Grapefruit Interactions with Drugs

Grapefruit Interactions with Drugs What is Grapefruit? Grapefruit, a relative newcomer to citrus clan, has a fascinating history. It is a large orange berry with a thick rind. It is the belief of the most botanists that grapefruit is a naturally occurring accidental hybrid between pomelo and orange. It is believed that, although its appearance is very much different from an ordinary grape, the name ‘grapefruit’ was used because they grow in clusters, and these clusters may seem as large yellow grapes. The original belief was that, the grape fruit is a kind of a pomelo. (1) But in 1837, James Macfayden, separated grapefruit from pomelo, in his Flora of Jamaica, giving it a botanical name, Citrus paradisi. After its hybrid nature was genetically identified, the botanical name was altered to Citrus X paradisi. (1) Nutritional value Grapefruit, like most of the other citrus fruits, is a great source of vitamin C, which helps the immune system. It is advantageous for the fight against, from simple cold to, asthma, rheumatoid fever, osteoarthritis, cancer, heart disease and stroke. (2) Lycopene, which gives grapefruit its red and pink colors, is a carotenoid phytonutrient, with high anti-tumor ability. Also lycopene has the highest capacity among the common dietary carotenoids to fight free radicals. (2) According to the availability of the content of phenolic compounds in the grapefruit juice, it is ranked among the highest in food products of antioxidant activity. (2) Limonoids, another phytonutrient in grapefruit, promotes the formation of glutathione-S-transferase, thus minimizing the tumor formation. Pectins, a form of soluble fiber in grapefruit is useful against the progression of atherosclerosis. (2) Also, the grapefruit juice increases urinary pH value and citric acid excretion, and significantly reduces the formation of calcium oxalate stones, thus minimizing kidney stone formation. (2) Naringenin, a flavonoid concentrated in grapefruit, helps to repair damaged DNA, especially in human prostate cancer cells. 8-oxoguanine-DNA glycosylase and DNA polymerase beta, enzymes are induced by Naringenin, which are useful in DNA base excision repair pathway. (2) Although the nutritional value of grapefruit is highly commended and proved, around a decade ago, scientists found that the availability of oral drugs can be severely reduced by grapefruit food products, especially grapefruit juice. The cytochrome P-450 3A4 system, in the intestine, which is facilitates the first pass metabolism in many drugs, can be inhibited by grapefruit. Also in the brush border of intestinal wall, there are P-glycoprotein pumps. They transport many of the substances used by cytochrome P-450 3A4. This system is also inhibited by grapefruit. Inhibition of both these systems can be dangerous. Because of these, knowledge and awareness of these interactions is massively important. These interactions can lead to severe effects and these interactions can occur very commonly as most of the times, both the drugs and grapefruit food products are used together at breakfast. (3) Mechanism of interaction Cytochrome 3A4 is a member of cytochrome P-450 enzyme system. In the endoplasmic reticulum of cells all over the body, it can be found. It is a heme-containing large multigene family. As oxidative bio-transformation of different exogenous and endogenous substances occurs in liver and intestinal wall, cytochrome P-450 is abundant in those places. In the apical brush border of enterocytes, P-glycoprotein can be found. It is a membrane transporter and a member of adenosine triphosphate binding cassette (ABC). Once lipophilic drug is taken into the enterocytes, it is pumped back into the lumen by P-glycoprotein or metabolized by cytochrome P-450 3A4. These actions limit the oral delivery of many drugs. With the intake of grapefruit juice, cytochrome P-450 system is inhibited, thus pre-systemic metabolism of drug is decreased and bioavailability of the drug increase. (4) Grapefruit juice causes massive reduction in translation of these enzymes from its m-RNA. However the transcription of m-RNA from DNA is not affected. Grapefruit also promotes the deterioration of these enzymes. These actions together, massively decline the cytochrome P-450 activity in a quick and irreversible manner. A decline of 47% of total levels of cytochrome P-450 3A4 levels can be seen within the four hours of grapefruit juice ingestion. With this decrease, increased bioavailability of the drug can be maintained for about a day. Even after that, for some time, 30% of its effect is still there. (5-7) Some studies indicate that effect on grapefruit juice on cytochrome p-450 3A4 system and P-glycoprotein system are controversial. Means grapefruit juice can activate the P-glycoprotein pumps in vitro in a way (9). This could result in massive efflux of drugs back into the lumen. This is believed to be the cause for diminished bioavailability of some particular substrates, or sometimes this can neutralize the effect of reduced cytochrome P-450 3A4 activity due to ingestion of grapefruit juice. However Digoxin, a prototypical P-glycoprotein substrate, is found as one of the substrates in P-glycoprotein pump, which is not affected by grapefruit juice (8, 10). By both inhibition of function and, down-regulation, grapefruit juice inhibits the function of P-glycoprotein pumps. Example: increased bioavailability of cyclosporine with the grapefruit juice. This is believed to be a result of P-glycoprotein inhibition, other than cytochrome P-450 3A4, since the increase of bioavailability, produced by reduced enterocyte cytochrome P-450 3A4 concentrations, are tend to differ than the obtained results (8). MRP2 (multi-drug resistant protein 2) an associated P-glycoprotein efflux protein, has also shown its inhibition of action, with the ingestion of grapefruit juice (11). In spite of all the acquired knowledge, researchers still further investigate the grapefruit and drug interactions. In vivo effect of grapefruit juice on P-glycoprotein is an area believed to be needed to investigate further more. OATPs or organic anion-transporting polypeptides also said to be potently inhibited by grapefruit juice. In the small intestine, they are involved in the process of apical to basal transport of drugs (8, 10, and 12). The knowledge and conclusions obtained with the studies carried out in vitro cytochrome P-450 3A4 inhibition by grapefruit, the likelihood of these interactions happening in a natural way (the ingestion of grapefruit food products) can be predicted. It is also believed that the reported ethnic differences and the activity of the cytochrome P-450 3A4 could be because of the dietary differences, such as consumption of grapefruit. All in all, because of the potential of grapefruit and grapefruit related food items to interact with drugs, intake of grapefruit should be carefully monitored, in order to maintain necessary drug concentrations within the body of a patient, within the therapeutic windows. Phytochemistry Another aspect that the researchers are still thoroughly studying on is knowledge about active constituents in grapefruit juice in the molecular level, which can interfere and act on P-glycoprotein pumps and cytochrome P-450 systems. Although these studies are not extensively studied or completely proven, they indicate various molecules that take part in the drug interaction process. Flavonoid glycosides such as naringin, naringinin, hesperidin, neohespiridin, narirutin, quercetin, and didymin are some of substances responsible. Also, sesquiterpen and furanocoumarins (such as 6,7-dihydroxybergamottin) are also responsible (3, 14-16). Naringin is the most abundant flavonoid contained in the grapefruit juice. Also the flavonoids in the grapefruit exist as glycosides. After ingestion, the actions of intestinal flora convert these to sugars and aglycones. These compounds can inhibit the cytochrome P-450 enzymes. Theoretically, it is believed that electron rich polyphenolic nature of these compounds is responsible for that. Most studies show the in vitro effect of these compounds on cytochrome P-450 enzyme system. But in vivo, researchers have not yet completely proven or identified their effects on cytochrome enzyme system (17). Naringinin, which is a metabolite of naringin, has a higher activity in vitro, although naringin has no visible effect. This leads to a complication and some suspicion among researchers that flavonoids may not be the main active substance in grapefruit, which is responsible for the whole drug interaction dilemma. Even though with all these debates, due to very high concentration of these compounds in grapefruit juice and the fact naringin is present only in grapefruit among the fruits in citrus clan, quest for flavonoids still continues. Recent researchers are mostly focusing on furanocoumarins. Main furanocoumarins are bergomottin and its derivative 6,7-dihydroxybergomottin(DHB)(18). Debates still going on about the extent of effect these compounds on interaction mechanism certain studies have shown that DHB and, to an average amount bergamottin are vital contributors of grapefruit-drug interaction process (18, 19). In one particular study, furanocoumarins, DHB and four others, mixed and tested. The inhibitory potency on cytochrome enzyme systems declinedeven when any one of these compounds taken out from the mixture, not just DHB. That created a complication. There are even studies supporting that perhaps DHB and bergomattin may not be the primary compounds in the inhibition process (20). With all these facts this idea also still in the process of intense research and suspicion. Drug-Grapefruit interactions Amiodarone and anti-hypertensive drugs 1,4-dihydropyridine calcium antagonists are used mostly for patients with angina pectoris and also for patients with essential hypertension. They are lipid soluble drugs, metabolized by cytochrome P-450 3A4 in vivo, and grapefruit juice can affect its bioavailability. Intensive study and research began with the effects of grapefruit juice with felodipine, another calcium channel blocker and an anti-hypertensive drug. It was found that when grapefruit juice is ingested, oral bioavailability of these drugs can increase by 112% (21). Furthermore it demonstrates that intra-venous pharmacokinetics of felodipine remains without a significant change with the grapefruit juice ingestion (21). Also the interaction frequency gradually increases with the increased grapefruit juice ingestion. Because of these reasons, it is recommended that interval of 2-3 days between administration of felodipine and ingestion of grapefruit juice. The elderly specially should be warned about this situation. Amioderone is used for cardiac arrhythmias. It is converted into N-desethylamioderone by cytochrome P-450 3A4. With the ingestion and interaction with grapefruit juice, N-desethyl amioderone production inhibits almost completely, with an overall decline in side effects produced by amiodarone (8). Furthermore benzothiazepine calcium channel antagonist diltiazem, nisoldipine, verapamil, ACE inhibitors like enalapril and aptopril also said to have effect with grapefruit juice interaction. Benzodiazepines and CNS drugs Midazolam is a drug of benzodiazepine class used for acute seizures for inducing sedation and in insomnia. Certain studies have proven that grapefruit juice has a great effect on first-pass metabolism, which reduces the metabolism efficiency badly and increase its bioavailability (22). Clinical importance is that especially for the patients with cirrhosis of the liver, intestine metabolism of cytochrome P-450 3A4 is vital. So the ingestion of grapefruit juice has to be avoided. Another use of midazolam is in pediatric dentistry. Oral midazolam is very commonly used for this. There have been incidents that because of the bitter taste acquired with the administration of oral midazolam, patients tend to take sweetened food items, sometimes grapefruit. If grapefruit was taken in after administration of oral midazolam, blood plasma midazolam levels can increase and patient may tend to have exaggerated seduction time. Triazolamand clozapine are some other drugs that can also affect. Antimicrobials Indinavir is commonly used to treat HIV in highly active antiretroviral therapy. It is a protease inhibitor. There are reports showing that ingestion of grapefruit juice can delay indinavir absorption with the increase of gastric pH, but it does not affect systemic bioavailability (23). It is believed, because primary metabolism may not take place in the intestine. Saquinavir is also another drug used for patients with HIV. It is also a protease inhibitor. It is shown that the ingestion of grapefruit juice can increase the bioavailability of saquinavir (24). Although it increased the bioavailability, the clearance of the drug won’t change. This could be an indication that inhibition of cytochrome P-450 3A4 is affected. Theoretically, because of the dose dependent nature of the saquinavir, it is possible that effectiveness can increase with the inhibition of cytochrome P-450 3A4. Artemether an anti-malarial drug, also shown its increasing oral bioavailability, when grapefruit juice is ingested. But its time dependent reduction of bioavailability does not affect by grapefruit (25). This could indicate the importance of cytochrome P-450 3A4 in the pre-systemic metabolism. Quinine, a natural drug used in broad range of aspects, seemed to be does not affected by grapefruit juice. It is because it is primarily metabolized in the liver. (Where inhibition of cytochrome P-450 3A4 with grapefruit mainly effect on the gut)(8) Its low clearance is also helpful for this. Furthermore in antibiotics, clarithromycin, show increased time for reach for its peak concentration, but pharmacokinetics seemed to be unaffected (26). While abendazole, an anti-parasitic, shows an increased bioavailability with the ingestion of grapefruit juice (27). Chemotherapeutics Cyclosporine is a widely used immunosuppressant drugs, used in organ transplants. Studies have shown that cyclosporine and its metabolites both show rapid increase in their concentrations in plasma, when grapefruit juice was administered (28). Anti-histamines and serotonin analogues Cisapride is a drug that increases the motility of the upper GI tract. It is a serotonin receptor agonist. Studies have shown that cisapride systemic bioavailability gradually increases with the administration of grapefruit juice (29), because of the inhibition of cytochrome P-450 3A4. Therefore it’s advisable, that the patients who are taking cisapride, especially with a risk of cardiac arrhythmias, should avoid drinking grapefruit juice. Terfenadine, anti-histamine, also show increased system bioavailability when grapefruit juice is taken in (30). This also play an important role, because in an electrocardiogram, increased systemic levels of terfenadine can prolong the QT interval. Statins and cholesterol-lowering drugs Simvastatin, a cholesterol lowering drug, also shown increased serum concentrations when grapefruit juice is taken (31). Also its active metabolite simvastatin acid levels and HMG-CoA reductase inhibitors also increase. Active metabolites of the grapefruit juice, Bergamottin and Naringenin are said to be responsible for this. It is also carried out from the inhibition of cytochrome P-450 3A4 and thus limiting the first pass metabolism in small intestine. Lovastatin, another cholesterol reducing drug said to have same effects as simvastatin, when the grapefruit juice is administered. Serum concentrations of lovastatin and its active metabolite lovastatin acid seem to be elevated. By the same mechanism, prevention of first pass metabolism in the small intestine by inhibiting cytochrome P-450 3A4. Conclusion Because of the vast difference of effects given by grapefruit-drug interactions, and its effects on pharmacokinetics, physicians should be vigilant about the whole procedure. And also warn their patients about the possible consequences which can happen in a drug-grapefruit interaction. Patient-to-patient variability, mostly the age of the patient, should be thoroughly remembered. And the elderly should be warned especially as they are more prone to the grapefruit-drug interactions (8). Also the knowledge about these interactions can be used for the advantage of the physician. Example: to lower the dosage. Still, because all these are mostly in a research level and safe procedures should always be followed as patients safety is the top priority.

Movie Essays - Romanticism in the Film Version of The Big Sleep

Romanticism in the Film Version of The Big Sleep      Ã‚  Ã‚  Ã‚   In Raymond Chandler's novel The Big Sleep, he presents two sisters, Vivian and Carmen. These women become the central characters, aside from Philip Marlowe, and they control much of the action in the novel. The 1946 film version of The Big Sleep, however, manipulates Chandler's characters considerably. Aside from playing with the dialogue of the novel, the screen-writers change the very essences of Vivian and Carmen. Perhaps it is the casting of the film which forces changes from the novel, or perhaps the Production Code keeps the writers from developing the women in the way that Chandler does; either way, the film version of The Big Sleep makes the story romantic and often cliche.    Vivian and Carmen, sisters, are presented by Chandler as psychotic and dangerous women. Vivian, is described in detective Philip Marlowe's thoughts as "tall and rangy and strong-looking...Her hair was black and wiry and parted in the middle and she had the hot black eyes of the portrait in the hall"(Chandler 17). She is cool and manipulative, instantly suspicious of Marlowe's presence in her world, and she plays her suspicions off as insults. When she meets Marlowe, she says, "So you're a private detective,...I didn't know they really existed, except in books. Or else they were greasy little men snooping around hotels"(Chandler 18). Marlowe plays right back at her, countering every snide remark with one of his own. When Vivian tells Marlowe she doesn't like his manners, his response is,    I'm not crazy about yours...I didn't ask to see you. You sent for me. I don't mind your ritzing me or drinking your lunch out of a Scotch bottle...I don't mind if you ... ...ynamic together, the script is allowed to be less than what the novel created. This is exactly what happened with The Big Sleep. Marlowe and Vivian took a backseat to Bogart and Bacall. The sisters, Vivian and Carmen, had to be altered to create the effect of romance and intrigue. There was really no other way to go within the restrictions of the Production Code, as Carmen couldn't be played up to her full potential, so the director took Vivian and made her the leading lady. The essences that Chandler created for these two women were dynamically altered for the film in order to create two women without the demons or psychoses that he had intended.    Works Cited    Chandler, Raymond. The Big Sleep. New York: Random House, 1939. "Memorable Quotes from Big Sleep, The (1946)." IMDB. Internet. Accessed: April 1999. Address: http://us.imdb.com/

Health Promotion Essay

The World Health Organization delineated health as â€Å"a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity† (WHO, 1946). Scientists define health promotion as the course of action taken to facilitate people to have power over and to enhance their health generally. To carry on and augment wellbeing some practices such as restraining from smoking, exercising at least three times a week to sustain fitness, reducing contact to radiation and toxic components, eating adequate amount of nutrients and minerals seem essential. In nursing practice, health promotion exists through education to facilitate inhabitants to create choices to keep them in good physical shape. According to the American Journal of Health, â€Å"Health Promotion is the science and the art of helping people change their lifestyles to move toward an optimal health.† Other factors that can encourage reaching out the purpose of health promotion are n ursing roles and responsibilities, implementation methods that covers all areas of nursing, and the levels of health support. The World Health Organization (WHO) created a movement named Healthy people 2010 to make all Americans cognizant of a variety of ways to prevent diseases and improve their health. The association placed nurses in the forefront by giving them the lead of the action due to the fact of their constant contact with individuals, families, and communities because they can help them make the right decision to promote health (WHO, 2000.) In addition, they acquire skills through evidence-based practice in critical moments of life to implement essential interventions through education after assessing, using a diagnosis, developing a plan the care of patients; a thorough evaluation of chosen activities always follows to assure a contented turning point. Nurses assist to promote health by helping groups of people in different settings to cultivate healthy lifestyle. The Institute of Medicine has a new research that clarifies responsibilities by stating the important role nurses play to implement and evaluate actions to promote health in the population. As advocate for the sick, the nurse-client interrelationship should take place for health promotion in order to teach people good habits in the choice of adequate diet to avoid obesity, to stop polluting the environment by quitting smoking for instance and access to clean water seem indispensable; moreover, inhabitants must not permit damaging social conditions that wipe out health to continue as they convey unhealthy states (Sullivan, 2000). Health promotion movements are meant to guard and advance health, and to avoid illness. These activities are grouped into three subsequent levels. The foremost and initial level of health promotion prevention is intended to stop diseases from starting or a trauma from happening. Diseases or trauma to prevent include immunization, household hazards, abstinence from smoking, measures that decrease the risk for stroke, educating and counseling regarding the use of vehicle passenger restraints and bicycle hat. The primary prevention averts the beginning of an aimed condition. It targets the greatest number of people in a community who might become at risk for a specific health dilemma like asthma which happened to be one of the most frequent respiratory diseases in modern countries. Furthermore, the secondary avoidance measures are those that spot and care for asymptomatic people at risk but in whom the provision is not clinically obvious. Activities of secondary escaping involve early case findings of disease without any sign that occurs and has major risk for harmful result exclusive of cure. Screening tests to detect hyperlipidemia, hypertension, breast and prostate cancer are model of secondary prevention actions. Lastly, when the disease has already started its course of action, tertiary prevention care is given to patient, attempts are made to re-establish highest function and stop sickness-related complications. Health is a store for everyday life that includes physical, mental, social comfort; consequently, health promotion activities will empower individuals and communities to raise their control over decisions that affect their health. With the possession of interpersonal skills, nurses contribute to encourage patients through teaching to make constructive changes that will keep them in good physical shape throughout life. The three levels of health promotion are supported through education. Within their scope of practice, nurses can allow individuals and communities to gain greater control over the determinants of their wellbeing to achieve the purpose of Health promotion. . References Edelman, C., & Mandle, C. L. (2010). Health promotion throughout the life spans (7th ed.). St. Louis: Mosby. Eisenberg & Neighbors, (2007). National Research Council and Institute of Medicine [NAS-IOM], (2009). A national study by Kessler et al. (2005) According to a report from Institute of Medicine and the National Research Council (IOM and NAS) National Prevention, Health Pro Nola J. Pender, Carolyn L. Murdaugh, and Mary Ann Parsons. Motion, and Public Health Council. (2011). Annual status report [Internet]. Washington (DC): The Council; 2011 Jun 30 [cited 2011 Sep 30]. Available from: http://www.healthcare.gov/ prevention/nphpphc/2011-annualstatus- report-nphpphc.pdf Nola J. Pender, Carolyn L. Murdaugh, & Mary Ann Parsons. (2006). Health Promotion in Nursing Practice (5th ed.) Upper Saddle River, NJ: Pearson Education INC

To Kill a Mockingbird Study Guide Plot, Characters, Themes

To Kill a Mockingbird is a searing portrayal of racial prejudice, justice, and innocence lost into a complex mixture of childish naivete and mature observation, while simultaneously being a sort of love letter to small town Southern life. The end result is a novel that is both a brilliant rendering of a specific time and place as well as a study in the meaning of justice, the loss of innocence, and the realization that a place can be both a beloved childhood memory and where you first realized there was evil in the world. Fast Facts: To Kill a Mockingbird Author: Harper LeePublisher: J.B. Lippincott Co.Year Published: 1960Genre: FictionType of Work: NovelOriginal Language: EnglishThemes: Prejudice, justice, innocenceCharacters: Scout Finch, Atticus Finch, Jem Finch, Tom Robinson, CalpurniaNotable Adaptation: 1962 film adaptation starring Gregory Peck as Atticus Finch Plot Summary Scout Finch lives with her father, a lawyer and widower by the name of Atticus, and her brother, a young boy named Jem. The first part of the To Kill a Mockingbird tells of one summer. Jem and Scout play, make new friends, and first come to know of a shadowy figure by the name of Boo Radley, who lives in a neighboring house and yet is never seen. A young black man named Tom Robinson is accused of raping a white woman. Atticus takes on the case, despite the vitriol this arouses in the largely white, racist townsfolk. When the time of the trial comes around, Atticus proves that the girl that Tom Robinson is accused of raping actually seduced him, and that the injuries to her face were caused by her father, angry that she had tried to sleep with a black man. The all-white jury nevertheless convicts Robinson and he is later killed by while trying to escape from jail. The girls father, who holds a grudge against Atticus because of some of the things he said in court, waylays Scout and Jem as they walk home one night. They are saved by the mysterious Boo, who disarms their attacker and kills him. Major Characters Scout Finch. Jean Louise ‛Scout’ Finch is the narrator and main character of the novel. Scout is a ‛tomboy’ who rejects traditional feminine roles and trappings. Scout initially believes that there is always a clear right and wrong in every situation; as Scout grows older, she begins to understand more about the world around her and begins to value reading and education more. Atticus Finch. Scout’s widower father is an attorney. Atticus is a bit of an iconoclast. He values education and indulges his children, trusting their judgment despite their young age. He is an intelligent, moral man who believes strongly in the rule of law and the necessity of blind justice. Jem Finch. Jeremy Atticus ‛Jem’ Finch is Scout’s older brother. He is protective of his status and often uses his superior age to force Scout to do things his way. He has a rich imagination and an energetic approach to life, but displays difficulty dealing with other people who do not rise to his standard. Boo Radley. A troubled recluse who lives next door to the Finches (but never leaves the house), Boo Radley is the subject of many rumors. Boo naturally fascinates the Finch children, and displays affection and kindness towards them, ultimately rescuing them from danger. Tom Robinson. Tom Robinson is a black man who supports his family by working as a field hand despite having a crippled left arm. He is charged with the rape of a white woman, and Atticus defends him. Major Themes Maturation. Scout and Jem are frequently confused about the motivations and reasoning of the adults around them. Lee explores the way that growing up and maturing into adults makes the world clearer while also less magical and more difficult, ultimately connecting racism with childish fears that adults ought not to experience. Prejudice. Lee explores the effects of prejudice of all kinds—racism, classism, and sexism. Lee makes it clear that racism is inextricably linked to economics, politics, and self-image. Sexism is explored in the novel through Scout and her constant battle to engage in behaviors she finds interesting instead of ‛appropriate’ behaviors for a girl. Justice and Morality. In the earlier parts of the novel Scout believes that morality and justice are the same thing. Tom Robinson’s trial and her observation of her father’s experiences teach her that there is often a stark difference between what is right and what is legal. Literary Style The novel utilizes subtly layered narration; it can be easy to forget that the story is actually being told by a grown-up, adult Jenna Louise and not the 6-year old Scout. Lee also restricts the point-of-view to Scout and what she directly observes, creating an air of mystery for the reader that mimics the childish sense of not quite understanding what all the adults are up to. About the Author Harper Lee was born in 1926 in Monroeville, Alabama. She published To Kill a Mockingbird in 1960 to instant acclaim, winning the Pulitzer Prize for fiction. She then worked with her friend Truman Capote on what would become Capote’s ‛nonfiction novel,’ In Cold Blood. Lee retreated from public life afterwards, granting few interviews and making almost no public appearances—and publishing almost no new material. She passed away in 2016 at the age of 89.