History of Cocaine Use Medical and Recreational Uses

History of Cocaine Use Medical and Recreational Uses Cocaine through the 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 his published word, ÃÅ"ber Coca, Sigmund defined effects of cocaine in following words: â€Å"exhilaration and lasting euphoria, which in no way differs from the normal euphoria of the healthy personYou perceive an increase of self-control and possess more vitality and capacity for work.In other words, you are simply normal, and it is soon hard to believe you are under the influence of any drug.Long intensive physical work is performed without any fatigueThis result is enjoyed without any of the unpleasant after-effects that follow exhilaration brought about by alcohol.Absolutely no craving for the further use of cocaine appears after the first, or even after repeated taking of the drug† 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, who was enrolled as a Ph.D. student at a German university, University of Gottingen , in 1859. Niemann wrote a dissertation describing steps of isolation which was published in 1860 and was entitled, â€Å" ÃÅ"ber eine neue organische Base in den Cocablà ¤ttern† (On a New Organic Base in the Coca Leaves). F. Gaedcke (1855) Formal Chemical Name (IUPAC) for cocaine: (1R,5S)-methyl 8-methyl-3-(phenylcarbonyloxy)-8-azabicyclo[3.2.1]octane-2-carboxylate. Chemical structure of cocaine: Structure of cocaine molecule was first defined by Richard Willstà ¤tter in 1898. 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. Following is taken from â€Å"On cocaine† by Sigmund Freud. â€Å"A few minutes after taking cocaine, one experiences a certain exhilaration and feeling of lightness. One feels a certain furriness on the lips and palate, followed by a feeling of warmth in the same areas; if one now drinks cold water, it feels warm on the lips and cold in the throat. One other occasions the predominant feeling is a rather pleasant coolness in the mouth and throat. During this first trial I experienced a short period of toxic effects, which did not recur in subsequent experiments. Breathing became slower and deeper and I felt tired and sleepy; I yawned frequently and felt somewhat dull. After a few minutes the actual cocaine euphoria began, introduced by repeated cooling eructation. Immediately after taking the cocaine I noticed a slight slackening of the pulse and later a moderate increase. I have observed the same physical signs of the effect of cocaine in others, mostly people my own age. The most constant symptom proved to be the repeated cooling eructation. This is often accompanied by a rumbling which must originate from high up in the intestine; two of the people I observed, who said they were able to recognize movements in their stomachs, declared emphatically that they had repeatedly detected such movements. Often, at the outset of the cocaine effect, the subjects alleged that they experienced an intense feeling of heat in the head. I noticed this in myself as well in the course of some later experiments, but on other occasions it was absent. In only two cases did coca give rise to dizziness. On the whole the toxic effects of coca are of short duration, and much less intense than those produced by effective doses of quinine or salicylate of soda; they seem to become even weaker after repeated use of cocaine.† 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†. Anything small and hollow, such as straws cut short, can serve as a tooter. 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) Route of administration Onset Peak effect (min.) Duration (min.) Half-life (min.) Inhalation 7s 1-5 20 40-60 Injection 15s 3-5 20-30 40-60 Nasal 3min 15 45-90 60-90 Oral 10min 60 60 60-90 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. The rate at which human BChE hydrolyzes cocaine is slow; however, scientists at Eppley Institute and Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, 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 and benzoylecgonine are excreted into maternal milk and can be detected up to 36 hours after administration. In smokers, cocaine is rapidly eliminated through exhalation of vapor. Ambre J et.al (1988) In an experiment, the effects of chronic oral cocaine administration in healthy volunteer subjects with a history of cocaine abuse were investigated. 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 sessions, cocain

Pakistan China Relation Development

MARIAM ABBAS 15-10079 The Major Developments in Pakistan’s Relations with China Almost sixty years have lapsed since Pakistan and China established diplomatic relationship. The relationship between the two countries are time tested, an unbridled relationship which continues to grow and strengthen with passage of time. The area in which the two nations reside has undergone numerous Geo-strategic changes namely Sino-Indo relations, the collapse of Soviet Union, 9/11 with Pakistan becoming front line state in the war against terror and so on.In context to all these developments, China and Pakistan find themselves on the same page , each strongly supporting each other at every forum thus exhibiting exemplary and unique brotherly relationship. The intensity of the relationship can be gauged by the frequency of the visits by the two heads of the state which continue unabated. President Zardari stated on his second visit to China in February 2009, within a year of taking over the pre sidency, â€Å"Perhaps no relationship between two sovereign states is as unique and durable as that between Pakistan and China.On the Pakistan side of the Himalayas, the mighty range that separates the two countries, China is seen as a true, time tested and reliable friend that has always come through for Pakistan. That the Pakistan-China friendship is higher than the peaks of Himalayas is now a truism without exaggeration. I am certain that on the Chinese side a similar sentiment exists for Pakistan. It is a friendship rooted in the hearts and minds of the people of the two countries. 1 An insight into the significance of developments of relationships between the two nations are outlined below: â€Å"In 2005, China and Pakistan signed a land mark Treaty of Friendship and Co-operation, whereby they committed that neither party will join any alliance or bloc which infringes upon the sovereignty, security and territorial integrity of either nation, while simultaneously positing tha t both parties would not conclude Treaties of this nature with any 3rd party. †2 The above agreement is manifest of the deep rooted friendship between the two states.The security and territorial integrity of any nation is the most vital element for existence for any nation. Pakistan China relationship were based on these foundations. Having build a solid foundation of friendship, China provided physical, technical and financial support to Pakistan on a number of vital projects bringing huge economic benefit. The infrastructure projects of Karakoram highway and Gwadar Port are a few significant developments. The construction of Gwader Port will bring immense economic activity in the area.It will also afford a strategic entrance to the Arabian Sea and the Indian Ocean thus gaining a considerable influence in the region. The People's Republic of China enjoys strong defence ties with Pakistan. China fully supported Pakistan in its 1965 war against India. China's source of military equipment to Pakistan has steadily increased over the years. Ever since the dependence on American military equipment has become unreliable and prone to undeclared conditions, the induction of Chinese hardware has increased. China has helped to establish ammunition factories, provided technological assistance in modernizing existing facilities.Joint ventures such as development of JF-17 Thunder fighter air craft, AWACS system, Al-Khalid tanks, Babur cruise missiles are symbol of deep rooted military co-operation. China has also a vital strategic interest in developing relationship with Pakistan. Ever since the China – India skirmish in the sixties over border dispute which resulted in India building up its forces along the disputed border leading to Chinese military intervention, China has opted for strong partnership with Pakistan to check any hemoginistic designs of India in the region.This analogy can best be summed up by Lisa Curtis in an article titled â€Å"Extent of Pakistan China Relationship† as under: â€Å"Pakistan and China have long-standing strategic ties, dating back five decades. China maintains a robust defence relationship with Pakistan and views a strong partnership with Pakistan as a useful way to contain Indian power in the region and divert Indian military force and strategic attention away from China.The China-Pakistan partnership serves both Chinese and Pakistani interests by presenting India with a potential two-front theater in the event of war with either country. Chinese officials also view a certain degree of India-Pakistan tension as advancing their own strategic interests, as such friction bogs India down in South Asia and interferes with New Delhi’s ability to assert its global ambitions and compete with China at the international level. †3 China is fast emerging as the biggest economic super power.Economic trade between China and Pakistan is rapidly increasing at a fast pace. Chinese products have f looded the Pakistani market. â€Å" Current trade between both countries is at $ 9 billion, making China the second largest trade partner of Pakistan. † 4 China has also played a significant role in the development of nuclear power plants for peaceful purposes. The material and technical support provided by China in the completion of Chasma Nuclear Power Complex is a manifest of the deep rooted relationship.This has been despite the fact of increasingly stringent export controls in western countries and opposition by major super powers thus it is true to state that Pak-China relationship is â€Å"Time tested and All weather. † In Chinese, Pakistan found a best and most reliable friend. China always helped Pakistan economically and militarily when there was no hope for external help. On the diplomatic front, Pakistan always find China firmly standing behind its back.As a reciprocal, Pakistan was not only the first country to recognize China but it always supported China 's claim to the Chinese seat in the United Nations. Pak-China friendship is an all weather and time tested relationship based on mutual trust and respect. Both the countries enjoy convergence of views on all bilateral regional and international issues. To conclude it can be said without any doubt that Pak-China relationship is exemplary, which continues to grow and is envy for others. It is a friendship which is rooted in the hearts and mind of the peoples.

Workers without Jobs

GAP cannot reflect positive or negative externalities Involve In the consumption and production UT these externalities do affect on people's living standard. Negative externalities such as pollution brings environmental costs to society but not calculated by GAP. Positive externalities such as technological advance benefits to society but it is not count in GAP. Economic well-being would be under-value or over-value if GAP is the only single measure of economic well-being. 3. Leisure helps people enjoy a better life.In countries with lower GAP, the welfare gain from leisure can compensate the welfare loss from low GAP. Explain why frictional and structural unemployment are unavoidable in most of the economies. There are always some workers without Jobs, even when the overall economy is doing well. For example, people now prefer cell phones from Apple than from Monika. Monika decides to cut down Its employees due to the decrease of revenue. It takes time for him (the worker) to search another job that is best suited for him. In this period when matching jobs and workers, he is unemployed and it is called frictional unemployment.Another example is that now most of the textile factories decide to move to mainland China. A worker in one of these factories loses her job, however, he Is unable to learn or change new working skills or knowledge on other specialist or other field. And therefore, she cannot find a new Job In her Orlando Industry and also in other industries. This imbalance between the skills and other characteristics of some workers and the needs of workers in the labor market causes unemployment called structural unemployment.When unemployment consist only frictional and structural unemployment, unemployment is at natural rate. In most of the economies, there are always some reasons causing frictional or structural unemployment. Employment rate never fall to zero it fluctuates around the natural rate of unemployment. Therefore, frictional and structura l unemployment are unavoidable in most of the economies. What are the three major functions of money? Discuss how these functions be affected by inflation. Account and a store of value.A medium of exchange is an item that buyers give to sellers when they purchase goods and services. When you buy a shirt at a clothing store, the store gives you the shirt, and you give the store your money. This transfer of money from buyer to seller allows the transaction to take place. When you walk into a store, you are confident that the store will accept your money for the items it is selling because money is the commonly accepted medium of exchange. A unit of account is the yardstick people use to post prices and record debts.When you go shopping, you might observe that a shirt costs $30 and a hamburger costs $3. Even though it would be accurate to say that the price of a shirt is 10 hamburgers and the price of a hamburger is 1110 of a shirt, prices are never quoted in this way. Similarly, if yo u take out a loan from a bank, the size of your future loan repayments ill be measured in dollars, not in a quantity of goods and services. When we want to measure and record economic value, we use money as the unit of account.A store of value is an item that people can use to transfer purchasing power from the present to the future. When a seller accepts money today in exchange for a good or service, that seller can hold the money and become a buyer of another good or service at another time. Money is not the only store of value in the economy: A person can also transfer purchasing power from the present to the future by holding monetary assets such as stocks and bonds. The term wealth is used to refer to the total of all stores of value, including both money and monetary assets.What assumptions are necessary to argue that the quantity equation of money implies that increases in the money supply lead to proportional increases in the general price (a) Discuss two reasons why the GAP deflator gives a different rate of inflation than the ICP does. 1. 12 PEP (6 marks) (b) Explain the likely effect of a binding minimum wage on the unemployment rate. (5 marks) (a) Suppose an economy that is initially at full employment faces a tremendous drop n imports. I.

The Constitution Of The United States Essay - 1618 Words

The First Amendment is arguably one of the most important amendments ever added to the Constitution of the United States. It is designed to protect four basic freedoms: the freedom of speech, freedom of religion, the right to assembly and freedom of the press. When this amendment was drafted by the founding fathers, it was done in response to some of the events that had precipitated the American Revolution. Over time, the interpretation of these freedoms has changed as seen by various actions in government, but especially in rulings from the Supreme Court. The First Amendment has had a special importance from its beginnings to today. The First Amendment was initially created to protect freedoms that the founding fathers felt had been violated by the British or other governments at one time or another. For example, the freedom of speech and of the press was deemed important to allow citizens to speak their thoughts and opinions about the government. The founding fathers agreed with a prevailing theory at the time that governments have power mainly through the consent of the governed. Should the people become dissatisfied with the government, it is important that their opinions and thoughts be heard. Freedom of the press is closely related to freedom of speech. During the American Revolution individuals like Thomas Paine wrote pamphlets about the problems that the Americans were having with the British government. These pamphlets were understandably unpopular with theShow MoreRelatedThe United States Constitution And The Constitution Essay1491 Words   |  6 PagesThe United States Constitution, this very detailed group of words was written in 1787, but it did not take effect until after it was ratified in 1789, when it replaced the Articles of Confederation. It remains the basic law of the United States then and till the present day of 2016. The first state to ratify the Constitution was Delaware; the last of the original thirteen to ratify was Rhode Island and since only nine were required, this was two years after it went into effect. When the U.S. ConstitutionRead MoreThe Constitution Of The United States Constitution Essay1185 Words   |  5 Pages(framers’ of the U .S. Constitution) position on the Presidency: The framers experienced the abuse of the English monarchs and their colonial governors. As a result, the framers were skeptical of the excessive executive authority. Furthermore, they also feared excessive legislative powers. This was something that the Articles of Confederation had given their own state legislatures. The framers of the constitution deliberately fragmented power between the national government, the states, and among the executiveRead MoreThe Constitution Of The United States885 Words   |  4 Pages In 1787, our founding fathers came up with a few principles that would establish what we now know as the United States of America. These principles were put on paper to serve as a guideline for how the United States would be operated and structured. This historical piece paper became known as the Constitution of the United States. In the Constitution, a Preamble is implemented at the beginning that essentially tells what the founding fathers set out to do. â€Å"We The People, in order to form a moreRead MoreThe Constitution Of The United States894 Words   |  4 Pagesthe substratum for that country. A Constitution can be defined as a document that is the substratum of the country’s principles. Elements in the Constitution may contain sundry information. Which can include: how many terms a leader may serve, what rights the citizens have, how the judicial system works, etc. The United States in no different from those countries. Every constitution is different, no country has the exact constitution as another. The U.S Constitution is a four-page document detailingRead MoreThe United States Constitution Essay1515 Words   |  7 PagesThe United States constitution was written in 1787 by the founding fathers of this country. Now it might be appropriate to question why a document that is the basis of the government for one of the most culturally and racially diverse countries in the world, was written by a group of heterosexual, cisgender, rich, white men. Some might think that a constitution written well over 200 years ago would be outdated and irrelevant to the American society of today but with some research, it is quite theRead MoreThe Constitution Of The United States756 Words   |  4 PagesPromulgation and Legislation in the U.S. Constitution: The federal system of government of the United States is based on its constitution. The Constitution grants all authority to the federal government except the power that is delegated to the states. Each state in the United States has its own constitution, local government, statute, and courts. The Constitution of the United States sets the judiciary of the federal government and defines the extent of the federal court’s power. The federalRead MoreThe Constitution Of The United States1007 Words   |  5 PagesThe United States of America has previously experienced failure every now and then. With trial and error, the country has learned to correct its ways and move toward(s) perfecting itself. Realizing the ineffectiveness of the Articles of Confederation is a prime example of the U.S. learning how to better itself. Subsequent to the Articles of Confederation, the Constitution of the United States was set as our new and improved framework of government. Possessing knowled ge on how America, although strongRead MoreThe Constitution Of The United States951 Words   |  4 Pageshappening again. Unlike the artifacts, The Constitution of the United States has not been forgotten, it is actually still very alive today. Unlike most relics, The Constitution still holds a very heroic and patriotic implication, freedom. With freedom comes self-government, freedom of speech, religious tolerance, etc. With all these things comes the great responsibility to adapt and fit to the wants and needs of the decade. Even though the Constitution was made for the interests of the people ofRead MoreThe Constitution Of The United States1338 Words   |  6 Pages The Constitution is the basis of law in The United States and has been since it was written in 1789. Since then it has been amended 27 times with the first ten amendments collectively known as the Bill of Rights. The US Constitution was preceded by the Articles of Confederation and supported by the Federalist Papers which we will touch more on later. James Madison, Alexander Hamilton, John Adams and Thomas Jefferson all wrote or influenced The Constitution in a very important way. Alexander HamiltonRead MoreThe Constitution Of The United States1388 Words   |  6 PagesInterpretation of the Constitution is one of the biggest conflicts within the United States–the highly contentious issue of states’ rights resulted from two different interpretations of what powers should belong to the federal government versus what powers belong to the individual states. No issue has ever caused as much turmoil as the issue of states’ rights–but one side must have more v alid arguments. Should the federal government’s power be superior, or should the authority of the individual states be held