Cocaine Drug Abuse

Cocaine Drug Abuse Cocaine through the ages: from elixir to poison. Cocaine through ages: from elixir to poison. Abstract: Cocaine, a plant alkaloid derived from coca leaves is a potent stimulant of CNS and has local anesthetic action as well. Historically, it was ingested in the form of chewing coca leaves, to suppress hunger and fatigue. With discovery of its local anesthetic properties, cocaine was introduced into world of medicine and a local anesthetic, but over last few decades, gained popularity as drug of abuse. Cocaine carries with it great potential for addiction and abuse. It is administered through various routes, smoking free-base crack and intranasal inhalation being most popular. Its primarily metabolized in liver and distributed to all body tissues. Due to lipid nature it tends to concentrate in brain and adipose tissues with chronic administration. Its mainly eliminated through kidneys, but saliva and stools are also routes of excretion. A number of health hazards have been shown to be associated with cocaine use including, cardiac abnormalities, psychological disturbances, addiction pot ential and renal failure with or without rhabdomyolysis. Acute and chronic cocaine toxicities with sufficient collected data are included. Techniques for detecting cocaine in blood including enzyme linked immunoassay and POCT (Point of care screening tests) have also been discussed. An analysis of recent trends in cocaine uses have been studied and presented along with graphical illustrations of epidemiological evidence to support the data. Introduction and objective: Objective: to display how cocaine has evolved through time in its uses and available forms, from simple coca leaf chewing custom of South Americans in 2500 BC to modern forms of freebase-coke among others as one of the most commonly abused toxic drug. Methodology: Data was mainly collected from electronic resources, but text on immunology and pharmacology was also consulted. From electronic sources, I mainly used search engines using a number of keywords including ; history of cocaine, crack, pharmacokinetics of cocaine, mode of action , coca leaf, acute cocaine poisoning, chronic cocaine toxicity, Karl Koller, Sigmund Freud, Immunoassay, etc. I also went through a number of journals available online, and a number of researches conducted which related to cocaine. My aim was to find changes in cocaine use from its discovery to date, and show, with help of collected data, that it has moved in a negative direction. Brief history: Cocaine, use of which, according to some sources, date back to at least 1200 years, has now, rightfully, earned itself a place in drugs of abuse list among others like Caffeine, Nicotine, Amphetamine, etc. To date, cocaines uses have evolved from gaining popularity as topical anesthetic agent, and as component of energizing drinks to becoming one of the most abused drugs in the world. It is a powerfully addictive stimulant drug, which acts by interfering with cerebral and peripheral synaptic transmission among neurons. Mode of action has been described in greater detail later in pharmacodynamics section, but for brief introduction, it interferes with reuptake of, and thereby enhance duration of action of, monoamines, dopamine, serotonin and nor epinephrine Brain PF et.al (1989). It also produces membrane stabilizing effect, more commonly referred to as local anesthetic effect. Latter is achieved through modulation of voltage gated sodium channels and consequent blockade of sensory im pulses conduction from that part of the neuron to central nervous system. Brain PF et.al (1989) Earliest records of cocaine use reveal it to be a part of South American custom of chewing coca leaves. This use is believed to date back to 2500BC. Steven Cohen (1981) Practice of chewing mixture of tobacco and coca leaves was defined by Nicolà ¡s Monardes, in 1569, to induce â€Å"great contentment†. Cocaine is the active component of coca leaves, which also contains nicotine. Karch SB (1998). In 1859, Italian doctor, Paulo Montegazza, after witnessing coca use by natives of Peru, and getting mesmerized by it, decided to study the effects of cocaine on himself. After his studies he concluded his findings into a paper in which he declared cocaine to be medically useful in treating furred tongue in the morning, flatulence and whitening the teeth. Steven R. King (1992). In 1863, French chemist, Angelo Mariani, introduced popular cocavine, Vin Mariani. Vin Mariani wasproduced from mixture of 6 mg coca leaves per fluid ounce of Bordeaux wine. Courtwright DT (2001) Angelo Mariani, creator of Vin Mariani, which later became the hallmark of cocavines was honored with Vatican gold medal by Pope Leo XIII for this achievement. Ethanol, a component of vin mariani, is believed to extract cocaine from coca leaves. In 1884, the concept of cocavine was adopted by John S. Pemberton, with introduction of Pembertons French Wine Coca. After prohibitions imposed on cocaine use and manufacture of cocaine-containing products including cocavine in 1885, Pemberton introduced carbonated, non-alcoholic form of Vin Mariani and called it Coca-cola. Richard Ashley (1975). From 1906 onwards, however, after Pure Food and Drug act was passed, decocainised forms of coca were used for manufacture of coca-cola. In 1884, Austrian physician Sigmund Freud, recommended cocaine for treatment of morphine and alcohol addiction. A strategy that was later employed in 1879 when cocaine was used to treat morphine addiction. Steven Cohen (1981). In 1985, use of cocaine for induction of spinal anesthesia was accidentally discovered by American neurologist Leonard Corning while he studying the effects of cocaine on spinal nerves in a dog and accidentally pierced the dura matter. Corning JL (1885) Cocaine was, however, not used as anesthetic in spinal surgery until 1989 when first planned cocaine induced spinal anesthesia was administered in a surgery, by August Bier. A. Bier, (1899) Coca leaves have traditionally been used as suppressants for fatigue, thirst, and hunger. Its use has now been limited to Andean countries, where coca leaf chewing and coca tea consumption are still practiced. Industrially, coca leaves serve as source of drug cocaine, and in some cosmetic and food industries, including coca cola. Richard Ashley (1975) From 1980s to date, cocaine has gained popularity as drug of abuse, and has widely replaced heroin and other narcotics as drug of abuse, being used in different forms and administered via various routes. Richard Ashley (1975) Discovery: Discovery of cocaine, as local anesthetic, is claim to fame for Austrian ophthalmologist, Karl Koller. Kollers name is credited with demonstration of anesthetic effect of cocaine, in 1884. Karl Koller was a close associate of Sigmund Freud who in same year recommended cocaine to be employed in treatment for morphine and alcohol addiction. Hruby K (1986). Koller studied effects of cocaine on eye by applying the drug to his own eye and later pricking it with pins. He presented his findings to the Heidelberg Ophthalmological Society in same year. Hruby K (1986) After successfully experimenting on himself, Koller used cocaine as local anesthetic in eye surgeries, a use that continues to this day. Cocaine was later employed in other fields including dentistry for induction of local anesthesia, Today, however, cocaine has largely been replaced by other local anesthetic agents like lidocaine, xylocaine, bupivacaine, etc, which produce local anesthetic effect as efficiently and do not carry potential for abuse.Hruby K (1986) Isolation: Friedrich Gaedcke, aGerman chemist, was first person to successfully isolate cocaine from coca leaves, in 1855. An improved isolation process was, however, developed by Albert Niemann, a Ph.D. student at the University of Gà ¶ttingen in Germany, in 1859. Niemann wrote a dissertation describing steps of isolation titled, â€Å" ÃÅ"ber eine neue organische Base in den Cocablà ¤ttern† (On a New Organic Base in the Coca Leaves), which was published in 1969. F. Gaedcke (1855) Formal Chemical Name (IUPAC) for cocaine: (1R,5S)-methyl 8-methyl-3-(phenylcarbonyloxy)-8-azabicyclo[3.2.1]octane-2-carboxylate. Medicalisation and popularization: Ever since its discovery, cocaines medical uses were quickly exploited through research and experimentation. Spanish physicians described first medical uses of cocaine as early as 1596, but the use of cocaine did not become more widespread until 1859, when Albert Niemann isolated the drug from coca leaves. Soon after it was isolated, cocaine was used to try to cure almost all the illnesses and maladies that were known to man. (Albert Niemann 1860) 1859s Montagezzis discovery about cocaine being useful in treating furred tongue in the morning, flatulence and whitening the teeth, was one of the earliest recorded studies that signified possible medical importance of cocaine. In 1879, Vassili von Anrep, of the University of Wà ¼rzburg, demonstrated analgesic properties of cocaine in an experiment that he conducted on a frog. He prepared two separate jars, one containing cocaine-salt solution, other containing salt water serving as control. One of frogs legs was submerged in cocaine solution and other in control followed by stimulation of leg in different ways. Reactions in two legs varied considerably. In the same year, cocaine began to be used in treatment of morphine addiction. The commercial production of purified cocaine gained momentum only in the mid-1880s. Its greatest medical value was in ophthalmology. Eye-surgery stood in desperate need of a good local anesthetic. This was because in eye operations it is often essential for a conscious patient to move his eye as directed by the surgeon without flinching. Karl Kollers demonstration of anesthetic properties of cocaine in 1884 was an important breakthrough establishing cocaines importance, medically when it was introduced in Germany as local anesthetic for eye surgery. (Altman Aj et.al 1985) Kollers discovery was later followed in 1985 by Leonard Cornings accidental demonstration of cocaines use in induction of spinal anesthesia, which became formally employed in spinal surgery in 1989 when first planned cocaine induced spinal anesthesia was administered by August Bier. Medical use of cocaine has largely been restricted to induction of local anesthesia. Even as local anesthetic agent, discovery of hazardous effects of cocaine use led to early development of safer alternative drugs like lidocaine, etc. One of its first non medical uses of cocaine was in military. In 1883 Theodor Aschenbrandt administered cocaine to members of the Bavarian army. It was found that the drug enhanced their endurance on maneuver. His positive findings were published in a German medical journal, which brought the effects of this wonder drug to a wider medical audience, including Sigmund Freud. Cocaine was sold as over the counter drug until 1916. It was widely used in tonics, toothache cures, patent medicines, and chocolate cocaine tablets. Prospective buyers were advised (in the words of pharmaceutical firm Parke-Davis) that cocaine could make the coward brave, the silent eloquent, and render the sufferer insensitive to pain. Cocaine was a popular ingredient in wines, notably Vin Mariani. Coca wine received endorsement from prime-ministers, royalty and even the Pope. The Vatican gold medal that Angelo Mariani received for it will forever signify the popularity of cocaine through that period of time. By the late Victorian, era use of cocaine had appeared as a vice in literature, for instance, Arthur Conan Doyles fictional Sherlock Holmes. . Number of admissions to drug treated programme in each year is plotted against time for both cocaine and heroin. Graph clearly displays the shift in trend from use of heroin towards cocaine. A combination gaining popularity is speedball, which is formulated by mixing heroin with cocaine. From 1980s to date, cocaine has gained popularity as drug of abuse, being used in different forms and administered via various routes, as evident by figure above which displays the escalation in crack / cocaine usage with concomitant reduction in heroin use. Prohibition: In first part of the twentieth century, with addictive properties of cocaine becoming more apparent with studies, cocaine found itself legally prohibited. Harrison Narcotics Tax Act (1914) outlawed unauthorized sales and distribution of cocaine incorrectly classifying it as a narcotic. In United Nations 1961 Single Convention on Narcotic Drugs, cocaine was listed as Schedule I drug, thereby making its manufacture, distribution, import, export, trade, use and possession illegal unless sanctioned by the state. In 1970s controlled substances act, cocaine was listed as a Schedule II drug in United States. It carries high abuse potential but also serves medicinal purpose. It is a class A drug in the United Kingdom, and a List 1 drug of Opium law in the Netherlands. Modern Usage: In late 90s and early 2000s, crack became very popular among Americans and in past few years has also taken its toll on UK. According to an estimate, U.S cocaine market exceeded $ 70 billion in year 2005, demonstrating the popularity of this menace. News reports are flooded with celebrity arrests on charge of cocaine posession or use. A section on recent facts and figures related to cocaine discusses the modern trends in greater detail later. Addiction potential: Along with amphetamine, cocaine is one of the most widely abused drugs in the world. Powerful stimulant properties of cocaine are beyond doubt. By inhibiting neuronal reuptake of excitatory neurotransmitters, dopamine, serotonin and norepinephrine, cocaine enhances synaptic concentrations of these neurotransmitters in specific brain areas; nucleus accumbens and amygdala which are referred to as the reward center of brain. During 1980s, cocaine widely replaced heroin as drug of abuse, due to its euphoric properties, wide availability and low cost. Different forms and Routes of administration of cocaine: Smoking: Crack, freebase or smokable form of cocaine, was produced and became popular drug of abuse in 1980s. Earliest reports of crack use indicate an epidemic in Bahamas from 1980. By 1985, crack gained popular ranking among drug users across America.Crack is produced by mixing 2 parts cocaine hydrochloride with one part baking soda (sodium bicarbonate). It differs from cocaine hydrochloride in being more volatile, a property that makes it better suited for inhalation administration (smoking) than cocaine hydrochloride. Smoking freebase cocaine releases methylecgonidine, an effect not achieved with insufflation or injection (described later), thereby making it a specific test marker for freebase cocaine smokers. Studies suggest that methylecgonidine is more harmful to heart, liver and lungs than other byproducts of cocaine. Inhalation leads to rapid absorption of cocaine into bloodstream via lungs, reaching brain within five seconds of ingestion. Following rush exceeds snorting in intensity but does not last long. Oral: Ancient tradition of South Americans to chew coca leaves in same manner is tobacco, is another method of cocaine consumption. Alternatively, coca leaves may be consumed like tea by mixing with liquid. Coca leaf consumers have raised a controversy over whether it should be abandoned or not. Rationale behind this controversy is that strong acid in our stomach hydrolyzes cocaine, attenuating its effects on brain; therefore, unless it is taken with an alkaline substance, such as lime, which neutralizes stomachs acid, cocaine intake should not be criminalized. Cocaine is also used as oral anesthetic, both medically and unofficially. Cocaine powder is applied to gums to numb the gingiva and teeth. Colloquial terms for this route of administration are; numbies, gummies and cocoa puffs. Another method for oral administration, commonly known as snow bomb, is to pack cocaine in rolled up paper and swallowing it. Insufflation: Colloquial terms for which are; snorting, sniffing, or blowing is believed to be most commonly employed method of cocaine ingestion in west. Cocaine is poured on a flat, hard surface and divided into fine powder before being insufflated in â€Å"bumps†, â€Å"lines†, or â€Å"rails†. Devices used as aid in insufflation are known as â€Å"tooters†. Rolled up banknotes, hollowed-out pens, cut straws, pointed ends of keys, specialized spoons, long fingernails, and (clean) tampon applicators may all be used a tooters. Injection: This achieves the greatest bioavailability, 100%, in shortest span of time, since drug is directly administered into bloodstream saving time and reduced bioavailability that occurs with drug absorption from site of drug administration into bloodstream. Resultant rush is intense and rapid. Risk of contracting blood-borne infections is greatest. â€Å"Speedball†, a mixture of cocaine with heroin used intravenously is a popular and dangerous method of cocaine ingestion. It claims credit for many deaths, including celebrities like John Belushi, Chris Farley ,Mitch Hedberg, River Phoenix and Layne Staley. ADME Pharmacokinetics: Absorption, Distribution, Metabolism and Excretion of Cocaine. Before beginning discussion about pharmacokinetics or ADME of cocaine, table below summarizes the relationship of route of administration with onset of action, time taken to achieve peak effect, duration of action and half life. (Clarke, 1986) Absorption: Absorption refers to movement of drug from site of administration into bloodstream.As with any drug, absorption of cocaine depends on various factors and varies considerably with them. Factors which influence drug absorption include; drug formulation, route of administration, lipid solubility, pH of the medium, blood supply and surface area available for absorption. As evident from tabulated figures above, cocaine differs greatly in onset of action varying between 7 seconds up to 10 minutes from one route of administration to another. This is a factor of absorption of drug which depends on route of administration. Each route is separately discussed below in greater details. (Clarke, 1986). Orally administered cocaine: Cocaine induces vasoconstriction in vessels supplying oral mucosa and resultant reduction in blood supply slows down its absorption by decreasing surface area from which drug is absorbed. Therefore when orally administered, drug is slowly absorbed into bloodstream, taking roughly 30 minutes. Absorption is also incomplete; roughly one third of administered dose is absorbed. Due to slow absorption, onset of action is also delayed and peak effect is, however, not achieved until about 50-90 minutes after administration. Effect is, however, longer lasting, roughly 60 minutes after attainment of peak effect. Another factor affecting absorption of orally administered cocaine is pH of the stomach. As previously mentioned, stomach acid hydrolyzes cocaine, resulting in inadequate and incomplete absorption. To improve absorption it is common practice to take cocaine along with an alkaline liquid to neutralize acidic pH. Insufflations: Insufflations results in coating of the mucosa covering sinuses with cocaine, from where it is absorbed. Absorption is similar to that from oral cavity, cocaine induced vasoconstriction beneath mucosa results in slow and incomplete absorption (30-60%). Efficiency of absorption increases with concentration of drug. According to a study, time taken to reach peak effect via this route of administration averages 14.6 minutes. Injection: Injected cocaine is directly administered into bloodstream eliminating need for absorption. According same study, as mentioned for insufflation, time taken to reach peak effect of cocaine through injection averaged 3.1 minutes, roughly five times less than time for insufflation. Smoking: Smoking crack delivers large quantities of the drug to the lungs, resultant absorption is rapid and effects created are comparable to intravenous administration. These effects, which are felt almost immediately after smoking, are intense and last for 5-10 minutes. According to Perez-Reyes et al, 1982, volunteers who smoked 50 mg of cocaine base in a controlled study experiment achieved rapidly elevated plasma cocaine level compared to intravenous cocaine administration. Distribution: Following absorption into bloodstream, cocaine is distributed, via blood, to all body tissues including vital organs like brain, lungs, liver, heart, kidneys and adrenals. It crosses both blood-brain and placental barrier. Being lipid soluble, it easily traverses biological membranes via simple diffusion. It is believed to accumulate in brain and adipose tissue with repeated administration, owing to its lipid nature. In an experiment, distribution and kinetics of cocaine in human body were studied using Positron Emission Topography (PET) technique with radioactively labeled (carbon-11) cocaine on 14 healthy male subjects. Rate of uptake and clearance were found to vary among organs. Following results were obtained for time, in minutes, taken by radioactively labeled cocaine to reach peak value in following organs: Lungs: 45 seconds. Heart and Kidneys: 2-3 minutes. Adrenals: 7-9 minutes. Liver: 10 minutes. Liver, which is the key site for metabolism of cocaine is where distribution is most sluggish, increasing the half-life of cocaine. The Journal of Nuclear Medicine ( 1992 ) Metabolism: As already mentioned, cocaine is primarily metabolised in liver. It is estimated to get metabolized within two hours of administration. Half-life varies between 0.7 1.5 hours (Clarke, 1986), depending on route of administration among various other factors. There are three possible routes for bio-transformation of cocaine. Ester linkages in cocaine are hydrolyzed by plasma pseudocholinesterases and hepatic enzymes, human liver carboxylesterase form 1 (hCE-1)and human liver carboxylesterase form 2 (hCE-2). Benzoyl group is eliminated to produce ecgonine methyl ester. This is the major route for metabolism of cocaine. A secondary route, suggested by Fleming et al. 1990, proposes spontaneous hydrolysis, possibly non-enzymatic, followed by demethylation to produce benzoylecgonine. N-demethylation of cocaine is a minor route which leads to formation of norcocaine. Final degradation of metabolites yields ecgonine. Principal inactive metabolites are; benzoylecgonine, ecgonine methyl ester, and ecgonine itself. Norcocaine is an active metabolite and may reveal itself in acute intoxication. Metabolism of cocaine may be influenced by a number of factors: Alcohol:When cocaine is co-administered with alcohol a compound called Cocaethylene is formed. Cocaethylene is associated with an increased risk of liver damage and premature death. Pregnancy. Liver disease. Aged men. Congenital cholinesterase deficiency. In all the aforementioned conditions, except alcohol, rate of cocaine metabolism is reduced, leading to elevated levels and duration of action of cocaine, enhancing its harmful effects of on the body. Following is a schematic representation of metabolic pathways of cocaine. According to Andrew (1997) have found that the continuous use of alcohol with cocaine produce cocaethylene which is similar in the action of cocaine but it has more blood stream concentration by three to five times than cocaine as a result of its high half life. Its much attractive to be used for abuse as a result of slower removal from the body. Different types of side effects are associated with cocaethylene like liver damage, seizure and immuno compromised functioning . Cocaethylene has more possibility for sudden death by 18 25 times than using cocaine alone . Butyrylcholinesterase (BChE) has been implicated as being important in metabolism of cocaine, even though it has limited capacity to fully hydrolyze cocaine. BChE is specially essential for cocaine detoxification. A lot of research has been done to study the effect of employing this enzyme in cocaine detoxification and in anti-cocaine medications. Cocaine are hydrolyzed by human BChE in a slow rate , however, in university of Nebraska medical center the scientist at molecular biology and biochemistry have developed a mutant (A328Y) of human butyrylcholinesterase, which promises four fold greater efficiency in accelerating cocaine metabolism. Elimination or excretion: 1-9% of cocaine is excreted unaltered in urine along with metabolites, ecgonine methyl ester, benzoylecgonine, and ecgonine. Unchanged cocaine may also be eliminated through GI tract and/or be excreted in saliva. Most of the parent drug is eliminated from plasma within 4 hours after administration but metabolites may remain detectable for up to 144 hours after administration. Elimination of cocaine via kidneys is enhanced by acidification of urine. As already mentioned, cocaine easily traverses placental barrier, and the active metabolite, norcocaine is believed to persist in amniotic fluid for up to 5 days. In lactating mothers, cocaine metabolite can be found and presets for longer time up to 36 hours after the first administration and it will be found after they excreted into maternal milk. On the other hand, it will be eliminated very fast through exhalation or vapor when it is administrated through smokes. Ambre J et.al (1988) In an experiment, the investigations of chronic cocaine oral administration effects in those healthy volunteers having a history of cocaine abuse were continued. There were sixteen daily sessions of oral cocaine administration while subjects were kept in a controlled clinical ward. In every session subjects received five equal doses of oral cocaine at one hour interval. Throughout session, the doses of cocaine were administrated by an elevating rate starting from 100 mg as an initial dose (500 mg/ day) reaching to 400 mg (2 g/day) by a rate of increase of 25 mg/ dose/ session (125 mg / session). Urine specimens were collected throughout the study while at the end of the study specimens like saliva and plasma were periodically collected during the one week withdrawal phase and during the dosing session. The analysis of cocaine and cocaine metabolite were carried out by solid phase extraction and followed by gas chromatographic mass spectrometric analysis in the SIM mode. ARE is defin ed as a method or plots used to calculate the Half-lives of urinary elimination for cocaine and cocaine metabolites which stand for ( the amount remaining to be excreted ) plots. The urinary elimination for cocaine and cocaines metabolites in the Result obtained yielded two phases. An initial elimination phase during withdrawal which was has the same elimination pattern observed after acute dosing, and a terminal phase. Results were as follows: Initial phase: Mean plasma cocaine elimination half-life: 1.5  ± 0.1 h. Mean salivary cocaine elimination half-life: 1.2  ± 0.2 h. Mean urinary cocaine elimination half-life: 4.1  ± 0.9 h. Terminal phase: Mean urinary cocaine elimination half-life: 19  ± 4.2 h. A terminal elimination phase was also observed for cocaine metabolites with half-life estimates ranging from 14.6 to 52.4 h, which greatly exceeded previous estimates from studies of acute cocaine administration. This experiment shows that with chronic use, cocaine accumulates in the body with resultant prolonged terminal elimination phase for itself and its metabolites. Like any pharmacokinetic feature of a drug, elimination may also be influenced by various factors. Since renal elimination is major route for cocaine excretion, state of renal function is essential determinant of efficiency of elimination. Patients with poor renal function are much more likely to develop toxicity than those with properly functioning kidneys. Also, as already mentioned, acidification of urine accelerates the elimination of cocaine from the body. Drummer O.H et.al ( 2001) Pharmacodynamics of cocaine: Mechanism of action. Cocaine mediates its actions through two basic mechanisms: Inhibition of re-uptake of monoamines; dopamine, nor adrenalin, and serotonin. Blockade of sodium channels. As previously stated, a major breakthrough in field of surgery was discovery of cocaine and establishment of its use as a local anesthetic. All local anesthetics achieve their effect by same mechanism, known as membrane stabilizing effect. They achieve this by blocking the voltage gated sodium channels in neuronal membranes. Figure 1.0 shows the action of cocaine on sodium channels. Nerves carry impulses in the form of action potentials. Conduction of action potential involve a wave of depolarization, followed by repolarization, to travel along the nerve fiber. Depolarization, movement of membrane potential away from resting potential, is achieved through opening of voltage gated sodium channels and consequent influx of sodium. Local anesthetics reversibly reduce the rate of depolarization and repolarization by blocking these voltage gated sodium channels and eventually, impulse conduction is completely obliterated. Since local anesthetics prevent depolarization of membranes, membrane potential stays near resting levels; this is why it is called membrane stabilizing effect. Local anesthetic drugs make the onset of neuronal blockade faster especially in rapidly firing neurons when they target open sodium channels which is known as state dependent blockade. Local anesthetic action of cocaine is pH dependant. Potency and rate of action tends to decrease with the pH. Inhibition of re-uptake of monoamines; dopamine, nor adrenalin, and serotonin. Image above, taken from web, clearly demonstrates the action of cocaine (shown as yellow block in the figure) on dopamine re-uptake. Figure on the left shows normal process of synaptic transmission from a dopaminergic nerve terminal. Dopamine is secreted by the nerve terminal into synaptic cleft and subsequently binds to its receptor on post synaptic membrane. This is followed by its re-uptake via dopamine re-uptake transporter on neuronal membrane back into nerve terminal where it is degraded by MAO (Monoamine oxidase) into monoamines. Figure on right shows similar synapse, in presence of cocaine. Cocaine binds to dopamine re-upta

Boucheron Luxury Brand’s Market Research

HISTORY The House of Boucheron is French family dynasty founded by Frederic Boucheron in 1858. Four generations of the Boucheron family helped the brand to become a worldwide leader in Haute-Couture Jewelry market, expanding the brand to the four corners of the globe. Frederic Boucheron was the first jeweler to move to Place Vendome which he did in 1983. Legend has it that he chose 26 Place Vendome, where Boucheron remains to our days, because it was sunniest corner of this square. He believed that the diamonds in the windows will sparkle all brilliantly. Czar Alexander III was a client, as was his son, the doomed Nicholas II.Her Majesty Queen Elizabeth, the Queen Mother was especially fond of Boucheron tiara which she inherited from Lady Greville, who originally purchased it from the House. Her grand son Prince Charles passed the tiara onto his wife Camille, Duchess of Cornwall as a wedding gift. Queen Elizabeth of England also has a collection of Boucheron jewels as did Wallis Simp son the Duchess of Windsor. American royalty are also collectors of Boucheron creations. Household names like Astors, Vanderbilts and Rockefellers have returned again and again to this jeweler for exceptional pieces of High Jewelry.Actors and artisits have also been fans of Boucheron since it opened its doors 150 years ago. Caroline otero, the temptress known as La Belle Otero, when she was a cabaret dancer at the return of the 19th century was a Boucheron enthusiast as was the famed theater actress Sarah Bernhardt and the writers Oscar Wilde and Marcel Proust. Why film stars including Greta Garbo, Rita Hayworth, Penelope Cruz, Cameron Diaz, Kristin Scott Thomas, Rachel Weisz and Diane Kruger have all come under the Boucheron spell of spectacular creations. TIMELINE: 858- Frederic Boucheron opens his first store in the Galerie de Valois at Palais Royal, during the heyday of the Second Empire. 1866- Boucheron creates its atelier. 1867- Paris Universal Exhibition: Frederic Boucheron w ins his first Gold Medal only 9 years after opening his firs boutique. 1878 – Paris Universal Exhibition: The Foliage necklace, a sapphire and diamond set with a central sapphire of 159 carats, created for Mrs. H. Mackay, wins the Grand Prize. 1883- The Russian Prince Felix Yousoupoff purchases a corsage decorated with 6 detachable diamond bows during one of his visits to Paris. 893- Frederic Boucheron moves to 26 Place Vendome in the residence of the Countess of Castiglione. He opens the largest boutique on the square. 1898- Boucheron opens a store in Moscow, later transferred to St. Petersburg in 1911. 1902- Frederic Boucheron dies, his son Louis cucceeds him. 1921- Boucheron is commissioned to make tiara for Lady Greville; it was later given to England`s Queen Elizabeth, the Queen Mother. 1928- Louis Boucheron is asked by the Maharajah of Patiala to Set the stones of his treasure, which are brought to the Place Vendome boutique by the private guards of the Prince. 930- The Shah of Iran asks Louis Boucheron to assess the Imperial Treasure of Persia and issues a decree naming him Official Curator and Guardian of the Treasure. 1959- Louis Boucheron dies, leaving his sons Fred and Gerard in charge of the business. Edith Piaf, the most popular French Singer of her time, purchases a Boucheron watch for the love of her life, Marcel Cerdan. 1962- Fred Boucheron retires, leaving his brother Gerard as head of the establishment. 1970- In the 1970s the best selling snake line was created. 1973- Boucheron`s first boutique opens in Japan. 980- Gerard Boucheron retires and Alain Boucheron becomes a president and General Director. 1988- Boucheron launches its first women`s fragrance in a ring shaped bottle. 1994- Boucheron takes of a new development in the sector of fashion accessories: The Boucheron Eyewear Collection. Boucheron sells to Schweizerhall. 2000- Gucci Group acquires the House of Boucheron. 2002- Boucheron launches the â€Å"Beaute geois† collect ion. 2003- Boucheron launches the â€Å"Not Bourgeois† collection 2004- Gucci Group is fully acquired by PPR. Jean-Christophe Bedois is appointed CEO.The â€Å"Jaipur† High Jewelry line and the â€Å"Dechainee† collections are launched. 2005- Launch of four new jewelry lines: Trouble, Quatre, Diablotine, Vingt-Six. Boucheron opens its firs boutique in Shanghai and its first flagship in Dubai. The start of the â€Å"Trouble Desir† High Jewelry Collection. 2006- Boucheron and Alexander McQueen collaborates together to create a limited edition Novak bag that incorporates the snake motif of Boucheron`s Trouble line. Boucheron opens its first boutique in Hong Kong and Kuala Lumpur. Launch of the â€Å" Exquises Confinces† line. 008- Boucheron marks its 150th anniversary with a yearlong celebration. CONCEPT AND UNIQUENESS The concept of Boucheron is to appeal to high-end customers who look for something unique in their jewelry. Through meeting target cus tomers standards about design, materials, price and brand Boucheron has created a market for luxury haute couture jewelry. Customers also appreciate the fact that all collections are manufactured in small quantities and that stones of the highest quality are used; in addition to diamonds, also sapphires, amethysts, emeralds, coral, onyx, and jade. We wanted to develop innovative and creative way to introduce our rich heritage and approach to fine jewelry in way that enchants, amazes and amuses. We have a rich history that is beautifully brought alive. † Jean Christophe-Bedos, President, Boucheron The Responsible Jewellery Council (RJC) has announced in 2011 that Boucheron has achieved certification by meeting the ethical, human rights, social and environmental standards as established by the RJC's Member Certification System. â€Å"RJC warmly congratulates Boucheron on its certification.The successful verification assessment of Boucheron was conducted by Philippe Arnaud from KPMG France, one of the independent third-party auditing firms accredited to the RJC's Member Certification System† Michael Rae, RJC's Chief Executive Officer. â€Å"Since 1858, Boucheron has adhered to the highest standards not only in the spectacular designs of its creations but also in upholding its strong ethical code. The RJC certification corresponds to the House's continued endeavor to embody excellence and responsible business practices both internally and externally; a commitment we share across the PPR Group† Pierre Bouissou, Boucheron's CEOBUSINESS STRATEGY With the understanding that the conservative way was not an option, Boucheron plays on its long history of rousing the passions of sensual desire. This attitude has driven Boucheron's design and delicate craftsmanship and resulted in a heritage of enthusiastic stories and myths. Today it could motivate an entirely new approach to the market. The House’s individual legacy sharped a way to connect th e new luxury consumer on a essentially more personal, more passionate and less superficial level.Boucheron has formed a marketplace approach that brings many industry innovations – a new service that redefines how the HNWI can experience and enjoy luxury jewelry; an exclusive retail concept that can voyage to the client rather than sit and wait for them; and product idea that raises the craft of the brand to the peak levels of art and business When Boucheron has entered the US market the first element of the strategy was a â€Å"Desir†, a collaboration with the creators of Spiegelworld, that brings alive the rich history of Boucheron in an personal and inspirational 100 year old hall of mirrors.It was launched in New York in August 2008 and was set to benefit from a sellout three-month run at the South Seaport before opening two-year tour of US’s most significant Luxury markets. â€Å"Set in a turn of the fin-de-siecle nightclub, Desir is meeting place for show girls and soldiers, bejeweled courtesans and maharajahs, a carnival world devoted to the pursuit of beauty, clever seductions and breathtaking displays of acrobatic wonder. It is a sparkling merry-go-round where the last love affair is merely an entree to the next encounter.More than any show in New York I can think of, Desir, with its cavalcade of professional beauties, does inspire thoughts of a time when well-dressed admirers queued up at dressing-room doors bearing gifts of flowers and jewelry. As for me, I'm thinking of coming back with a bouquet of catnip for that charming, fluffy-haired Persian who stopped the show when it walked a tightrope. † Ben Brantley, New York Times. Additionally to the show there was the Boutique Desir, a traveling boutique where, guests can find out Boucheron’s universe and its creations; can touch, try and familiarize themselves with the pieces in a private ambiance.Clients were then invited to the exclusive Bar Vendome, a VIP lounge wh ere they could get pleasure from an memorable evening under the stars. Boucheron chose to launch their products in the BRIC countries as well, which consists of some of the most emerging markets in the world today. Additionally, the Middle East and India are also two extremely important markets for Boucheron, partly due to the strong responsiveness for jewelry. The sales in these countries are larger than in the western countries and the luxury company is exploiting the new wealth of the generations with high luxury awareness and taste.MARKETING MIX Product: Boucheron sells hand-made haute-couture luxury jewelry made from fine materials like gold, platinum, diamonds, emeralds and sapphires. Along with every purchase the buyer receives superior service and is entitled to service which assists users with exclusive services like delivery and customization. One of the Boucheron`s specialties is color. Clients easily can distinguish  Boucheron’s line of jewelry  by its designs . Its signature is visible in the form of motifs like floral, peacock feathers and snakes. Boucheron produces: * Necklaces * Pendants Bracelets * Brooches * Cufflinks * Earrings * Rings * Wedding Jewelry * Watches * Perfumes (18 editions) * Sunglasses Price: Boucheron prices range: Rings from 2. 000 eur up to 30. 000 eur Earrings from 4. 000 eur to 41. 800 eur Necklaces from 12. 000 eur to 1. 000. 000 eur Brooches from 5. 000eur to 10. 400 eur The prices vary with the different collections and the materials that are used in them. Place: Boucheron jewelry is very selectively distributed. It is available at company-owned boutiques and flagship stores like London Jewelers, Goldsmiths, and Colette.They recent store was opened in Doha`s West Bay community in Middle East. In keeping with its global design concept, the space is decorated using its signature aubergine and gold colour palette and affluent wooden decor. The Doha boutique domiciled Boucheron’s iconic most collections, a long with a range of exquisite high jeweler’s creations. Boucheron locates its stores in luxury shopping districts, famous â€Å"Golden Triangles† of large metropolitan areas and opens relatively few stores.Today, Boucheron operates more than 50 boutiques and over 100 certified retailers worldwide in addition to an online sales website. The boutiques are, intimate and have a luxury feeling. All sale locations can be found on www. boucheron. fr . Promotion: Boucheron acquires much publicity from sales to celebrities like: * Chanel Iman * Diane Kruger * Natalia Vodianova * Kira Knightley * Julianne Moore * Raquel Zimmermann * Anne Hathaway * Mary-Kate Olsen * Natsha Poly * Lily Donaldson * Salma Hayek * And many others As well Boucheron has collaborated with Vertu.Boucheron launches diverse collections at different times and only makes a certain number of some jewels in order to keep a prestigious image and be a focus for HNWI. Boucheron has an own website for publicity which features product descriptions and prices. Mostly promotion is running in Fashion Magazines like Vogue. POSITIONING Seeking to embody the opulence and grandeur of Parisienne life, Boucheron draws often upon iconic French women, each epitomizing a facet of the golden age, to act as muses in the creation of distinct sets of jewelry.Each woman has its own distinctive way of wearing jewelry, which is the privilege of a woman, but she can vary own excitement strategy. Blink of an eye, the center will become a decorative pattern of brooches, pendants into earrings, necklace, or a deduction into a multifaceted hairpin. Boucheron blends the art of seduction and a charm with a woman`s desire to wear jewelry. Boucheron has positioned itself as the top-of-the-line targeting HNWI. Boucheron achieving this by using only the finest materials to create their products which are all handcrafted ensuring that every product is of perfect quality.Boucheron will launch different collections each fe aturing different materials and designs which make the collections unique and prestigious; their most expensive line ever was a necklace Julia which cost 800,000eur and Boucheron snake necklace for Maison du Chocolat which costs 900. 000 eur. Boucheron collaborated with VERU luxury mobile phone maker, to extend their success and increase awareness in the luxury product world. Boucheron offers superior and personalized service to its clients, guaranteeing customer satisfaction and loyalty. They also position hemselves by showcasing the celebrities who own their products as an indication that their products are for the rich and famous. Boucheron has flagship stores all over the world in 50 countries however they open relatively few boutiques solely in luxury shopping districts of large cities and thus are considered selectively distributed. Boucheron boutiques are decadent, small, intimate venues which offer personalized service to clients wishing to make a purchase. Boucheron house v ery successfully preserves a prominent image with its ultra-luxurious products and superior service through its positioning.TARGET CONSUMER The Boucheron jewelry is a highly luxurious product, which doubtlessly is made to fit the extremely wealthy population of this world. The main customers are rich and found in the urban areas, who are constantly searching for the extraordinary products. Furthermore, their flagship stores are situated in the finest areas, in order to attract the highly rich international shoppers. CONSUMER-BASED BRAND EQUITY PYRAMID Brand Salience For Boucheron achieving right brand identity involves brand salience. Only richest people are aware of Boucheron because promotion is quite narrow.However their target consumer for sure can recall and recognize this brand. So conclusion here is that Brand salience is more depth than breadth. This basically means that even thou there are not yet many people knowing Boucheron, but those who do, they know all insights of it , can easily remember it and realize what this brand is about. Brand Performance The product itself is at the heart of brand equity, as it is the primary influence of what consumers experience with a brand, what they hear about the brand from others, and what the brand can tell customers about the brand in their communication.Brand Performance relates to the ways in which the product or service attempts to meet customers` functional needs. This is on top level for Boucheron brand. It is crucial to contribute to customers` desires, wants and needs. Boucheron brand highly represents all what their HNWI customers want to have for paying a high price. The product is highly durable; it has distinctive logo, premium pricing and quality handcraft. All customer services provided for clients by Boucheron also attributes to brand`s performance. Brand ImageryAnother variable CBBE Pyramid is second type of brand meaning which involves brand imagery. Imagery deals with such a properties of a pro duct, which meets customers` psychological needs. It is more about what people think of it, how they see it. Boucheron imagery is extremely individualistic and stylish. When customer is buying Boucheron cell he/she buys a beauty of it. As of Boucheron customer has a strong judgment of a brand as high quality luxury product. Credibility is high and customer see Boucheron as superior, advantageous brand. Brand JudgmentsBrand judgments focus upon customers` personal opinions and evaluation with regard to brand. This involves how consumer put together all from performance and imagery association to make kind of an evaluation. Boucheron clients evaluate this brand as a high quality luxury brand. Brand Feelings This variable shows emotional response with respect to Boucheron brand. It shows what feelings are evoked by the marketing strategy for the Boucheron and how does it affect feelings about themselves and relationships with others. Customer of Boucheron is for sure status-conscious p erson.Customers of Boucheron have a unique and warmth feeling about the brand. It can be exciting due to special relationship of beauty and handcraft in brand`s products. Customer feels it is trendy and relates to special status and therefore social approval. Customer feels high security within this brand due to all advantages provided. As Boucheron makes consumer feel better self-respect, pride, fulfillment and accomplishment also occurs. Brand Resonance Final variable of pyramid shows brand relationships with a customer based on Salience, Performance, Imagery, Judgments and Feelings.As for Boucheron even if general awareness is low the behavioral loyalty is very high, customer want to get back to this brand, consequently repeat purchase is possible. Brand loyalty is necessary but not sufficient for resonance to occur. Within Boucheron brand customer is not returning to this brand again due to, for example, scarce of substitutes. Boucheron attained their main goal- strong personal attachment to brand. SWOT ANALISYS FOR BOUCHERON STRENGTH * Masterpiece of design and craftsmanship * Innovative brand Strong reputation (Products have established strong reputation in their field) * Global expansion (Includes significant growth over last 10 years) * Customer service * Control of Quality WEAKNESSES * Extremely high production price (which leads to high product price) * Limited access as distribution is exclusive and limited * Not enough practical promotion and advertising OPPORTUNITIES * Emerging markets * Mix Boucheron styling with some big Fashion Brand like Gucci * Change of consumer lifestyle (growing demand from young and senior people) THREATS Increasing Quality of Competing Products and Number of those * Importance of counterfeiting COMPETITORS * GRAFF * VAN CLEEF ; ARPELS * PIAGET REFERENCES http://luxurysociety. com/articles/2012/01/the-latest-boutiques-burberry-bally-boucheron http://www. luxury-insider. com/luxury-news/2010/03/boucheron-jewellery-show-at- mandarin-oriental-hk http://en. wikipedia. org/wiki/Boucheron http://www. verybest. com/cat/49/jewelry/235/2/ http://jewelhistory. com/2010/10/27/in-and-around-town/ http://www. mycompanion. cz/en/list/boucheron-paris-boutique

Chestnut Hill College SAT Scores, Tuition, Admit Rate

Society s Misconception Of Welfare Recipients - 881 Words

Society’s Misconception of Welfare Recipients You’re invited to pull back the curtain on the ultimate faà §ade that really needs to be exposed. You’ll find them at the nail shop and buying knock off Gucci out of the trunks of Monte Carlos in the parking lot at the Boulevard Mall. The glittering galaxy life of all your favorite Instagram stars and let’s not forget our very special guest, the cunning, the conniving county con artist that lives the lack luster lifestyle of the broke and stressed out. She is this paper’s unchallenged authority on doing it big on a budget and the fabulous food stamp life. She has been all over the country creating a lifestyle that Welfare critics will never stop talking about. A real life Cinderella that never went to the ball and never found her prince charming, America’s Welfare Queen. Society has this strange misconception that welfare recipients prefer to remain uneducated, unemployed, and are uninterested in self-sufficiency. The term ‘Welfare Queen’ envelopes the preconceived notion that single mothers are living lavishly at the government’s and tax payer’s expense. This could be nothing farther from the truth when the average monthly welfare stipend is around $167 per person, meaning a family of four has to survive an average of 30 days on $668. All while taking into account that an average of $94 of the $167 is in food stamps, leaving a meager $292 in cash to feed, clothe, and house four people. What kind of kingdom can a Queen ruleShow MoreRelatedShould Welfare Be A Welfare?958 Words   |  4 Pagesthe 70’s the term Welfare Queen has been used to describe our nation’s poor single mothers that receive welfare benefits instead of being gainfully employed. Society’s misconception is that they can be found buy ing fake Gucci purses out of the trunks of late model BMWs in gas station parking lots and appear on Snapchat, Twitter, and Instagram. These undereducated young mothers seem like cunning, conniving, county con artists that celebrate their poverty and hide the fact that being a welfare recipientRead MoreAmerica s Welfare Of Welfare876 Words   |  4 Pagesfabulous food stamp life. She has been all over the country creating a lifestyle that Welfare critics will never stop talking about. A real life Cinderella that never went to the ball and never found her prince charming, America’s Welfare Queen. Society has this strange misconception that welfare recipients prefer to remain uneducated, unemployed, and are uninterested in self-sufficiency. The term ‘Welfare Queen’ envelopes the preconceived notion that single mothers are living lavishly at theRead MoreWhat Ways Does Cultural Racism Manifest Itself?1651 Words   |  7 Pagessmaller, weaker cultural identity. Certain views expressed of the Muslin culture in recent years can be viewed as a similar form of cultural racism. 31-35) In what ways does institutional racism affect the status and standing of minorities in American society? Be specific. R - Institutional racism affect minorities in several ways. For example, when laws are enacted, the decision are made based on the choice of a superior majority, which has a negative impact on the rights of minority entities to say theRead MoreFinancial Assistance Programs And Policies For The Poor1548 Words   |  7 Pages87 percent† (Sherman et al., 2013). These programs can help to significantly improve upon a family’s economic well-being, so long as they, too, are playing their part. Additionally, many people rely on financial assistance to live. In West Virginia s urban McDowell County, for example, â€Å"nearly 47 percent of personal income... is from Social Security, disability insurance, food stamps and other federal programs† (Gabriel, 2014). Without these programs, people in poverty, especially those strugglingRead MoreEquality, A Social Justice Warrior s Favorite Word1414 Words   |  6 Pagesplays a major role in equality, especially for African-Amer icans. African-Americans have been on the margins of society ever since 1641 with the implementations of slavery. For over four hundred years, African-Americans have been fighting for equality, which should be something one should not have to acquire through marches and protests, but should be a given right. Even in modern society, many people believe whites and blacks are not equal. Racial stereotypes of African-Americans have misconstruedRead MoreSocial and Economic Analysis of America1671 Words   |  7 Pages‘American’ jobs. If they are illegal, immigrants must also worry about keeping a low profile to avoid deportation. While it has improved, racism still exists in our society. It is hard to raise oneself out of poverty, and if institutions and society are working against you it is even harder. Question 2: Despite campaigns since the 1970’s, women still make only $0.77 for every $1.00 their male colleagues make. They are more likely to be unemployed and living below the poverty threshold. They are alsoRead MoreU.s. Welfare And The Welfare System2269 Words   |  10 PagesIntroduction U.S. Welfare started as a federally funded program in the 1930’s during the Great Depression to help aid those families and individuals who had little to no income. The Federal Government was in charge of the U.S. welfare system for sixty years, until the 1990’s when there was an uproar of Americans who were unsatisfied with the way the Federal Government was handling those who were receiving government aid. Many Americans believed that these individuals were abusing the welfare program byRead MoreThe Misconceptions Of Impoverished Workers And The American Dream2055 Words   |  9 PagesThe Misconceptions of Impoverished Workers’ and the American Dream After thoroughly examining some the hardships experienced by underpaid workers’, it has become evident that the definition of poverty is often misconstrued by society. Demonstrated through numerous case studies and as presented in David K. Shipler’s â€Å"The Working Poor: Invisible in America†, the lives of many low income workers’ are adversely impacted by the lack of a sufficient salary. After gathering materials from such resourcesRead MoreHiring Ex-Offenders3239 Words   |  13 PagesHiring Ex-offenders Everyone deserves a second chance. You should never judge a book by its cover. These are some of the things that should be considered when an employer considers hiring an ex-offender reentering society after release from the prison system. Once a criminal, always a criminal is not always the case. Some ex-offenders have proven to be loyal and trustworthy employees. As well as tax-paying individual who open their own businesses. There are positives and negatives to hiringRead MoreThe Transatlantic Trade And Investment Partnership2035 Words   |  9 Pagesprivate tribunals is a threat to our society, our public system, our democracy, therefore a threat to the establishment of our public policies. It is time to stop this exploitative agreement. In the next paragraphs, I will give my views as to why ISDS negotiations should be suspended by all means and why it is an impediment to the foundation of our constitutional rights as well as the mandated judicial system in place to promo te the well-being of our society. Obstructing our democracy: ISDS provisions