhaler for use in the treatment of nasal congestion.


While highly effective, the requirement for injection limited the use of norepinephrine[clarification needed] and orally active derivatives were sought. A structurally similar compound, ephedrine, was identified by Japanese chemists in the Ma Huang plant and marketed by Eli Lilly as an oral treatment for asthma. Following the work of Henry Dale and George Barger at Burroughs-Wellcome, academic chemist Gordon Alles synthesized amphetamine and tested it in asthma patients in 1929. The drug proved to have only modest anti-asthma effects, but produced sensations of exhilaration and palpitations. Amphetamine was developed by Smith, Kline and French as a nasal decongestant under the trade name Benzedrine Inhaler. Amphetamine was eventually developed for the treatment of narcolepsy, post-encepheletic parkinsonism, and mood elevation in depression and other psychiatric indications. It received approval as a New and Nonofficial Remedy from the American Medical Association for these uses in 1937 and remained in common use for depression until the development of tricyclic antidepressants in the 1960s.


A series of experiments performed from the late 1800s to the early 1900s revealed that diabetes is caused by the absence of a substance normally produced by the pancreas. In 1869, Oskar Minkowski and Joseph von Mering found that diabetes could be induced in dogs by surgical removal of the pancreas. In 1921, Canadian professor Frederick Banting and his student Charles Best repeated this study, and found that injections of pancreatic extract reversed the symptoms produced by pancreas removal. Soon, the extract was demonstrated to work in people, but development of insulin therapy as a routine medical procedure was delayed by difficulties in producing the material in sufficient quantity and with reproducible purity. The researchers sought assistance from industrial collaborators at Eli Lilly and Co. based on the company's experience with large scale purification of biological materials. Chemist George Walden of Eli Lilly and Company found that careful adjustment of the pH of the extract allowed a relatively pure grade of insulin to be produced. Under pressure from Toronto University and a potential patent challenge by academic scientists who had independently developed a similar purification method, an agreement was reached for non-exclusive production of insulin by multiple companies. Prior to the discovery and widespread availability of insulin therapy the life expectancy of diabetics was only a few months.


In 1903 Hermann Emil Fischer and Joseph von Mering disclosed their discovery that diethylbarbituric acid, formed from the reaction of diethylmalonic acid, phosphorus oxychloride and urea, induces sleep in dogs. The discovery was patented and licensed to Bayer pharmaceuticals, which marketed the compound under the trade name Veronal as a sleep aid beginning in 1904. Systematic investigations of the effect of structural changes on potency and duration of action led to the discovery of phenobarbital at Bayer in 1911 and the discovery of its potent anti-epileptic activity in 1912. Phenobarbital was among the most widely used drugs for the treatment of epilepsy through the 1970s, and as of 2014, remains on the World Health Organizations list of essential medications. The 1950s and 1960s saw increased awareness of the addictive properties and abuse potential of barbiturates and amphetamines and led to increasing restrictions on their use and growing government oversight of prescribers. Today, amphetamine is largely restricted to use in the treatment of attention deficit disorder and phenobarbital in the treatment of epilepsy.


In 1911 arsphenamine, the first synthetic anti-infective drug, was developed by Paul Ehrlich and chemist Alfred Bertheim of the Institute of Experimental Therapy in Berlin. The drug was given the commercial name Salvarsan. Ehrlich, noting both the general toxicity of arsenic and the selective absorption of certain dyes by bacteria, hypothesized that an arsenic-containing dye with similar selective absorption properties could be used to treat bacterial infections. Arsphenamine was prepared as part of a campaign to synthesize a series of such compounds, and found to exhibit partially selective toxicity. Arsphenamine proved to be the first effective treatment for syphilis, a disease which prior to that time was incurable and led inexorably to severe skin ulceration, neurological damage, and death.[citation needed]


The modern pharmaceutical industry traces its roots to two sources. The first of these were local apothecaries that expanded from their traditional role distributing botanical drugs such as morphine and quinine to wholesale manufacture in the mid 1800s. Rational drug discovery from plants started particularly with the isolation of morphine, analgesic and sleep-inducing agent from opium, by the German apothecary assistant Friedrich Sertürner, who named the compound after the Greek god of dreams, Morpheus. Multinational corporations including Merck, Hoffman-La Roche, Burroughs-Wellcome (now part of Glaxo Smith Kline), Abbott Laboratories, Eli Lilly and Upjohn (now part of Pfizer) began as local apothecary shops in the mid-1800s. By the late 1880s, German dye manufacturers had perfected the purification of individual organic compounds from coal tar and other mineral sources and had also established rudimentary methods in organic chemical synthesis. The development of synthetic chemical methods allowed scientists to systematically vary the structure of chemical substances, and growth in the emerging science of pharmacology expanded their ability to evaluate the biological effects of these structural changes.


Ehrlich’s approach of systematically varying the chemical structure of synthetic compounds and measuring the effects of these changes on biological activity was pursued broadly by industrial scientists, including Bayer scientists Josef Klarer, Fritz Mietzsch, and Gerhard Domagk. This work, also based in the testing of compounds available from the German dye industry, led to the development of Prontosil, the first representative of the sulfonamide class of antibiotics. Compared to arsphenamine, the sulfonamides had a broader spectrum of activity and were far less toxic, rendering them useful for infections caused by pathogens such as streptococci. In 1939, Domagk received the Nobel Prize in Medicine for this discovery. Nonetheless, the dramatic decrease in deaths from infectious diseases that occurred prior to World War II was primarily the result of improved public health measures such as clean water and less crowded housing, and the impact of anti-infective drugs and vaccines was significant mainly after World War II.


Early progress toward the development of vaccines occurred throughout this period, primarily in the form of academic and government-funded basic research directed toward the identification of the pathogens responsible for common communicable diseases. In 1885 Louis Pasteur and Pierre Paul Émile Roux created the first rabies vaccine. The first diphtheria vaccines were produced in 1914 from a mixture of diphtheria toxin and antitoxin (produced from the serum of an inoculated animal), but the safety of the inoculation was marginal and it was not widely used. The United States recorded 206,000 cases of diphtheria in 1921 resulting in 15,520 deaths. In 1923 parallel efforts by Gaston Ramon at the Pasteur Institute and Alexander Glenny at the Wellcome Research Laboratories (later part of GlaxoSmithKline) led to the discovery that a safer vaccine could be produced by treating diphtheria toxin with formaldehyde. In 1944, Maurice Hilleman of Squibb Pharmaceuticals developed the first vaccine against Japanese encephelitis. Hilleman would later move to Merck where he would play a key role in the development of vaccines against measles, mumps, chickenpox, rubella, hepatitis A, hepatitis B, and meningitis.


In 1937 over 100 people died after ingesting "Elixir Sulfanilamide" manufactured by S.E. Massengill Company of Tennessee. The product was formulated in diethylene glycol, a highly toxic solvent that is now widely used as antifreeze. Under the laws extant at that time, prosecution of the manufacturer was possible only under the technicality that the product had been called an "elixir", which literally implied a solution in ethanol. In response to this episode, the U.S. Congress passed the Federal Food, Drug, and Cosmetic Act of 1938, which for the first time required pre-market demonstration of safety before a drug could be sold, and explicitly prohibited false therapeutic claims.


The aftermath of World War II saw an explosion in the discovery of new classes of antibacterial drugs including the cephalosporins (developed by Eli Lilly based on the seminal work of Giuseppe Brotzu and Edward Abraham), streptomycin (discovered during a Merck-funded research program in Selman Waksman's laboratory), the tetracyclines (discovered at Lederle Laboratories, now a part of Pfizer), erythromycin (discovered at Eli Lilly and Co.) and their extension to an increasingly wide range of bacterial pathogens. Streptomycin, discovered during a Merck-funded research program in Selman Waksman's laboratory at Rutgers in 1943, became the first effective treatment for tuberculosis. At the time of its discovery, sanitoriums for the isolation of tuberculosis-infected people were an ubiquitous feature of cities in developed countries, with 50% dying within 5 years of admission.


During the years 1940-1955, the rate of decline in the U.S. death rate accelerated from 2% per year to 8% per year, then returned to the historical rate of 2% per year. The dramatic decline in the immediate post-war years has been attributed to the rapid development of new treatments and vaccines for infectious disease that occurred during these years. Vaccine development continued to accelerate, with the most notable achievement of the period being Jonas Salk's 1954 development of the polio vaccine under the funding of the non-profit National Foundation for Infantile Paralysis. The vaccine process was never patented, but was instead given to pharmaceutical companies to manufacture as a low-cost generic. In 1960 Maurice Hilleman of Merck Sharp & Dohme identified the SV40 virus, which was later shown to cause tumors in many mammalian species. It was later determined that SV40 was present as a contaminant in polio vaccine lots that had been administered to 90% of the children in the United States. The contamination appears to have originated both in the original cell stock and in monkey tissue used for production. In 2004 the United States Cancer Institute announced that it had concluded that SV40 is not associated with cancer in people.


On 2 July 2012, GlaxoSmithKline pleaded guilty to criminal charges and agreed to a $3 billion settlement of the largest health-care fraud case in the U.S. and the largest payment by a drug company. The settlement is related to the company's illegal promotion of prescription drugs, its failure to report safety data, bribing doctors, and promoting medicines for uses for which they were not licensed. The drugs involved were Paxil, Wellbutrin, Advair, Lamictal, and Zofran for off-label, non-covered uses. Those and the drugs Imitrex, Lotronex, Flovent, and Valtrex were involved in the kickback scheme.


In the US, starting in 2013, under the Physician Financial Transparency Reports (part of the Sunshine Act), the Centers for Medicare & Medicaid Services has to collect information from applicable manufacturers and group purchasing organizations in order to report information about their financial relationships with physicians and hospitals. Data are made public in the Centers for Medicare & Medicaid Services website. The expectation is that relationship between doctors and Pharmaceutical industry will become fully transparent.


A Federal Trade Commission report issued in 1958 attempted to quantify the effect of antibiotic development on American public health. The report found that over the period 1946-1955, there was a 42% drop in the incidence of diseases for which antibiotics were effective and only a 20% drop in those for which antibiotics were not effective. The report concluded that "it appears that the use of antibiotics, early diagnosis, and other factors have limited the epidemic spread and thus the number of these diseases which have occurred". The study further examined mortality rates for eight common diseases for which antibiotics offered effective therapy (syphilis, tuberculosis, dysentery, scarlet fever, whooping cough, meningococcal infections, and pneumonia), and found a 56% decline over the same period. Notable among these was a 75% decline in deaths due to tuberculosis.


In March 2001, 40 multi-national pharmaceutical companies brought litigation against South Africa for its Medicines Act, which allowed the generic production of antiretroviral drugs (ARVs) for treating HIV, despite the fact that these drugs were on-patent. HIV was and is an epidemic in South Africa, and ARVs at the time cost between 10,000 and 15,000 USD per patient per year. This was unaffordable for most South African citizens, and so the South African government committed to providing ARVs at prices closer to what people could afford. To do so, they would need to ignore the patents on drugs and produce generics within the country (using a compulsory license), or import them from abroad. After international protest in favour of public health rights (including the collection of 250,000 signatures by MSF), the governments of several developed countries (including The Netherlands, Germany, France, and later the US) backed the South African government, and the case was dropped in April of that year.


Prior to the 20th century drugs were generally produced by small scale manufacturers with little regulatory control over manufacturing or claims of safety and efficacy. To the extent that such laws did exist, enforcement was lax. In the United States, increased regulation of vaccines and other biological drugs was spurred by tetanus outbreaks and deaths caused by the distribution of contaminated smallpox vaccine and diphtheria antitoxin. The Biologics Control Act of 1902 required that federal government grant premarket approval for every biological drug and for the process and facility producing such drugs. This was followed in 1906 by the Pure Food and Drugs Act, which forbade the interstate distribution of adulterated or misbranded foods and drugs. A drug was considered misbranded if it contained alcohol, morphine, opium, cocaine, or any of several other potentially dangerous or addictive drugs, and if its label failed to indicate the quantity or proportion of such drugs. The government's attempts to use the law to prosecute manufacturers for making unsupported claims of efficacy were undercut by a Supreme Court ruling restricting the federal government's enforcement powers to cases of incorrect specification of the drug's ingredients.


Patents have been criticized in the developing world, as they are thought to reduce access to existing medicines. Reconciling patents and universal access to medicine would require an efficient international policy of price discrimination. Moreover, under the TRIPS agreement of the World Trade Organization, countries must allow pharmaceutical products to be patented. In 2001, the WTO adopted the Doha Declaration, which indicates that the TRIPS agreement should be read with the goals of public health in mind, and allows some methods for circumventing pharmaceutical monopolies: via compulsory licensing or parallel imports, even before patent expiration.


Pharmaceutical fraud involves deceptions which bring financial gain to a pharmaceutical company. It affects individuals and public and private insurers. There are several different schemes used to defraud the health care system which are particular to the pharmaceutical industry. These include: Good Manufacturing Practice (GMP) Violations, Off Label Marketing, Best Price Fraud, CME Fraud, Medicaid Price Reporting, and Manufactured Compound Drugs. Of this amount $2.5 billion was recovered through False Claims Act cases in FY 2010. Examples of fraud cases include the GlaxoSmithKline $3 billion settlement, Pfizer $2.3 billion settlement and Merck & Co. $650 million settlement. Damages from fraud can be recovered by use of the False Claims Act, most commonly under the qui tam provisions which rewards an individual for being a "whistleblower", or relator (law).


A 2009 Cochrane review concluded that thiazide antihypertensive drugs reduce the risk of death (RR 0.89), stroke (RR 0.63), coronary heart disease (RR 0.84), and cardiovascular events (RR 0.70) in people with high blood pressure. In the ensuring years other classes of antihypertensive drug were developed and found wide acceptance in combination therapy, including loop diuretics (Lasix/furosemide, Hoechst Pharmaceuticals, 1963), beta blockers (ICI Pharmaceuticals, 1964) ACE inhibitors, and angiotensin receptor blockers. ACE inhibitors reduce the risk of new onset kidney disease [RR 0.71] and death [RR 0.84] in diabetic patients, irrespective of whether they have hypertension.


Others have argued that excessive regulation suppresses therapeutic innovation, and that the current cost of regulator-required clinical trials prevents the full exploitation of new genetic and biological knowledge for the treatment of human disease. A 2012 report by the President's Council of Advisors on Science and Technology made several key recommendations to reduce regulatory burdens to new drug development, including 1) expanding the FDA's use of accelerated approval processes, 2) creating an expedited approval pathway for drugs intended for use in narrowly defined populations, and 3) undertaking pilot projects designed to evaluate the feasibility of a new, adaptive drug approval process.


In 1952 researchers at Ciba discovered the first orally available vasodilator, hydralazine. A major shortcoming of hydralazine monotherapy was that it lost its effectiveness over time (tachyphylaxis). In the mid-1950s Karl H. Beyer, James M. Sprague, John E. Baer, and Frederick C. Novello of Merck and Co. discovered and developed chlorothiazide, which remains the most widely used antihypertensive drug today. This development was associated with a substantial decline in the mortality rate among people with hypertension. The inventors were recognized by a Public Health Lasker Award in 1975 for "the saving of untold thousands of lives and the alleviation of the suffering of millions of victims of hypertension".


In the U.S., a push for revisions of the FD&C Act emerged from Congressional hearings led by Senator Estes Kefauver of Tennessee in 1959. The hearings covered a wide range of policy issues, including advertising abuses, questionable efficacy of drugs, and the need for greater regulation of the industry. While momentum for new legislation temporarily flagged under extended debate, a new tragedy emerged that underscored the need for more comprehensive regulation and provided the driving force for the passage of new laws.


Other notable new vaccines of the period include those for measles (1962, John Franklin Enders of Children's Medical Center Boston, later refined by Maurice Hilleman at Merck), Rubella (1969, Hilleman, Merck) and mumps (1967, Hilleman, Merck) The United States incidences of rubella, congenital rubella syndrome, measles, and mumps all fell by >95% in the immediate aftermath of widespread vaccination. The first 20 years of licensed measles vaccination in the U.S. prevented an estimated 52 million cases of the disease, 17,400 cases of mental retardation, and 5,200 deaths.


The thalidomide tragedy resurrected Kefauver's bill to enhance drug regulation that had stalled in Congress, and the Kefauver-Harris Amendment became law on 10 October 1962. Manufacturers henceforth had to prove to FDA that their drugs were effective as well as safe before they could go on the US market. The FDA received authority to regulate advertising of prescription drugs and to establish good manufacturing practices. The law required that all drugs introduced between 1938 and 1962 had to be effective. An FDA - National Academy of Sciences collaborative study showed that nearly 40 percent of these products were not effective. A similarly comprehensive study of over-the-counter products began ten years later.


The firm continued to pressure Kelsey and the agency to approve the application—until November 1961, when the drug was pulled off the German market because of its association with grave congenital abnormalities. Several thousand newborns in Europe and elsewhere suffered the teratogenic effects of thalidomide. Though the drug was never approved in the USA, the firm distributed Kevadon to over 1,000 physicians there under the guise of investigational use. Over 20,000 Americans received thalidomide in this "study," including 624 pregnant patients, and about 17 known newborns suffered the effects of the drug.[citation needed]


Prior to the second world war, birth control was prohibited in many countries, and in the United States even the discussion of contraceptive methods sometimes led to prosecution under Comstock laws. The history of the development of oral contraceptives is thus closely tied to the birth control movement and the efforts of activists Margaret Sanger, Mary Dennett, and Emma Goldman. Based on fundamental research performed by Gregory Pincus and synthetic methods for progesterone developed by Carl Djerassi at Syntex and by Frank Colton at G.D. Searle & Co., the first oral contraceptive, Enovid, was developed by E.D. Searle and Co. and approved by the FDA in 1960. The original formulation incorporated vastly excessive doses of hormones, and caused severe side effects. Nonetheless, by 1962, 1.2 million American women were on the pill, and by 1965 the number had increased to 6.5 million. The availability of a convenient form of temporary contraceptive led to dramatic changes in social mores including expanding the range of lifestyle options available to women, reducing the reliance of women on men for contraceptive practice, encouraging the delay of marriage, and increasing pre-marital co-habitation.


In April 1994, the results of a Merck-sponsored study, the Scandinavian Simvastatin Survival Study, were announced. Researchers tested simvastatin, later sold by Merck as Zocor, on 4,444 patients with high cholesterol and heart disease. After five years, the study concluded the patients saw a 35% reduction in their cholesterol, and their chances of dying of a heart attack were reduced by 42%. In 1995, Zocor and Mevacor both made Merck over US$1 billion. Endo was awarded the 2006 Japan Prize, and the Lasker-DeBakey Clinical Medical Research Award in 2008. For his "pioneering research into a new class of molecules" for "lowering cholesterol,"[sentence fragment]


Drug discovery is the process by which potential drugs are discovered or designed. In the past most drugs have been discovered either by isolating the active ingredient from traditional remedies or by serendipitous discovery. Modern biotechnology often focuses on understanding the metabolic pathways related to a disease state or pathogen, and manipulating these pathways using molecular biology or biochemistry. A great deal of early-stage drug discovery has traditionally been carried out by universities and research institutions.


Drug discovery and development is very expensive; of all compounds investigated for use in humans only a small fraction are eventually approved in most nations by government appointed medical institutions or boards, who have to approve new drugs before they can be marketed in those countries. In 2010 18 NMEs (New Molecular Entities) were approved and three biologics by the FDA, or 21 in total, which is down from 26 in 2009 and 24 in 2008. On the other hand, there were only 18 approvals in total in 2007 and 22 back in 2006. Since 2001, the Center for Drug Evaluation and Research has averaged 22.9 approvals a year. This approval comes only after heavy investment in pre-clinical development and clinical trials, as well as a commitment to ongoing safety monitoring. Drugs which fail part-way through this process often incur large costs, while generating no revenue in return. If the cost of these failed drugs is taken into account, the cost of developing a successful new drug (new chemical entity, or NCE), has been estimated at about 1.3 billion USD(not including marketing expenses). Professors Light and Lexchin reported in 2012, however, that the rate of approval for new drugs has been a relatively stable average rate of 15 to 25 for decades.


Some of these estimates also take into account the opportunity cost of investing capital many years before revenues are realized (see Time-value of money). Because of the very long time needed for discovery, development, and approval of pharmaceuticals, these costs can accumulate to nearly half the total expense. A direct consequence within the pharmaceutical industry value chain is that major pharmaceutical multinationals tend to increasingly outsource risks related to fundamental research, which somewhat reshapes the industry ecosystem with biotechnology companies playing an increasingly important role, and overall strategies being redefined accordingly. Some approved drugs, such as those based on re-formulation of an existing active ingredient (also referred to as Line-extensions) are much less expensive to develop.


In 1971, Akira Endo, a Japanese biochemist working for the pharmaceutical company Sankyo, identified mevastatin (ML-236B), a molecule produced by the fungus Penicillium citrinum, as an inhibitor of HMG-CoA reductase, a critical enzyme used by the body to produce cholesterol. Animal trials showed very good inhibitory effect as in clinical trials, however a long term study in dogs found toxic effects at higher doses and as a result mevastatin was believed to be too toxic for human use. Mevastatin was never marketed, because of its adverse effects of tumors, muscle deterioration, and sometimes death in laboratory dogs.


Every major company selling the antipsychotics — Bristol-Myers Squibb, Eli Lilly, Pfizer, AstraZeneca and Johnson & Johnson — has either settled recent government cases, under the False Claims Act, for hundreds of millions of dollars or is currently under investigation for possible health care fraud. Following charges of illegal marketing, two of the settlements set records last year for the largest criminal fines ever imposed on corporations. One involved Eli Lilly's antipsychotic Zyprexa, and the other involved Bextra. In the Bextra case, the government also charged Pfizer with illegally marketing another antipsychotic, Geodon; Pfizer settled that part of the claim for $301 million, without admitting any wrongdoing.


In contrast to this viewpoint, an article and associated editorial in the New England Journal of Medicine in May 2015 emphasized the importance of pharmaceutical industry-physician interactions for the development of novel treatments, and argued that moral outrage over industry malfeasance had unjustifiably led many to overemphasize the problems created by financial conflicts of interest. The article noted that major healthcare organizations such as National Center for Advancing Translational Sciences of the National Institutes of Health, the President’s Council of Advisors on Science and Technology, the World Economic Forum, the Gates Foundation, the Wellcome Trust, and the Food and Drug Administration had encouraged greater interactions between physicians and industry in order to bring greater benefits to patients.


An investigation by ProPublica found that at least 21 doctors have been paid more than $500,000 for speeches and consulting by drugs manufacturers since 2009, with half of the top earners working in psychiatry, and about $2 billion in total paid to doctors for such services. AstraZeneca, Johnson & Johnson and Eli Lilly have paid billions of dollars in federal settlements over allegations that they paid doctors to promote drugs for unapproved uses. Some prominent medical schools have since tightened rules on faculty acceptance of such payments by drug companies.


Often, large multinational corporations exhibit vertical integration, participating in a broad range of drug discovery and development, manufacturing and quality control, marketing, sales, and distribution. Smaller organizations, on the other hand, often focus on a specific aspect such as discovering drug candidates or developing formulations. Often, collaborative agreements between research organizations and large pharmaceutical companies are formed to explore the potential of new drug substances. More recently, multi-nationals are increasingly relying on contract research organizations to manage drug development.


In the UK, the Medicines and Healthcare Products Regulatory Agency approves drugs for use, though the evaluation is done by the European Medicines Agency, an agency of the European Union based in London. Normally an approval in the UK and other European countries comes later than one in the USA. Then it is the National Institute for Health and Care Excellence (NICE), for England and Wales, who decides if and how the National Health Service (NHS) will allow (in the sense of paying for) their use. The British National Formulary is the core guide for pharmacists and clinicians.


There are special rules for certain rare diseases ("orphan diseases") in several major drug regulatory territories. For example, diseases involving fewer than 200,000 patients in the United States, or larger populations in certain circumstances are subject to the Orphan Drug Act.  Because medical research and development of drugs to treat such diseases is financially disadvantageous, companies that do so are rewarded with tax reductions, fee waivers, and market exclusivity on that drug for a limited time (seven years), regardless of whether the drug is protected by patents.


Ben Goldacre has argued that regulators – such as the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK, or the Food and Drug Administration (FDA) in the United States – advance the interests of the drug companies rather than the interests of the public due to revolving door exchange of employees between the regulator and the companies and friendships develop between regulator and company employees. He argues that regulators do not require that new drugs offer an improvement over what is already available, or even that they be particularly effective.


In many non-US western countries a 'fourth hurdle' of cost effectiveness analysis has developed before new technologies can be provided. This focuses on the efficiency (in terms of the cost per QALY) of the technologies in question rather than their efficacy. In England and Wales NICE decides whether and in what circumstances drugs and technologies will be made available by the NHS, whilst similar arrangements exist with the Scottish Medicines Consortium in Scotland, and the Pharmaceutical Benefits Advisory Committee in Australia. A product must pass the threshold for cost-effectiveness if it is to be approved. Treatments must represent 'value for money' and a net benefit to society.


The top ten best-selling drugs of 2013 totaled $75.6 billion in sales, with the anti-inflammatory drug Humira being the best-selling drug worldwide at $10.7 billion in sales. The second and third best selling were Enbrel and Remicade, respectively. The top three best-selling drugs in the United States in 2013 were Abilify ($6.3 billion,) Nexium ($6 billion) and Humira ($5.4 billion). The best-selling drug ever, Lipitor, averaged $13 billion annually and netted $141 billion total over its lifetime before Pfizer's patent expired in November 2011.


Depending on a number of considerations, a company may apply for and be granted a patent for the drug, or the process of producing the drug, granting exclusivity rights typically for about 20 years. However, only after rigorous study and testing, which takes 10 to 15 years on average, will governmental authorities grant permission for the company to market and sell the drug. Patent protection enables the owner of the patent to recover the costs of research and development through high profit margins for the branded drug. When the patent protection for the drug expires, a generic drug is usually developed and sold by a competing company. The development and approval of generics is less expensive, allowing them to be sold at a lower price. Often the owner of the branded drug will introduce a generic version before the patent expires in order to get a head start in the generic market. Restructuring has therefore become routine, driven by the patent expiration of products launched during the industry's "golden era" in the 1990s and companies' failure to develop sufficient new blockbuster products to replace lost revenues.


In the United States, new pharmaceutical products must be approved by the Food and Drug Administration (FDA) as being both safe and effective. This process generally involves submission of an Investigational New Drug filing with sufficient pre-clinical data to support proceeding with human trials. Following IND approval, three phases of progressively larger human clinical trials may be conducted. Phase I generally studies toxicity using healthy volunteers. Phase II can include pharmacokinetics and dosing in patients, and Phase III is a very large study of efficacy in the intended patient population. Following the successful completion of phase III testing, a New Drug Application is submitted to the FDA. The FDA review the data and if the product is seen as having a positive benefit-risk assessment, approval to market the product in the US is granted.


Advertising is common in healthcare journals as well as through more mainstream media routes. In some countries, notably the US, they are allowed to advertise directly to the general public. Pharmaceutical companies generally employ sales people (often called 'drug reps' or, an older term, 'detail men') to market directly and personally to physicians and other healthcare providers. In some countries, notably the US, pharmaceutical companies also employ lobbyists to influence politicians. Marketing of prescription drugs in the US is regulated by the federal Prescription Drug Marketing Act of 1987.


There has been increasing controversy surrounding pharmaceutical marketing and influence. There have been accusations and findings of influence on doctors and other health professionals through drug reps, including the constant provision of marketing 'gifts' and biased information to health professionals; highly prevalent advertising in journals and conferences; funding independent healthcare organizations and health promotion campaigns; lobbying physicians and politicians (more than any other industry in the US); sponsorship of medical schools or nurse training; sponsorship of continuing educational events, with influence on the curriculum; and hiring physicians as paid consultants on medical advisory boards.


The rivalries between the Arab tribes had caused unrest in the provinces outside Syria, most notably in the Second Muslim Civil War of 680–692 CE and the Berber Revolt of 740–743 CE. During the Second Civil War, leadership of the Umayyad clan shifted from the Sufyanid branch of the family to the Marwanid branch. As the constant campaigning exhausted the resources and manpower of the state, the Umayyads, weakened by the Third Muslim Civil War of 744–747 CE, were finally toppled by the Abbasid Revolution in 750 CE/132 AH. A branch of the family fled across North Africa to Al-Andalus, where they established the Caliphate of Córdoba, which lasted until 1031 before falling due to the Fitna of al-Ándalus.


Ali was assassinated in 661 by a Kharijite partisan. Six months later in the same year, in the interest of peace, Hasan ibn Ali, highly regarded for his wisdom and as a peacemaker, and the Second Imam for the Shias, and the grandson of Muhammad, made a peace treaty with Muawiyah I. In the Hasan-Muawiya treaty, Hasan ibn Ali handed over power to Muawiya on the condition that he be just to the people and keep them safe and secure, and after his death he not establish a dynasty. This brought to an end the era of the Rightly Guided Caliphs for the Sunnis, and Hasan ibn Ali was also the last Imam for the Shias to be a Caliph. Following this, Mu'awiyah broke the conditions of the agreement and began the Umayyad dynasty, with its capital in Damascus.


At the time, the Umayyad taxation and administrative practice were perceived as unjust by some Muslims. The Christian and Jewish population had still autonomy; their judicial matters were dealt with in accordance with their own laws and by their own religious heads or their appointees, although they did pay a poll tax for policing to the central state. Muhammad had stated explicitly during his lifetime that abrahamic religious groups (still a majority in times of the Umayyad Caliphate), should be allowed to practice their own religion, provided that they paid the jizya taxation. The welfare state of both the Muslim and the non-Muslim poor started by Umar ibn al Khattab had also continued. Muawiya's wife Maysum (Yazid's mother) was also a Christian. The relations between the Muslims and the Christians in the state were stable in this time. The Umayyads were involved in frequent battles with the Christian Byzantines without being concerned with protecting themselves in Syria, which had remained largely Christian like many other parts of the empire. Prominent positions were held by Christians, some of whom belonged to families that had served in Byzantine governments. The employment of Christians was part of a broader policy of religious assimilation that was necessitated by the presence of large Christian populations in the conquered provinces, as in Syria. This policy also boosted Muawiya's popularity and solidified Syria as his power base.


The Umayyad Caliphate (Arabic: الخلافة الأموية, trans. Al-Khilāfat al-ʾumawiyya) was the second of the four major Islamic caliphates established after the death of Muhammad. This caliphate was centered on the Umayyad dynasty (Arabic: الأمويون, al-ʾUmawiyyūn, or بنو أمية, Banū ʾUmayya, "Sons of Umayya"), hailing from Mecca. The Umayyad family had first come to power under the third caliph, Uthman ibn Affan (r. 644–656), but the Umayyad regime was founded by Muawiya ibn Abi Sufyan, long-time governor of Syria, after the end of the First Muslim Civil War in 661 CE/41 AH. Syria remained the Umayyads' main power base thereafter, and Damascus was their capital. The Umayyads continued the Muslim conquests, incorporating the Caucasus, Transoxiana, Sindh, the Maghreb and the Iberian Peninsula (Al-Andalus) into the Muslim world. At its greatest extent, the Umayyad Caliphate covered 15 million km2 (5.79 million square miles), making it the largest empire (in terms of area - not in terms of population) the world had yet seen, and the fifth largest ever to exist.


Most historians[who?] consider Caliph Muawiyah (661–80) to have been the second ruler of the Umayyad dynasty, even though he was the first to assert the Umayyads' right to rule on a dynastic principle. It was really the caliphate of Uthman Ibn Affan (644–656), a member of Umayyad clan himself, that witnessed the revival and then the ascendancy of the Umayyad clan to the corridors of power. Uthman placed some of the trusted members of his clan at prominent and strong positions throughout the state. Most notable was the appointment of Marwan ibn al-Hakam, Uthman's first cousin, as his top advisor, which created a stir among the Hashimite companions of Muhammad, as Marwan along with his father Al-Hakam ibn Abi al-'As had been permanently exiled from Medina by Muhammad during his lifetime. Uthman also appointed as governor of Kufa his half-brother, Walid ibn Uqba, who was accused by Hashmites of leading prayer while under the influence of alcohol. Uthman also consolidated Muawiyah's governorship of Syria by granting him control over a larger area and appointed his foster brother Abdullah ibn Saad as the Governor of Egypt. However, since Uthman never named an heir, he cannot be considered the founder of a dynasty.


Following the death of Husayn, Ibn al-Zubayr, although remaining in Mecca, was associated with two opposition movements, one centered in Medina and the other around Kharijites in Basra and Arabia. Because Medina had been home to Muhammad and his family, including Husayn, word of his death and the imprisonment of his family led to a large opposition movement. In 683, Yazid dispatched an army to subdue both movements. The army suppressed the Medinese opposition at the Battle of al-Harrah. The Grand Mosque in Medina was severely damaged and widespread pillaging caused deep-seated dissent. Yazid's army continued on and laid siege to Mecca. At some point during the siege, the Kaaba was badly damaged in a fire. The destruction of the Kaaba and Grand Mosque became a major cause for censure of the Umayyads in later histories of the period.


According to tradition, the Umayyad family (also known as the Banu Abd-Shams) and Muhammad both descended from a common ancestor, Abd Manaf ibn Qusai, and they originally came from the city of Mecca. Muhammad descended from Abd Manāf via his son Hashim, while the Umayyads descended from Abd Manaf via a different son, Abd-Shams, whose son was Umayya. The two families are therefore considered to be different clans (those of Hashim and of Umayya, respectively) of the same tribe (that of the Quraish). However Muslim Shia historians suspect that Umayya was an adopted son of Abd Shams so he was not a blood relative of Abd Manaf ibn Qusai. Umayya was later discarded from the noble family. Sunni historians disagree with this and view Shia claims as nothing more than outright polemics due to their hostility to the Umayyad family in general. They point to the fact that the grand sons of Uthman, Zaid bin amr bin uthman bin affan and Abdullah bin Amr bin Uthman got married to the Sukaina and Fatima the daughters of Hussein son of Ali to show closeness of Banu hashem and Bani Ummayah.


Following this battle, Ali fought a battle against Muawiyah, known as the Battle of Siffin. The battle was stopped before either side had achieved victory, and the two parties agreed to arbitrate their dispute. After the battle Amr ibn al-As was appointed by Muawiyah as an arbitrator, and Ali appointed Abu Musa Ashaari. Seven months later, in February 658, the two arbitrators met at Adhruh, about 10 miles north west of Maan in Jordon. Amr ibn al-As convinced Abu Musa Ashaari that both Ali and Muawiyah should step down and a new Caliph be elected. Ali and his supporters were stunned by the decision which had lowered the Caliph to the status of the rebellious Muawiyah I. Ali was therefore outwitted by Muawiyah and Amr. Ali refused to accept the verdict and found himself technically in breach of his pledge to abide by the arbitration. This put Ali in a weak position even amongst his own supporters. The most vociferous opponents in Ali's camp were the very same people who had forced Ali into the ceasefire. They broke away from Ali's force, rallying under the slogan, "arbitration belongs to God alone." This group came to be known as the Kharijites ("those who leave"). In 659 Ali's forces and the Kharijites met in the Battle of Nahrawan. Although Ali won the battle, the constant conflict had begun to affect his standing, and in the following years some Syrians seem to have acclaimed Muawiyah as a rival caliph.


The Quran and Muhammad talked about racial equality and justice as in The Farewell Sermon. Tribal and nationalistic differences were discouraged. But after Muhammad's passing, the old tribal differences between the Arabs started to resurface. Following the Roman–Persian Wars and the Byzantine–Sassanid Wars, deep rooted differences between Iraq, formally under the Persian Sassanid Empire, and Syria, formally under the Byzantine Empire, also existed. Each wanted the capital of the newly established Islamic State to be in their area. Previously, the second caliph Umar was very firm on the governors and his spies kept an eye on them. If he felt that a governor or a commander was becoming attracted to wealth, he had him removed from his position.


While the Umayyads and the Hashimites may have had bitterness between the two clans before Muhammad, the rivalry turned into a severe case of tribal animosity after the Battle of Badr. The battle saw three top leaders of the Umayyad clan (Utba ibn Rabi'ah, Walid ibn Utbah and Shaybah) killed by Hashimites (Ali, Hamza ibn ‘Abd al-Muttalib and Ubaydah ibn al-Harith) in a three-on-three melee. This fueled the opposition of Abu Sufyan ibn Harb, the grandson of Umayya, to Muhammad and to Islam. Abu Sufyan sought to exterminate the adherents of the new religion by waging another battle with Muslims based in Medina only a year after the Battle of Badr. He did this to avenge the defeat at Badr. The Battle of Uhud is generally believed by scholars to be the first defeat for the Muslims, as they had incurred greater losses than the Meccans. After the battle, Abu Sufyan's wife Hind, who was also the daughter of Utba ibn Rabi'ah, is reported to have cut open the corpse of Hamza, taking out his liver which she then attempted to eat. Within five years after his defeat in the Battle of Uhud, however, Muhammad took control of Mecca and announced a general amnesty for all. Abu Sufyan and his wife Hind embraced Islam on the eve of the conquest of Mecca, as did their son (the future caliph Muawiyah I).


Umar is honored for his attempt to resolve the fiscal problems attendant upon conversion to Islam. During the Umayyad period, the majority of people living within the caliphate were not Muslim, but Christian, Jewish, Zoroastrian, or members of other small groups. These religious communities were not forced to convert to Islam, but were subject to a tax (jizyah) which was not imposed upon Muslims. This situation may actually have made widespread conversion to Islam undesirable from the point of view of state revenue, and there are reports that provincial governors actively discouraged such conversions. It is not clear how Umar attempted to resolve this situation, but the sources portray him as having insisted on like treatment of Arab and non-Arab (mawali) Muslims, and on the removal of obstacles to the conversion of non-Arabs to Islam.


After the assassination of Uthman in 656, Ali, a member of the Quraysh tribe and the cousin and son-in-law of Muhammad, was elected as the caliph. He soon met with resistance from several factions, owing to his relative political inexperience. Ali moved his capital from Medina to Kufa. The resulting conflict, which lasted from 656 until 661, is known as the First Fitna ("civil war"). Muawiyah I, the governor of Syria, a relative of Uthman ibn al-Affan and Marwan I, wanted the culprits arrested. Marwan I manipulated everyone and created conflict. Aisha, the wife of Muhammad, and Talhah and Al-Zubayr, two of the companions of Muhammad, went to Basra to tell Ali to arrest the culprits who murdered Uthman. Marwan I and other people who wanted conflict manipulated everyone to fight. The two sides clashed at the Battle of the Camel in 656, where Ali won a decisive victory.


Early Muslim armies stayed in encampments away from cities because Umar feared that they might get attracted to wealth and luxury. In the process, they might turn away from the worship of God and start accumulating wealth and establishing dynasties. When Uthman ibn al-Affan became very old, Marwan I, a relative of Muawiyah I, slipped into the vacuum, became his secretary, slowly assumed more control and relaxed some of these restrictions. Marwan I had previously been excluded from positions of responsibility. In 656, Muhammad ibn Abi Bakr, the son of Abu Bakr, the adopted son of Ali ibn Abi Talib, and the great grandfather of Ja'far al-Sadiq, showed some Egyptians the house of Uthman ibn al-Affan. Later the Egyptians ended up killing Uthman ibn al-Affan.


In 680 Ibn al-Zubayr fled Medina for Mecca. Hearing about Husayn's opposition to Yazid I, the people of Kufa sent to Husayn asking him to take over with their support. Al-Husayn sent his cousin Muslim bin Agail to verify if they would rally behind him. When the news reached Yazid I, he sent Ubayd-Allah bin Ziyad, ruler of Basrah, with the instruction to prevent the people of Kufa rallying behind Al-Husayn. Ubayd-Allah bin Ziyad managed to disperse the crowd that gathered around Muslim bin Agail and captured him. Realizing Ubayd-Allah bin Ziyad had been instructed to prevent Husayn from establishing support in Kufa, Muslim bin Agail requested a message to be sent to Husayn to prevent his immigration to Kufa. The request was denied and Ubayd-Allah bin Ziyad killed Muslim bin Agail. While Ibn al-Zubayr would stay in Mecca until his death, Husayn decided to travel on to Kufa with his family, unaware of the lack of support there. Husayn and his family were intercepted by Yazid I's forces led by Amru bin Saad, Shamar bin Thi Al-Joshan, and Hussain bin Tamim, who fought Al-Husayn and his male family members until they were killed. There were 200 people in Husayn's caravan, many of whom were women, including his sisters, wives, daughters and their children. The women and children from Husayn's camp were taken as prisoners of war and led back to Damascus to be presented to Yazid I. They remained imprisoned until public opinion turned against him as word of Husayn's death and his family's capture spread. They were then granted passage back to Medina. The sole adult male survivor from the caravan was Ali ibn Husayn who was with fever too ill to fight when the caravan was attacked.


In the year 712, Muhammad bin Qasim, an Umayyad general, sailed from the Persian Gulf into Sindh in Pakistan and conquered both the Sindh and the Punjab regions along the Indus river. The conquest of Sindh and Punjab, in modern-day Pakistan, although costly, were major gains for the Umayyad Caliphate. However, further gains were halted by Hindu kingdoms in India in the battle of Rajasthan. The Arabs tried to invade India but they were defeated by the north Indian king Nagabhata of the Pratihara Dynasty and by the south Indian Emperor Vikramaditya II of the Chalukya dynasty in the early 8th century. After this the Arab chroniclers admit that the Caliph Mahdi "gave up the project of conquering any part of India."


The second major event of the early reign of Abd al-Malik was the construction of the Dome of the Rock in Jerusalem. Although the chronology remains somewhat uncertain, the building seems to have been completed in 692, which means that it was under construction during the conflict with Ibn al-Zubayr. This had led some historians, both medieval and modern, to suggest that the Dome of the Rock was built as a destination for pilgrimage to rival the Kaaba, which was under the control of Ibn al-Zubayr.


Muawiyah also encouraged peaceful coexistence with the Christian communities of Syria, granting his reign with "peace and prosperity for Christians and Arabs alike", and one of his closest advisers was Sarjun, the father of John of Damascus. At the same time, he waged unceasing war against the Byzantine Roman Empire. During his reign, Rhodes and Crete were occupied, and several assaults were launched against Constantinople. After their failure, and faced with a large-scale Christian uprising in the form of the Mardaites, Muawiyah concluded a peace with Byzantium. Muawiyah also oversaw military expansion in North Africa (the foundation of Kairouan) and in Central Asia (the conquest of Kabul, Bukhara, and Samarkand).


Yazid died while the siege was still in progress, and the Umayyad army returned to Damascus, leaving Ibn al-Zubayr in control of Mecca. Yazid's son Muawiya II (683–84) initially succeeded him but seems to have never been recognized as caliph outside of Syria. Two factions developed within Syria: the Confederation of Qays, who supported Ibn al-Zubayr, and the Quda'a, who supported Marwan, a descendant of Umayya via Wa'il ibn Umayyah. The partisans of Marwan triumphed at a battle at Marj Rahit, near Damascus, in 684, and Marwan became caliph shortly thereafter.


Marwan was succeeded by his son, Abd al-Malik (685–705), who reconsolidated Umayyad control of the caliphate. The early reign of Abd al-Malik was marked by the revolt of Al-Mukhtar, which was based in Kufa. Al-Mukhtar hoped to elevate Muhammad ibn al-Hanafiyyah, another son of Ali, to the caliphate, although Ibn al-Hanafiyyah himself may have had no connection to the revolt. The troops of al-Mukhtar engaged in battles both with the Umayyads in 686, defeating them at the river Khazir near Mosul, and with Ibn al-Zubayr in 687, at which time the revolt of al-Mukhtar was crushed. In 691, Umayyad troops reconquered Iraq, and in 692 the same army captured Mecca. Ibn al-Zubayr was killed in the attack.


Geographically, the empire was divided into several provinces, the borders of which changed numerous times during the Umayyad reign. Each province had a governor appointed by the khalifah. The governor was in charge of the religious officials, army leaders, police, and civil administrators in his province. Local expenses were paid for by taxes coming from that province, with the remainder each year being sent to the central government in Damascus. As the central power of the Umayyad rulers waned in the later years of the dynasty, some governors neglected to send the extra tax revenue to Damascus and created great personal fortunes.


Hisham suffered still worse defeats in the east, where his armies attempted to subdue both Tokharistan, with its center at Balkh, and Transoxiana, with its center at Samarkand. Both areas had already been partially conquered, but remained difficult to govern. Once again, a particular difficulty concerned the question of the conversion of non-Arabs, especially the Sogdians of Transoxiana. Following the Umayyad defeat in the "Day of Thirst" in 724, Ashras ibn 'Abd Allah al-Sulami, governor of Khurasan, promised tax relief to those Sogdians who converted to Islam, but went back on his offer when it proved too popular and threatened to reduce tax revenues. Discontent among the Khurasani Arabs rose sharply after the losses suffered in the Battle of the Defile in 731, and in 734, al-Harith ibn Surayj led a revolt that received broad backing from Arabs and natives alike, capturing Balkh but failing to take Merv. After this defeat, al-Harith's movement seems to have been dissolved, but the problem of the rights of non-Arab Muslims would continue to plague the Umayyads.


The Hashimiyya movement (a sub-sect of the Kaysanites Shia), led by the Abbasid family, overthrew the Umayyad caliphate. The Abbasids were members of the Hashim clan, rivals of the Umayyads, but the word "Hashimiyya" seems to refer specifically to Abu Hashim, a grandson of Ali and son of Muhammad ibn al-Hanafiyya. According to certain traditions, Abu Hashim died in 717 in Humeima in the house of Muhammad ibn Ali, the head of the Abbasid family, and before dying named Muhammad ibn Ali as his successor. This tradition allowed the Abbasids to rally the supporters of the failed revolt of Mukhtar, who had represented themselves as the supporters of Muhammad ibn al-Hanafiyya.


From the caliphate's north-western African bases, a series of raids on coastal areas of the Visigothic Kingdom paved the way to the permanent occupation of most of Iberia by the Umayyads (starting in 711), and on into south-eastern Gaul (last stronghold at Narbonne in 759). Hisham's reign witnessed the end of expansion in the west, following the defeat of the Arab army by the Franks at the Battle of Tours in 732. In 739 a major Berber Revolt broke out in North Africa, which was subdued only with difficulty, but it was followed by the collapse of Umayyad authority in al-Andalus. In India the Arab armies were defeated by the south Indian Chalukya dynasty and by the north Indian Pratiharas Dynasty in the 8th century and the Arabs were driven out of India. In the Caucasus, the confrontation with the Khazars peaked under Hisham: the Arabs established Derbent as a major military base and launched several invasions of the northern Caucasus, but failed to subdue the nomadic Khazars. The conflict was arduous and bloody, and the Arab army even suffered a major defeat at the Battle of Marj Ardabil in 730. Marwan ibn Muhammad, the future Marwan II, finally ended the war in 737 with a massive invasion that is reported to have reached as far as the Volga, but the Khazars remained unsubdued.


The final son of Abd al-Malik to become caliph was Hisham (724–43), whose long and eventful reign was above all marked by the curtailment of military expansion. Hisham established his court at Resafa in northern Syria, which was closer to the Byzantine border than Damascus, and resumed hostilities against the Byzantines, which had lapsed following the failure of the last siege of Constantinople. The new campaigns resulted in a number of successful raids into Anatolia, but also in a major defeat (the Battle of Akroinon), and did not lead to any significant territorial expansion.


With limited resources Muawiyah went about creating allies. Muawiyah married Maysum the daughter of the chief of the Kalb tribe, that was a large Jacobite Christian Arab tribe in Syria. His marriage to Maysum was politically motivated. The Kalb tribe had remained largely neutral when the Muslims first went into Syria. After the plague that killed much of the Muslim Army in Syria, by marrying Maysum, Muawiyah started to use the Jacobite Christians, against the Romans. Muawiya's wife Maysum (Yazid's mother) was also a Jacobite Christian. With limited resources and the Byzantine just over the border, Muawiyah worked in cooperation with the local Christian population. To stop Byzantine harassment from the sea during the Arab-Byzantine Wars, in 649 Muawiyah set up a navy; manned by Monophysitise Christians, Copts and Jacobite Syrian Christians sailors and Muslim troops.


Only Umayyad ruler (Caliphs of Damascus), Umar ibn Abd al-Aziz, is unanimously praised by Sunni sources for his devout piety and justice. In his efforts to spread Islam he established liberties for the Mawali by abolishing the jizya tax for converts to Islam. Imam Abu Muhammad Adbullah ibn Abdul Hakam stated that Umar ibn Abd al-Aziz also stopped the personal allowance offered to his relatives stating that he could only give them an allowance if he gave an allowance to everyone else in the empire. Umar ibn Abd al-Aziz was later poisoned in the year 720. When successive governments tried to reverse Umar ibn Abd al-Aziz's tax policies it created rebellion.


Around 746, Abu Muslim assumed leadership of the Hashimiyya in Khurasan. In 747, he successfully initiated an open revolt against Umayyad rule, which was carried out under the sign of the black flag. He soon established control of Khurasan, expelling its Umayyad governor, Nasr ibn Sayyar, and dispatched an army westwards. Kufa fell to the Hashimiyya in 749, the last Umayyad stronghold in Iraq, Wasit, was placed under siege, and in November of the same year Abu al-Abbas was recognized as the new caliph in the mosque at Kufa.[citation needed] At this point Marwan mobilized his troops from Harran and advanced toward Iraq. In January 750 the two forces met in the Battle of the Zab, and the Umayyads were defeated. Damascus fell to the Abbasids in April, and in August, Marwan was killed in Egypt.


The books written later in the Abbasid period in Iran are more anti Umayyad. Iran was Sunni at the time. There was much anti Arab feeling in Iran after the fall of the Persian empire. This anti Arab feeling also influenced the books on Islamic history. Al-Tabri was also written in Iran during that period. Al-Tabri was a huge collection including all the text that he could find, from all the sources. It was a collection preserving everything for future generations to codify and for future generations to judge if it was true or false.


The Diwan of Umar, assigning annuities to all Arabs and to the Muslim soldiers of other races, underwent a change in the hands of the Umayyads. The Umayyads meddled with the register and the recipients regarded pensions as the subsistence allowance even without being in active service. Hisham reformed it and paid only to those who participated in battle. On the pattern of the Byzantine system the Umayyads reformed their army organization in general and divided it into five corps: the centre, two wings, vanguards and rearguards, following the same formation while on march or on a battle field. Marwan II (740–50) abandoned the old division and introduced Kurdus (cohort), a small compact body. The Umayyad troops were divided into three divisions: infantry, cavalry and artillery. Arab troops were dressed and armed in Greek fashion. The Umayyad cavalry used plain and round saddles. The artillery used arradah (ballista), manjaniq (the mangonel) and dabbabah or kabsh (the battering ram). The heavy engines, siege machines and baggage were carried on camels behind the army.


Mu'awiyah introduced postal service, Abd al-Malik extended it throughout his empire, and Walid made full use of it. The Umayyad Caliph Abd al-Malik developed a regular postal service. Umar bin Abdul-Aziz developed it further by building caravanserais at stages along the Khurasan highway. Relays of horses were used for the conveyance of dispatches between the caliph and his agents and officials posted in the provinces. The main highways were divided into stages of 12 miles (19 km) each and each stage had horses, donkeys or camels ready to carry the post. Primarily the service met the needs of Government officials, but travellers and their important dispatches were also benefitted by the system. The postal carriages were also used for the swift transport of troops. They were able to carry fifty to a hundred men at a time. Under Governor Yusuf bin Umar, the postal department of Iraq cost 4,000,000 dirhams a year.


However many early history books like the Islamic Conquest of Syria Fatuhusham by al-Imam al-Waqidi state that after the conversion to Islam Muawiyah's father Abu Sufyan ibn Harb and his brothers Yazid ibn Abi Sufyan were appointed as commanders in the Muslim armies by Muhammad. Muawiyah, Abu Sufyan ibn Harb, Yazid ibn Abi Sufyan and Hind bint Utbah fought in the Battle of Yarmouk. The defeat of the Byzantine Emperor Heraclius at the Battle of Yarmouk opened the way for the Muslim expansion into Jerusalem and Syria.


Non-Muslim groups in the Umayyad Caliphate, which included Christians, Jews, Zoroastrians, and pagan Berbers, were called dhimmis. They were given a legally protected status as second-class citizens as long as they accepted and acknowledged the political supremacy of the ruling Muslims. They were allowed to have their own courts, and were given freedom of their religion within the empire.[citation needed] Although they could not hold the highest public offices in the empire, they had many bureaucratic positions within the government. Christians and Jews still continued to produce great theological thinkers within their communities, but as time wore on, many of the intellectuals converted to Islam, leading to a lack of great thinkers in the non-Muslim communities.


The Umayyad caliphate was marked both by territorial expansion and by the administrative and cultural problems that such expansion created. Despite some notable exceptions, the Umayyads tended to favor the rights of the old Arab families, and in particular their own, over those of newly converted Muslims (mawali). Therefore, they held to a less universalist conception of Islam than did many of their rivals. As G.R. Hawting has written, "Islam was in fact regarded as the property of the conquering aristocracy."


Many Muslims criticized the Umayyads for having too many non-Muslim, former Roman administrators in their government. St John of Damascus was also a high administrator in the Umayyad administration. As the Muslims took over cities, they left the peoples political representatives and the Roman tax collectors and the administrators. The taxes to the central government were calculated and negotiated by the peoples political representatives. The Central government got paid for the services it provided and the local government got the money for the services it provided. Many Christian cities also used some of the taxes on maintain their churches and run their own organizations. Later the Umayyads were criticized by some Muslims for not reducing the taxes of the people who converted to Islam. These new converts continues to pay the same taxes that were previously negotiated.


The Umayyads have met with a largely negative reception from later Islamic historians, who have accused them of promoting a kingship (mulk, a term with connotations of tyranny) instead of a true caliphate (khilafa). In this respect it is notable that the Umayyad caliphs referred to themselves not as khalifat rasul Allah ("successor of the messenger of God", the title preferred by the tradition), but rather as khalifat Allah ("deputy of God"). The distinction seems to indicate that the Umayyads "regarded themselves as God's representatives at the head of the community and saw no need to share their religious power with, or delegate it to, the emergent class of religious scholars." In fact, it was precisely this class of scholars, based largely in Iraq, that was responsible for collecting and recording the traditions that form the primary source material for the history of the Umayyad period. In reconstructing this history, therefore, it is necessary to rely mainly on sources, such as the histories of Tabari and Baladhuri, that were written in the Abbasid court at Baghdad.


Asphalt/bitumen also occurs in unconsolidated sandstones known as "oil sands" in Alberta, Canada, and the similar "tar sands" in Utah, US. The Canadian province of Alberta has most of the world's reserves of natural bitumen, in three huge deposits covering 142,000 square kilometres (55,000 sq mi), an area larger than England or New York state. These bituminous sands contain 166 billion barrels (26.4×10^9 m3) of commercially established oil reserves, giving Canada the third largest oil reserves in the world. and produce over 2.3 million barrels per day (370×10^3 m3/d) of heavy crude oil and synthetic crude oil. Although historically it was used without refining to pave roads, nearly all of the bitumen is now used as raw material for oil refineries in Canada and the United States.


The first use of asphalt/bitumen in the New World was by indigenous peoples. On the west coast, as early as the 13th century, the Tongva, Luiseño and Chumash peoples collected the naturally occurring asphalt/bitumen that seeped to the surface above underlying petroleum deposits. All three used the substance as an adhesive. It is found on many different artifacts of tools and ceremonial items. For example, it was used on rattles to adhere gourds or turtle shells to rattle handles. It was also used in decorations. Small round shell beads were often set in asphaltum to provide decorations. It was used as a sealant on baskets to make them watertight for carrying water. Asphaltum was used also to seal the planks on ocean-going canoes.