Dolutegravir Drug for Virologic Suppression

Dolutegravir Drug for Virologic Suppression Graphical abstract: Dolutigravir, second generation integrase inhibitor: A new hope for HIV patients Geeta Yadav Mesra, Ranchi Abstract: Undeterred efforts have been made and will be made in future to make it possible for HIV-infected individuals to achieve the goals of virologic suppression and one more result of this rigrous exercise is dolutegravir drug. It is the recent integrase inhibitor approved by the US Food and Drug Administration (FDA) for use in the treatment-naà ¯ve, treatment-experienced, HIV-infected adults who have previously taken HIV therapy and also for children ages 12 years and older weighing at least 40 kilograms (kg) who are treatment-naà ¯ve or treatment-experienced but have not previously taken other integrase strand transfer inhibitors. This article has reviewed all the aspects of drug including the structural and functional analyses, in vitro activity, pharmacokinetics, drug-drug interactions, MOA, metabolism, excretion, dosing/ adverse effects and resistance profile of dolutegravir. Dolutegravir is a potent and generally well tolerated antiretroviral agent that may play an impor tant role in the treatment of patients harboring resistance to other antiretrovirals.Some new combinations of drug with other antiretrovirals are also in pipeline which may hope to increase the immunologic response of the HIV patients. Key words:Dolutegravir,  antiretroviral,  integrase inhibitor,  HIV Introduction With the use of antiretrovirals with improved potency, tolerability, and resistance profiles, people with HIV are living longer and receiving longer-term care but even after so much advancement in therapy, they are struggling with an unknown fear of death [1, 2]. So, the need for new antiretroviral agents still continues to be substantial even after more than 20 years into the era of antiretroviral therapy, which have better tolerability, higher barriers to resistance, distinct resistance profiles, and fewer drug–drug interactions. These features of desiring drug have been inspiring the scientist all over the world to develop new agents that are not only focused on traditional targets but also on new novel therapeutic targets. The development of drugs targeting on critical steps in the life cycle of HIV-1 are drug classes that include HIV-1 reverse-transcriptase inhibitors (both nucleoside analogues and non-nucleoside inhibitors), HIV-1 protease inhibitors, and HIV-1 entry inh ibitors (fusion inhibitors and CCR5 antagonists). The newest class of drugs in HIV treatment is the integrase inhibitor (INI) class. Retroviral DNA Integration with the host DNA is an essential step in the life cycle of human immunodeficiency virus (HIV) [3], as shown in figure 1. This integration process is facilitated by the viral integrase (IN) enzyme which catalyzes the insertion of the viral DNA into the host genome in a multistep process. The process of HIV-1 integration occurs through 3 essential steps: formation of the preintegration viral DNA complex, 3’ processing and strand transfer [4]. HIV IN recognizes and binds specific sequences in the long terminal repeats (LTRs) of the viral retrotranscribed DNA in the cytoplasm. After DNA binding, IN cleaves GT dinucleotides from the 3’ termini of the linear cDNA in a process called 3’ processing .The processed viral DNA, as part of the preintegration complex, is then translocated into the nucleus, where IN inserts the viral DNA into the host chromosome by a process called strand transfer [4-6]. Figure 1 Schematic representation of HIV integration Abbreviations: LTRs, long-term repeats; PIC, preintegration complex. Integrase inhibitors (INIs) represent a class of drugs for the treatment of human immunodeficiency virus (HIV) infected individuals, blocking HIV genome transfer and integration into the host cell DNA [7]. In this category, first drug which got FDA approval was raltegravir (RAL) which have been found to be highly effective for the treatment of antiretroviral- naive and antiretroviral-experienced subjects and one more recent drug is elvitegravir (EVG) [8-12]. However, these first-generation INIs share common resistance pathways. During clinical studies of RAL, subjects with virologic failure and reduced RAL susceptibility typically are found to have virus with 1 of 3 signature mutational pathways (ie, N155H, Q148H/K/R, or Y143C/H/R) in the integrase gene [13]. So, continuing RAL treatment in these circumstances may lead to the addition of secondary mutations or pathways and N155H may evolve to Y143 or Q148 pathways [10]. In addition to this, EVG does not appear to have activity agains t RAL-resistant isolates and same case is with RAL [14-16]. Therefore, there is a need for an INI with a high barrier to resistance and activity in subjects with human immunodeficiency virus type. So, recent addition included in this category is Dolutegravir (DTG). This review article aims to covers all the aspects related to the dolutegravir which will help the scientists, academicians and common men to statisfy their knowledge pangs, like in vitro activity, pharmacokinetics, drug-drug interactions, MOA, metabolism, excretion, dosing/ adverse effects and resistance profile of dolutegravir as shown in figure 2, which exemplify methodology and evaluation of dolutegravir with the help of different information sources Dolutegravir (DTG) discovered by a Shionogi and GlaxoSmithKline research collaboration, is a second generation novel HIV-1 integrase strand transfer inhibitor having activity against INI resistant viruses. In addition to it, also have favorable pharmacokinetic properties [17, 18]. It is indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 in adults and children aged 12 years and older weighing at least 40 kg. It is available as a small, yellow, 50-mg tablet. Moreover, it can be taken with or without food and at any time of the day. Structural and functional analyses of Dolutegravir (DTG) Dolutegravir (DTG, S/GSK1349572) effectively inhibits HIV-1 IN variants which are resistant to the first-generation INIs. The structural basis for the increased potency of DTG resistant INIs is that it occupies almost the same physical space within the IN active site and make contacts with the ÃŽ ²4-ÃŽ ±2 loop of the catalytic core domain. Dolutegravir molecule has been divided into three main structural parts like tricyclic metal-chelating core, difluorophenyl ring and linker group which play a significant role in its binding to the protein as shown in figure 3. Tricyclic metal-chelating core binds to the intasome active site with the three coplanar oxygen atoms coordinated to Mg2+ cations The extended linker region connecting the metal chelating core and the halobenzyl group of DTG allows it to enter farther deeper into the pocket vacated by the displaced viral DNA base and to make more intimate contacts with viral DNA [19]. Figure 3 Structural and functional analysis of Dolutegravir IN VITRO ACTIVITY Dolutegravir has shown potent in vitro activity against both wild-type HIV and many INI-resistant mutants. It has potential for a higher genetic barrier to resistance. Dolutegravir has shown potent in vitro activity against HIV-1, with mean EC50 values of 0.5 nM (0.21 ng/mL) to 2.1 nM (0.85 ng/mL), IC50 of 2.7 nM and an IC90 of 2.0 nM in peripheral blood mononuclear cells (PBMC) and MT-4 cells. It also shows activity against HIV-2 virus with EC50 of 0.09 nM to 0.61 nM in PBMC assays. Cellular toxicity is also in the micromolar range for a variety of cell types, indicating that the observed antiviral effect of S/GSK1349572 are not due to cytotoxicity. S/GSK1349572 shows potency against all integrase- resistant single mutants with an FC as high as 3.6-fold. In the presence of S/GSK1349572 no virus with high resistance to S/GSK1349572 was observed with 32 nM or higher concentrations of S/GSK1349572 in the culture medium. In vitro experimental studies reported that dolutegravir does not cause toxicity when used in combination, but had a synergistic effect with nevirapine, efavirenz, abacavir, stavudine, lopinavir, amprenavir, and enfuvirtide, as well as an additive effect when only used in combination with maraviroc. Efficacy of dolutegravir is also not affected on exposure to the adefovir and ribavirin [20]. Pharmacokinetics Dolutegravir has a favourable pharmacokinetic profile without requirement of boosters and its terminal half-life is approximately 13–15 h [21, 22]. AUC0–24h and Cmax values are slightly less than the dose in the range of 2–50mg following single and multiple doses. One noteable change is the nonlinearness in Cmax and AUC with the increase in dose, So, a twice-daily 50mg regimen has been evaluated in the phase 3 ARV-experienced clinical trial rather than a once-daily 100mg dose [22-24]. The geometric mean steady-state concentration at the end of the dosing interval (Ctau) for a 50 mg dose was reported to be 1.6 ÃŽ ¼g/mL, which was approximately 25-fold higher than the protein-adjusted IC90 (0.064 ÃŽ ¼g/mL). A monotherapy study of, 10 days of dolutegravir 50mg daily dose in integrase inhibitor naà ¯ve HIV-1-infected adults demonstrated a 2.48 mean log10 reduction in HIV-1 RNA. This reduction was sustained for 4 days after discontinuation of dolutegravir only becoz of plasma concentrations which remained above the protein adjusted IC90. Overall, variability in exposure was minimal: 50 mg dosing to steady-state conditions achieved a geometric mean Cmax of 3.34 mg/ml (16% coefficient of variation), an AUC0–24h of 43.4 mg_h/ml (20% coefficient of variation), a t1/2 of 12.0 h (22% coefficient of variation) and a C24h of 0.83 mg/ml (26% coefficient of variation) [22]. A pediatric granule formulation of dolutegravir is currently in development. Preliminary data investigation reported that granules mixed in purified water have increased exposure compared with the tablet formulation with a geometric least-squares mean ratio (90% CI) for AUC0-inf of 1.57 (1.45–1.69) [23]. Drug–drug interactions Dolutegravir pharmacokinetics has been evaluated in a single-dose crossover study for the effect of food and found that its absorption is modestly increased with food according to fat content [24]. Fat content affects the absorption of dolutegravir as noticed by the increased median Tmax from 2h to 3, 4, and 5h for low-fat, moderate-fat, and high-fat meals, respectively. Whereas dolutegravir AUC increased from 33 to 66% when administered with low-fat (300 kcal, 7% fat), moderate fat (600 kcal, 30% fat) and high fat food (870 kcal, 53% fat), respectively. [22, 24]. But these changes are not expected to affect safety or efficacy, So, dolutegravir can be dosed without regard to food. Dolutegravir causes drug-drug interactions with integrase inhibitors and some other drugs which is shown in Table 2. Table 2. Dolutegravir (DTG) drug interaction with integrase inhibitors and other category drugs S.No Interacting drug class Interacting drug Effect on dolutegravir 1 Antiretrovirals NRTIs Tenofovir No significant effect observed[25] 2 Antiretrovirals NNRTIs Efavirenz DTG AUC, Cmax, and Cmin decreased 57, 39, and 75% [26] Etravirine DTG AUC, Cmax, and Cmin decreased 70.6, 51.6, and 87.9%. [27] ETR/DRV/r administration results in 25, 11.8, and37.1% decreases in DTG AUC, Cmax, and Cmin ETR/LPV/r administration results in 11, 7, and 28% increases in DTG AUC, Cmax, and Cmin [27] 3 Antiretrovirals PIs Darunavir/r DTG AUC, Cmax, and Cmin decreased 22, 11, and 38% [28] Atazanavir DTG AUC, Cmax, and Cmin increased 91, 50, and 180% [29] Lopinavir/r No significant effect observed [28] Fosamprenavir DTG AUC, Cmax, and Cmin decreased 35, 24, and 49% [30] Tipranavir DTG AUC, Cmax, and Cmin decreased 59, 46, and 76% [26] 4 Antituberculosis drugs Rifampin DTG AUC and Cmin increased 33 and 22% with DTG 50mg b.i.d.+ rifampin 600mg q.d. compared with DTG 50mg daily [31] Rifabutin DTG AUC and Cmin decreased 5 and 30%, Cmax increased 15 % [32] 5 Acid-reducing agents- PPIs/H2 RA Omeprazole No significant effect observed [33] Antacids DTG AUC, Cmax, and Cmin decreased 73.6, 72.4, and 74.4% [33] DTG, Dolutegravir; ETR, Etravirine; EVG, Elvitegravir; LPV, Lopinavir; NNRTI, Non-nucleoside reverse transcriptase inhibitor; NRTI, Nucleos(t)ide reverse transcriptase inhibitor; PI, Protease Inhibitor; PPI, Proton pump inhibitor; r, Ritonavir; RAL, Raltegravir. Mechanism of Action Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration which is essential for the HIV replication cycle as demonstrated in Figure 4. In this process, the integrase inhibitor chelate with the two Mg2+ ions in the integrase catalytic active site, unable the integrase enzyme to complete the strand transfer [21]. Inhibition of the integrase strand transfer reaction by DTG has been confirmed in studies with live virus, which demonstrated an accumulation of 2- long terminal repeat (2-LTR) circles in treated cells at DTG concentrations Figure 4. Mechanism of action of DTG Metabolism/Excretion Dolutegravir metabolism occurs through CYP3A4 (UGT1A1 glucuronidation) a major pathway while UGT1A3 and UGT1A9 are only minor pathways, which is catalysed by UDP-glucuronosyltransferase (UGT) 1A1 enzyme. In vitro studies reported that it is not a cytochrome P450 (CYP) inducer and neither an inhibitor. However, dolutegravir is an OCT2 inhibitor [21, 36]. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp in vitro [37]. It is the predominant circulating compound in plasma and the renal elimination of unchanged drug is extremely low ( Figure 5. Metabolic pathway of dolutegravir Dose/Adverse effects Dolutegravir tablets are usually taken unboosted, orally and without regard to food [39]. Different dose combination studies with other drugs are reported to be performed to find the best combination with high resistance barrier as shown in table1. The most common adverse effects reported to be associated with dolutegravir Phase III SPRING-2 trial were nausea, headache, nasophryngitis, diarrhea and also a slight increase in creatinine level due to inhibition of creatinine secretion; however, dolutegravir had no effect on glomerular filtration rate [47, 48]. Some common drug -related adverse events were also notified during Phase III VIKING-3 trial in treatment-experienced subjects were diarrhea, nausea, and headache [49]. S.No Phase study Patients Dolutegravir vs other drug combinatons 1 Phase III SPRING-2 Study Treatment naà ¯ve Dolutegravir 50 mg once daily versus raltegravir 400 mg twice daily, each in combination with either tenofovir DF/emtricitabine (Truvada) or abacavir/lamivudine (Epzicom) 40 2 Phase III SINGLE Study Treatment naà ¯ve Dolutegravir 50 mg in combination with abacavir/lamivudine (Epzicom) once daily versus tenofovir DF/emtricitabine/ efavirenz (Atripla) once daily41 3 Phase III SAILING Study Treatment experienced, integrase inhibitor-naà ¯ve Dolutegravir 50 mg once daily versus raltegravir 400 mg twice daily, each in combination with background therapy42 4 Phase III VIKING-3 Study Treatment-experienced with previous or current failure on raltegravir or elvitegravir Open-label dolutegravir 50 mg twice daily with current failing background regimen for 7 days, then with an optimized background regimen43 5 Phase III VIKING-4 Study Treatment-experienced with virus resistant to raltegravir and/ or elvitegravir at screening Dolutegravir 50 mg twice daily versus placebo , each in combination with current failing background regimen for 7 days, then with open-label dolutegravir 50 mg twice daily in combination with an optimized background regimen for both arms44 6 Combination under study A fixed-dose combination (FDC) tablet (dolutegravir 50 mg abacavir 600 mg/lamivudine 300 mg) and a dolutegravir pediatric granule45,46 Resistance Dolutegravir (DTG) have been found to have a higher genetic barrier to resistance than raltegravir and elvitegravir [50]. Primary integrase resistance mutations associated with dolutegravir have not yet been identified. But viruses containing G140S, E138K, R148H, R263K, and G140S/Q148HRK mutations may show some level of resistance to dolutegravir. [50,39]. Raltegravir-resistant virus carrying a mutation at position Q148 had more reduced susceptibility to dolutegravir than isolates with other raltegravir mutations [51]. In vitro selection studies reported R263K mutation which commonly emerges in integrase in the presence of dolutegravir. R263K confers low-level resistance against dolutegravir and diminishes HIV DNA integration and viral fitness and no secondary mutation H51Y and E138K has been shown to compensate for the defects associated with the R263K primary resistance mutation against dolutegravir. All secondary mutations have a modest effect on resistance against this drug [52, 53]. Future of dolutegravir ViiV Healthcare has requested US regulatory for the approval of a new single-tablet regimen (STR) containing dolutegravir, abacavir and lamivudine. A European regulatory application has also been submitted, according to the company. This combination, taken as separate pills, worked well in the aforementioned trials. If approved, the new co-formulation will offer the first one-pill, once-daily regimen that does not contain tenofovir/emtricitabine and could be particularly beneficial for people with, or at risk for, kidney disease or osteoporosis. Results from the primary analysis, presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) also reported that 90% of people taking dolutegravir and 83% taking darunavir/ritonavir achieved undetectable viral load in a snapshot analysis, with dolutegravir meeting the criteria for statistical superiority. Based on these findings the researchers concluded that dolutegravir provide a potent and well-tolerated new option for first-line HIV treatment [54]. Conclusion HIV-1 integrase is a unique target for antiretroviral therapy. Dolutegravir, a once-daily HIV strand integrase inhibitor currently approved for HIV-1 infected patients, provides at least equivalent antiviral efficacy and better tolerability compared with approved antiretroviral drugs. Efforts are ongoing for the approval of new single-tablet regimen (STR) containing dolutegravir, abacavir and lamivudine and also it would minimize the number of pills required for effective and acceptable antiretroviral treatment. Because of its unique mechanism of action, demonstrated virologic activity, resistance profile and tolerability, it is a significant advancement in HIV-1 therapeutics which will help HIV patients in long run.

Zheng He or Christopher Columbus?

who was the greatest explorer Christopher Columbus or Zheng He? Tristan Stanchfield A great explorer in my mind requires being a visionary thats willing to pursue his goal despite the challenges faced, supported by high risk undertakings where the winnings are all or nothing, set on the uncertain future with a non back looking persona. That, and if the outcome is great is what my judging is based on. Zheng He, originally named Ma He, was born into a Muslim family just beyond the borders of China (later Yunnan Province in the southwestern part of China) in 1371.In 1402, after Emperor Cheng Zu of the Ming Dynasty ascended the throne, he dispatched Zheng He and Wang Jinghong to lead a giant fleet to the Western Sea (today's Southeast Asia), carrying members of soldiers and large quantity of goods. The fleet reached the countries of Southeast Asia, east Africa and Arabia, initiating a feat in the history of navigation and regarded as an unprecedented great historical period in Chinese hi story of trade and cultural exchanges. He led his fleet to voyage to the Western Sea for seven times.The number of ships of his fleet was from 40 to 63 each time, taking many soldiers and sailors on the voyage, with a total party over 27,000 people. and also took with him ships almost four-hundred feet long. Explorer and navigator Christopher Columbus was born in 1451 in the Republic of Genoa, Italy. His first voyage into the Atlantic Ocean in 1476 nearly cost him his life. (attacked by french privateers). In 1492, Columbus left Spain in the Santa Maria, with the Pinta and the Nina along side in search of a new trade route to Asia.Instead he sailed West and discovered America, and has been credited for the colonization of America also. in my opinion the greatest explorer was christopher columbus. this was because he was he founded America, and this took the high risk of sailing across the north atlantic ocean which he acomplished. Then he made several more voyages back and fourth fr om europe and America trading goods also at the same time creating colonies in the new world we live in today known as the United states of America. cites: iphone siri, http://www. biography. com/people/christopher-columbus-9254209, wikipedia. com.

Spain Rise and Fall

Before the 16th century, Spain was not recognized as a legitimate powerhouse in Europe. They were known as a very strong Catholic orientated country located in the Iberian Peninsula north of Morocco. However, in the matter of a span of little over a hundred years, Spain obtained a great amount of wealth and power through conquests and inheritance from the king. Just as they were the greatest empire in the world, it fell apart and soon declined into the status of a third-rate power in Europe.King Charles V of Spain inherited many lands of Europe because of his family background. In 1506, he had obtained the Burgundain Lands, which included the Low Countries and Flanders. He was also the grandson of King Ferdinand and Queen Isabella, the great two Spanish monarchs from the late 15th century. In 1516, he became the first monarch to rule a united Spain. He was not done yet. In 1519 he was granted the Habsburg domains in Austria. Not only that, but in 1530 he was named Holy Roman Emperor. This meant that Charles V has control over the three leading dynasties of Europe at the time- the House of Habsburg of the Habsburg Monarchy, the House of Valois-Burgundy house of the Burgundian Netherlands, and the House of Trastamara of the Crowns of Castile and Aragon. This meant in Europe Charles V had control completly over the Central, Western, and Southern lands. No other monarch in Europe had as much land as Charles V had in the European continent. Not only did he have that land, but also from the Spanish conquests in the Americas and Asia, Charles V had the first global empire in the world.His empire became very rich and powerful from those conquests and imported goods they received from those places. The Columbian Exchange was the exchange of plants and animals from the Old World and the New World in which Spain and other empires successfully benefited from. From 1493, Columbus introduced horses, cattle, sheep, dogs, pigs, chicken, and goats. The rate at which these animal s grew were spectacular, thus leading to more food for the Spanish population which gave them a population increase and more money flowing in because of the extra meats.Not only that, but Spain brought back maize from Mexico, white potatoes from Peru, and various beans, squash, pumpkins, avocados, and tomatoes. Maize was a great gift for the Spanish because it was used as food for all peoples and livestock of the world. Since it gave a high yield per unit of land and a short growing season, it proved to be an especially important cash crop for them. The discovery of silver in the Americas was what really established Spain as the economic powerhouse of the world. In 1545, the Spanish discovered an enormous amount of silver in the city of Potosi.When it was discovered, no one lived in Potosi. By 1600 however, 160,000 people lived there. This made it about the size of the city of London at the time. Potosi yielded about 60 percent of all the world's silver mined in the world and made S pain very powerful and oh so rich once again. Another way the Spanish became successfully rich was from the slave trade. Their slave system was called the encomienda system, which was a legal form of slavery there. The Crown gave permission the conquerors the right to employ groups of Amerindians as agricultural or mining laborers.However as soon as the rapid decline of Amerindian population followed, the Spanish turned to the black slaves of Africa. This started what soon called the Triangular Trade route. The ships were crammed and packed with hundreds of captives in the boats in order for them to increase profits because the more slaves you had alive in your ship, the more money you received. However, the dominance of Spain proved to be temporary and short lived. Through the result of all the increase of the amount of food and land, it was no surprise that the population experienced a steady increase.This also created a sharp rise in the demand of foods and goods throughout the e mpire. Since Spain had removed their best farmers and businessmen- the Muslims and the Jews- in the fifteenth century, the economy was suffering greatly and could not meet the new demands, so prices rose. As well as that, the cost of manufacturing cloth and other goods increased, and Spanish products were not able to compete with cheaper products made elsewhere in the international market. King Charles V was no longer king of Spain by 1556 because he was tired from he long decades of ruling the vast empire. Through his reign he spent time warring with the French and the Ottoman Empire throughout his reign. He also spent his time devoting his time to stamp out the Protestant Reformation. Thus, the throne was passed down to his son Phillip II. The main event and problem that crucially hit the Spanish Empire was the â€Å"British problem. † On 1586 Mary, Queen of Scots who was the cousin and heir of Elizabeth, became involved in a plot to assassinate her. This was for the hope f or England to reunite with Catholic Europe.Phillip fully supported the plot. Not long after, Mary was discovered and was beheaded on February 18, 1587. Phillip soon heard of the news and went after to conquer England. Conquering England promised the additional benefit of cutting off financial support to Dutch rebels since Spain was in a bitter war with the Dutch at the time. Phillip's strategy was to prepare a vast fleet to sail from Lisbon to Flanders. They would fight off Elizabeth's navy if needed, rendezvous with the duke of Parma, and escort barges carrying Parma's troops across the English Channel.On May 9, 1588 Phillip's fleet of 130 set sail from the Lisbon harbor. The fleet was part of the great Spanish Armada. The Armada met an English fleet in the Channel. The English ships were smaller but faster, allowing more maneuverability in the water. Many of the ships had greater firing power than the Armada ships. The combination of storms, spoiled food and rank water, lacking am munition, and the scattering of the Spanish ships from the English fire ships gave England victory. The Armada was defeated even before they reached the Netherlands.On the way back, many other ships went down near Ireland and about 65 of the ships were able to make it back home. The defeat of the Armada prevented Phillip II from re-imposing religious unity on Western Europe by force. He unfortunately did not conquer England, and Elizabeth continued with her financial and military support of the Dutch. In 1609, Phillip III of Spain (r. 1598-1621) agreed to a truce. This truce recognized the independence of the United Provinces. In the seventeenth-century, memory of the loss of the Spanish Armada contributed to a spirit of defeatism.It was all set and done in little over a century. Spain had completed its epic collapse from being the global empire of the world, to now being a third-rate power in the seventeenth-century. Spain obtained a great amount of wealth and power through conques ts and inheritance from the king in the sixteenth-century. Just as they were the greatest empire in the world, it all fell apart and soon declined into the status of a third-rate power in Europe. In all, we can see how things can quickly change from being outstanding to disastrous.

The Impact Of Religion On Human Culture - 1200 Words

For centuries, human culture has been influenced in a multitude of ways by many means but none have had such an impact as religion. It has had countless wars waged in its name, even to this day. Billions believe in some divine being(s) that transcends the ugliness of humanity that s omnipotent and omniscient. Religion became a guide and a representation of how our lives should be led. However, history has brought evidence that made it possible for this notion to be criticized and rather, flipped. The majority of the human race believes that religion shaped our culture but it is rather the other way round, in that the culture of our ancestors, the Mesopotamians and the Hebrews shaped religion to explain the natural world and as a reflection of their lives and tribulations. During the age of Mesopotamia, climate change was still a key factor in the survival of civilizations but did not work on a global scale as it did before during cooling and warming periods. 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Scientific studies reveal that more similar traits are being share by human and our non-human primates compared to other animals. As human evolve from our apelike ancestors, changes in our DNA differentiate ourselves from our non-human primate. Even though we evolve from our non-human ancestors and share similar anatomicalRead MoreSocio-Cultural Influences On Sexuality. Socio-Cultural1156 Words   |  5 Pagesemotional, cultural and economic aspects. Time and time again research has proven that socio-cultural influences have a significant role in human sexuality. Culture is the manner of life of the people. Thus, culture shapes the ideas of what behaviors are acceptable for men and women (King Regan, 2014). Sexuality is a big part of one’s life because it produces us human. It is how an individual sees himself or herself through sexual attitudes. According to (Krantz Tolan, 2016) sexuality means a collection