Kapan buy cocaine

__________________________

📍 Verified store!

📍 Guarantees! Quality! Reviews!

__________________________

▼▼ ▼▼ ▼▼ ▼▼ ▼▼ ▼▼ ▼▼

▲▲ ▲▲ ▲▲ ▲▲ ▲▲ ▲▲ ▲▲

Kapan buy cocaine

I could go on and on and on, cataloging the contradictions and abandonment of principle, all gobsmacking. Kennedy Jr. He quit when he was arrested after overdosing on a flight from Minneapolis to the Black Hills and found by police in South Dakota to be carrying heroin; he pleaded guilty and received only probation. Sometime during my freshman year, I tried cocaine, enjoyed it, and later decided to procure a gram for myself. A friend told me about a kid in our class who was selling coke. The dealer was Bobby Kennedy. His roommate, whom I knew, was the future journalist Peter Kaplan—with whom I, like Kennedy, remained friends for the rest of his life. He left as I arrived. I wondered whether he always did that when Bobby had customers. Another kid, tall, lanky, and handsome, was in the room. Kennedy II, two years older, the future six-term Massachusetts congressman. He poured out a line for me to sample, and handed me an inch-and-a-half length of plastic drinking straw. I snorted. We chatted for a minute. But cocaine bought from a Kennedy accompanied by a Kennedy brother —the moment of glamour seemed worth it. Back in my dorm room 10 minutes later, I got a phone call. Because … it was a crummy piece of plastic straw. But Bobby was pissed. You took it. The residue of powdered cocaine mixed with mucus formed crystals over time? What did I know. It reminded me of some science-fair project. It was the last time I ever bought coke from anyone. His almost fetishistic obsession with a bit of plastic trash. His greedy little burst of anger cloaked in righteousness. His faith that he was cultivating precious cocaine crystals. That is, Donald Trump, if he becomes president as Kennedy is now working to make happen, wants to start executing drug dealers. Elizabeth Bruenig: Trump dreams of a swifter death penalty. It takes one day. One day. They execute the drug dealers. They have zero drug problem. And so, one question for reporters to ask the new Trump campaigner and potential Trump-administration official Robert F. Given that you sold cocaine in your youth, how do you feel about his advocacy of a regime that might have resulted in your own execution at age 19? Skip to content Site Navigation The Atlantic. Popular Latest Newsletters. Search The Atlantic. Quick Links. Sign In Subscribe. About the Author.

TEXAS TECH UNIVERSITY

Kapan buy cocaine

Official websites use. Share sensitive information only on official, secure websites. Fax: 33 1 ; E-mails: pham. Although they have the same chemical structure, most isomers of chiral drugs exhibit marked differences in biological activities such as pharmacology, toxicology, pharmacokinetics, metabolism etc. Some mechanisms of these properties are also explained. Therefore, it is important to promote the chiral separation and analysis of racemic drugs in pharmaceutical industry as well as in clinic in order to eliminate the unwanted isomer from the preparation and to find an optimal treatment and a right therapeutic control for the patient. In this article, we review the nomenclature, pharmacology, toxicology, pharmacokinetics, metabolism etc of some usual chiral drugs as well as their mechanisms. Different techniques used for the chiral separation in pharmaceutical industry as well as in clinical analyses are also examined. Keywords: analysis, chiral drugs, chiral separation, chiral terms, enantioselective antibodies, metabolism, pharmacokinetics, pharmacology, toxicology. Chiral chemistry was discovered by Louis Pasteur, a French chemist and biologist, when he separated by hand for the first time, in , the two isomers of sodium ammonium tartrate 1 , 2. However, it needed about a century later to find that the phenomenon of chirality plays a key role not only in the life of plants and animals but also in pharmaceutical, agricultural and other chemical industries. All proteins, enzymes, amino acids, carbohydrates, nucleosides and a number of alkaloids and hormones are chiral compounds. In contrast to chiral artificial products, all natural compounds are under single enantiomeric form, for example, all natural amino acids are l-isomer levorotatory as well as all natural sugars carbohydrates are d-isomer dextrorotatory. Although they have the same chemical structure, most enantiomers of racemic drugs exhibit marked differences in biological activities such as pharmacology, toxicology, pharmacokinetics, metabolism etc. The mechanisms of chiral drugs with biological environment are now explained. Chirality is now a top-class subject for academic research as well as for pharmaceutical development. Accounting for the important role of chiral separation, the Nobel Prize in Chemistry has been awarded to three scientists: Dr. William S. Knowles and Pr. Ryori Nyori in Japan, for their development of asymmetric synthesis using chiral catalysts in the production of single enantiomer drugs or chemicals 6 , 7. Thanks to a wide range of new technologies for chiral separation, US Food and Drug Administration FDA recently recommends the assessments of each enantiomer activity for racemic drugs in body and promotes the development of new chiral drugs as single enantiomers 7. In this article, we review the nomenclature of chiral compounds, the biological activities such as pharmacology, toxicology, pharmacokinetics, metabolism etc of some usual racemic drugs in therapeutics as well as their mechanisms. The terminology used to describe different stereochemical properties is resumed as following 8 - Chirality also sometimes called stereoisomerism or enantiomerism or dissymmetry is a property of an object which is non-superimposable with its mirror image. When a molecule cannot be superimposed on its mirror image, this molecule and its image are called chiral. It is like left and right hands. The two non-superimposable mirror-image forms of chiral molecules are called enantiomers. Enantiomers are most commonly formed when a carbon atom contains four different substituents asymmetric carbon atom or stereogenic carbon or also called chiral center. A chiral molecule is a molecule having at least one asymmetric carbon. Carbon is not the only atom that can act as an asymmetric center. Sulfur, phosphorus and nitrogen can sometimes form chiral molecules such as omeprazole, cyclophosphamide and methaqualone, respectively. Chiral molecules exhibit optical activity, so enantiomers are also sometimes called optical isomers. Optical isomers or enantiomers are molecules having the same chemical formula, the same physical and chemical properties, but differing in their optical activity and their spatial arrangement. Enantiomers are now determined by their spatial arrangement 3 dimensions of substituents groups around a chiral center asymmetric carbon in the molecule. This configuration follows the Cahn-Ingold-Prelog CIP convention 11 which is used to assign priorities to substituent groups. This system is based on a set of rules for ordering the substituents attached to the asymmetric atom by using sequence rules to assign priorities. First, draw a picture so that the atom with lowest priority, for example H, seems below the plane of the picture Fig. If the counting goes in a clockwise direction, the configuration is designated as R rectus or right ; otherwise in a counter clockwise direction, it is S sinister or left. A racemate is designated as R,S. The optical activity of an enantiomer is determined by a polarimeter or by optical rotary dispersion and circular dichroism. Diastereomers are any molecules which have two or more chiral centers. A diastereomer with two chiral carbon has four isomers. Unlike enantiomers, the physical and chemical properties of diastereomers can differ and consequently, their chemical characterization is easy and their biological activities are often different. This is the basis for derivatization of enantiomers to form diastereomers in chiral separation and also for the explanation of enantiomer activities with their chiral receptors in the body. Diastereomers, enantiomers and geometric isomers form a family called stereoisomers that are molecules having the same chemical formulas but differing only with respect to the spatial arrangement. Eutomer refers to bioactive enantiomer or enantiomer having higher pharmacological activity. Its opposite is called distomer. Enantioselectivity is a property of a process whereby one enantiomer is expressed exclusively or predominantly over the other. In pharmacological terms, that means a biological structure enzyme, antibody or receptor which exhibits affinity towards one enantiomer over the other. Enantioselective assay is an analytical method capable of separating and quantifying enantiomers. In a stereoselective synthesis, one of a set of isomers is predominantly or exclusively formed whereas in a stereospecific synthesis, one isomer leads to one product while another isomer leads to the opposite product. Homochirality is the biological chirality in which all biologic compounds have the same chirality such as all amino acids are levorotary isomers. Chiral switch is a procedure used to transform an old racemic drug into its single active enantiomer. This new enantiomeric drug developed by a pharmaceutical manufacturer will receive additional patent protection and a new generic name. The body with its numerous homochiral compounds being amazingly chiral selector, will interact with each racemic drug differently and metabolize each enantiomer by a separate pathway to generate different pharmacological activity. Thus, one isomer may produce the desired therapeutic activities, while the other may be inactive or, in worst cases, produce undesired or toxic effects 9 , 12 , 13 , 15 , 25 , In pharmacology area, only racemic drugs will be examined and their activity can be divided into three main groups. The majority of racemic pharmaceuticals have one major bioactive enantiomer called eutomer , the other is inactive or less active distomer or toxic or can exert other desired or undesired pharmacological properties. The second category is intended to drugs where the two enantiomers are equally active and have the same pharmacodynamics. The last one is racemic drugs having only one eutomer, but the distomer could be transformed in body into its bioactive antipode by chiral inversion 12 - In this group, there are a number of cardiovascular drugs, agents widely used for the treatment of hypertension, heart failure, arrhythmias, and other diseases. However, it has been demonstrated that d,l- and d-propranolol can inhibit the conversion of thyroxin T4 to triiodothyronin T3 , contrary to its l-form 19 - It is to know that for a racemic drug, each enantiomer possesses its own pharmacological activities that can be null, similar, different or opposite. Many calcium channel antagonists are used under racemic form such as verapamil, nicardipine, nimodipine, nisoldipine, felodipine, mandipine etc, except diltiazem is a diastereoisomer with two pairs of enantiomers. On the other hand, verapamil has another possible application in cancer chemotherapy as a modifier of multidrug resistance. Unfortunately, for this purpose, verapamil must be used at high concentrations leading to high cardiotoxicity. Therefore, the R-enantiomer would be preferable as a modifier of multidrug resistance in cancer chemotherapy, while the S-enantiomer or the racemate would be preferable as a calcium channel blocker for cardiovascular therapy All ACE inhibitors such as captopril, benazepril, enalapril, idapril are chiral compounds under diastereoisomeric form and most of them are marketed as single isomer. Valsartan, an angiotensin II receptor antagonist, is used as a single S-enantiomer and the activity of the R-enantiomer is clearly lower than the S-enantiomer They are longtime marketed as racemate. The Food and Drug Administration recently approved a chiral switch drug, levalbuterol the pure l-isomer of albuterol as a preservative-free nebulizer solution. However, some clinical studies recently reported that it is neither safer nor more effective than a same dose of racemic albuterol. In contrast, levalbuterol may cost as much as 5 times more than its racemate 26 - In neurology and psychiatry, many pharmaceuticals used are chiral compounds and most of them are marketed as racemates. Hypnotics such as hexobarbital, secobarbital, mephobarbital, pentobarbital, thiopental, thiohexital are racemic compounds and overall, only l-isomer is hypnotic or sedative, the other is either inactive or excitative. Ketamine is an intravenous anesthetic. Isoflurane is an inhalational general anesthetic widely used in surgical operations as a racemic mixture of its two optical isomers. Methadone is a chiral synthetic compound used in therapy under racemic mixture. The list of racemic drugs with one eutomer is long. It includes anticonvulsants such as mephenytoine, ethosuximide; antiarrhythmics and local anesthetics such as propafenone, disopyramide, prilocaine, tocainide; antibiotics such as ofloxacin, moxalactam; anticoagulants such as warfarine, acenocoumarol; antihistaminics such as terfenadine, loratadine; antihyperlipidemic such as atorvastatin; psychostimulants such as amphetamine, metamphetamine; proton pump inhibitors such as omeprazole, pantoprazole, lansoprazole, etc 15 , 31 - Some of these racemates recently undergo chiral switch to single enantiomer such as levofloxacin from ofloxacin , levalbuterol from albuterol , escitazolam from citalopram , esomeprazole from omeprazole , dexketoprophen from ketoprophen , dexmethylphenidate from methylphenidate , etc. There are only some racemic drugs that could belong to this group such as cyclophosphamide antineoplastic , flecainide antiarrhythmic , fluoxetine antidepressant There are two kinds of drug chiral inversion: unidirectional and bidirectional inversion Unidirectional enzyme mediated inversion was previously described only with 2-arylpropionate nonsteroidal anti-inflammatory drugs NSAID , namely ibuprofen, ketoprofen, fenprofen, benoxaprophen, etc. For this group, only S-enantiomer is active i. For example, S-ibuprofen is over fold more potent as an inhibitor of cyclooxygenase I than R -ibuprofen. In the body, only inactive R-enantiomer can undergo chiral inversion by hepatic enzymes into the active S-enantiomer and not vice-versa 9 , Bidirectional chiral inversion or racemization should be represented by 3-hydroxy-benzodiazepines oxazepam, lorazepam, temazepam and thalidomide in which R and S enantiomer can racemize in vitro by aqueous solution. However, in vivo this phenomenon could occur with thalidomide, but not with hydroxyl-benzodiazepines because of the differences in substituents around their chiral carbon. Some authors 33 have found for the first time the difference in R- and S-oxazepam concentrations in treated rabbit serum. They explained that the chiral inversion by tautomerization of oxazepam cannot occur in vivo because each enantiomer is transported by protein albumin with different affinity. The binding affinities of the enantiomers to albumin may inhibit the attack of hydroxyl ions water and thus retard the epimerization and racemization in vivo. Therefore, R- and S-oxazepam concentrations can be found different in the serum of these treated rabbits. Thalidomide is a former racemic sedative withdrawn from the market in the s due to severe teratogenic effects phocomelia, amelia. Single thalidomide enantiomers and its derivative, N-hydroxythalidomide, were also synthetized by asymmetric technique in order to study their individual biological and chemical activities 37 , It seems that a multitude of its pharmacological activities could be due not only to the mother molecule but also to its numerous chiral and achiral metabolites. Because of this in vivo interconversion of thalidomide, it is difficult to determine exactly the pharmacological effect of each enantiomer. The main pharmacological potency observed from two isomers of some current racemic drugs is gathered in the Table 1. Since there are frequently large pharmacodynamic and pharmacokinetic differences between enantiomers, it is not surprising that enantiomers may result in stereoselective toxicity. In toxicology, the different toxic effects of chiral drugs can reside either in one enantiomer only or in both ones. The toxicological properties in a pair of enantiomers can be identical or entirely different. They can reside in the pharmacologically active enantiomer or in the inactive one 9 , 12 , 15 , 25 , 32 , 40 , Some following drugs are marketed as single enantiomer solely because their toxicities reside almost in one of their two enantiomers. Dopa or dihydroxy-3,4 phenylalanine is a precursor of dopamine that is effective in the treatment of Parkinson disease. Dopa was used under racemic form: d,l- dopa, but owing to the grave toxicity agranulocytosis of d-isomer, therefore, only levoratory form called L-Dopa is actually used in therapeutics. Tetramisole is a nematocide, first used under racemic form. Because of numerous side-effects vertigo, headache, vomiting, abdominal pain mainly due to d-isomer, therefore, only l-isomer called levamisole is now used in medicine. Actually, some racemic drugs cited in the chapter of pharmacology are transformed by chiral switch into their single active isomer because one of two isomer has side-effects and no pharmacological activity 9 , 14 , 15 , 41 , However, a number of chiral drugs are still marketed under racemic form because either their chiral separation is difficult, or their pharmacologic and toxic effects reside in the same enantiomer or their high cost production 9 , 14 , 15 , Toxicity of chiral drugs like ketamine anesthetic , penicillamine chelating agent , ethambutol antitubercular agent reside exclusively in their distomer. In the case of cyclophosphamide, its two isomers exert the same toxicity 42 , For thalidomide, theoretically, only the inactive S - -isomer is teratogenic, but practically, both isomers are genotoxic because of its in vivo interconversion and of its species-dependence 42 , Tests with mice in suggested that only one enantiomer was teratogenic while the other possessed the therapeutic activity. Unfortunately, subsequent test with rabbits showed that both enantiomers had both teratogenicity. However, attempts to formulate the R-isomer have not solved the problem of teratogenicity, as the two isomers are readily interconvertible in vivo 14 , Moreover, toxicity of thalidomide could be due to its numerous chiral and achiral metabolites of which pharmacological and toxicological studies remain very scarce. The processes of absorption, distribution, elimination and metabolism are crucial determinants of drug action and can assume equal relevance to the actual biological effect of the drug at its receptor site. The potential for discrimination between enantiomers at each of these stages is therefore important and emphasizes the need for stereo-pharmacokinetic studies and stereospecific drug assays Indeed, numerous studies have demonstrated that stereoisomers of a chiral drug often exhibited pronounced differences in their pharmacokinetic and metabolic profiles both quantitatively and qualitatively 45 - According to Mehvar et al. The absorption of chiral antiarrhythmics appears to be nonstereoselective. However, their distribution, metabolism and renal excretion usually favour one enantiomer versus the other. In terms of distribution, plasma protein binding is stereoselective for most of these drugs, resulting in up to two-fold differences between the enantiomers in their unbound fractions in plasma and volume of distribution. Hepatic metabolism plays a significant role in the elimination of these antiarrhythmics. Additionally, in most cases, significant stereoselectivity is observed in different pathways of metabolism of these drugs. Therefore, it is not surprising that a wide interindividual variability exists in the metabolism of these drugs. Overall, substantial stereoselectivity has been observed in both the pharmacokinetics and pharmacodynamics of chiral antiarrhythmic agents. Because the effects of these drugs are related to their plasma concentrations, this information is of special clinical relevance Plasma concentrations of these d and l-enantiomers usually differ significantly and in wide ranges when the racemic mixture is administered orally or intravenously. However, the relative magnitude of the concentrations of the enantiomers in plasma is not constant in all situations and varies from drug to drug. Further, various factors related to the drug e. Methadone is mainly metabolized by hepatic cytochrome P 3A4 and secondary by P 2D6 to a major methadone metabolite, EDDP, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine. In human urine, EDDP levels were always higher about 1. An understanding of the stereospecific pharmacokinetics of all chiral drugs may help clinicians to interpret and predict differences among patients in pharmacologic responses to the racemic drugs and to adjust their dosage for each patient. As many target organs can distinguish the two enantiomers of a chiral drug, it is not surprising that the immune system may recognize them in the same manner by producing selectively and specifically each corresponding enantiomer antibody. Such enantioselective antibody can distinguish even minor differences in composition or configuration of a chiral drug. As drugs are small molecules called haptens, they need to be conjugated to a support or to a carrier molecule protein by forming an immunogen so that the immune system B cells could produce corresponding antibody 54 , The conjugation of a hapten such as an enantiomer with a protein is a delicate and difficult step of the immunogen preparation. The specificity and sensitivity of an antibody against an enantiomer drug mainly depends on the hapten preparation and the conjugation technique. According to Sahui-Gnassi et al. In the literature, some enantioselective antibodies have been successfully used to separate enantiomers, such as antibodies to propranolol enantiomers 56 methadone enantiomers 58 amphetamine enantiomers 55 warfarin enantiomers 55 etc. However, they are still scarce in comparison with numerous antibodies to achiral drugs. The application of enantioselective antibodies to chiral drugs plays a key role in biochemistry. They can be used as a specific reagent not only for immunoassays such as radioimmunoassay 55 enzymatic immunoassay 57 but also for histologic immunoassay, immunoaffinity chromatography, immunoextraction of chiral drugs, liquid chromatography using antibodies as chiral selectors, etc. These immunoassays can be applied to pharmacokinetics, drug therapeutic monitoring, toxicological diagnostic, drug pharmacological assessment, identification of drug fixed on target organ, etc. The enantiomers of a chiral drug may vary in their interactions with chiral environments such as enzymes, proteins, receptors, etc of the body. These variations may lead to differences in biological activities such as pharmacology, pharmacokinetics, metabolism, toxicity, immune response etc. Indeed, biological systems can recognize the two enantiomers as two different substances, and their interaction each other will therefore elicit different responses. But, why do enantiomers have different biological activities? The reason for chiral recognition by drug receptors is a three-point interaction of the drug with the receptor site proposed by Easson and Stedman 44 , 47 , The difference between two enantiomers of a drug with its receptor is illustrated in Figure 2 published by McConathy and Owens 47 using a hypothetical interaction between a chiral drug and its chiral binding site In this case, one enantiomer is biologically active while the other enantiomer is not. The substituents of the active enantiomer drug labeled A, B, and C must interact with the corresponding regions of the binding site labeled a, b, and c of the receptor in order to have an alignment Aa, Bb, Cc. In this case, this fitting interaction can produce an active biological effect. In contrast, the inactive enantiomer cannot bind in the same way with its receptor when it rotates in space, consequently, there is no active response 44 , To resume this hypothesis, the attachment of an enantiomer to the chiral receptor is similar to a hand fitting into a glove or to a key into a lock. Indeed, a right hand can only fit into a right hand glove, so a particular enantiomer can only fit into a receptor site having the complimentary shape. The other enantiomer will not fit, like a right hand in a left glove, but may fit into a receptor site elsewhere in the body and cause an eventual unwanted or toxic effect. On the other hand, enantiomers can show different chemical behaviour due to different chiral discrimination by diastereomeric formations with a chiral environment 9 , 12 , 44 , 47 , Easson-Stedman hypothetical interaction between the two enantiomers of a racemic drug with a receptor at the drug binding sites. The three substituents A, B, C of the active enantiomer left can interact with three binding sites a, b, c of a receptor by forming three contacts Aa, Bb and Cc, whereas the inactive enantiomer right cannot because the contact is insufficient. Note: This figure is in the publication of McConalthy and Owens Chiral separation, also called chiral resolution, is a procedure used to separe the two isomers of a racemic compound in pharmaceutical industry as well as in clinical analysis. Various methodologies used for chiral separation on both analytical and preparative scales will be described below. During chemical synthesis, many drugs obtained can be racemized in situ by a variety of chemical reactions, even the procedure used has started with pure enantiomeric reagents. In industry, two main categories of techniques are often applied for chiral resolution: the classical methods and the modern technologies 60 , For the classical approach, the most widely used technique is the resolution by diastereomeric salt formation. In this strategy, an acid-base reaction is involved between a racemic drug and a pure single enantiomer called resolving agent. This reaction leads to the formation of two diastereomeric salts that now have different physical and chemical properties. These two diastereomers obtained can be easily separated either by crystallization or by filtration if one is soluble and the other is insoluble. Finally, the salt is decomposed by treatment with either acid or base, then the pure enantiomer is obtained 44 , The two diastereomers formed can also be separated by classical achiral liquid chromatography. This method has been used in the resolution of -methyl-L-dopa, asparagine and glutamic acid Another classical approach is the enzymatic or kinetic resolution. In this methodology, resolution is achieved by means of biochemical process that destroys one enantiomeric form. Certain microorganisms such as yeasts, molds, bacteria can only degrade one of two isomers of a racemate by enzymatic assimilation, the other which is not digested remains in solution, then it is isolated 60 , Enzymatic resolution has been used in the preparation of lotrafiban benzodiazepine , levofoxacin antibacterial drug , and S-naproxen antiinflammatory drug For the modern technologies, preparative high-performance liquid chromatography HPLC is the method of choice for the enantiomer separation. Chiral HPLC has proven to be one of the best methods for the direct separation and analysis of enantiomers. In chromatographic methods, two techniques are used: indirect and direct. The indirect HPLC involves derivatization of samples with a chiral derivatization reagent i. This indirect HPLC method is rarely used in industry, but frequently performed in biological analysis because of its high sensitivity. The last technique is rarely used in industry because of its high cost and low efficiency. Direct chiral separations using CSPs are more widely used and are more predictable, in mechanistic terms, than those using chiral additives in the mobile phase. Among a hundred HPLC CSPs commercially available, only some types of chiral sorbents following are presently the most widely used for preparative HPLC in industry: carbohydrate cellulose, amylose , polyacrilamide, diallyltartardiamide, Pirkle phases, chirobiotic phases vancomycin, teicoplanin However, there is no single CSP that can be considered universal, i. Choosing the right column for the enantioseparation of a racemic compound is difficult. The decision relies mostly on empirical data and experience However, the understanding of the recogntion mechanisms of chiral selectors with enantiomers can help the chromatographists to resolve some problems of resolution and to economize time-consuming. According to Aboun-Enein and Ali 60 all chiral selectors provide a chiral surface to enantiomers, which form with the selectors temporary complexes, having different bonding energies. The enantiomers differ in their binding energies because they fit differently into the chiral selector structures. Consequently, the two enantiomers can be eluted at different times by the mobile phase and then separately collected. Brieftly, in general, the recognition mechanism on a chiral selector is based on a key-and-lock arrangement However, many other factors such as mobile phase composition pH, electrolytes, solvent nature , size and length of column, temperature etc also play a key role for chiral resolution. As reported by Burke and Henderson 44 the basic concept of SMB technology is the continuous countercurrent movement of stationary and mobile phases in which the movement of a stationary phase is simulated. The small particles in this component are packed into single columns and connected to form a circle. Four external valves allow the addition and subtraction of feed and effluent. The mobile phase is pumped through the circle and when it passes the stationary phase a slight separation occurs, the less absorbable compound running in front and the more absorbable compound staying behind. When steady state is reached, the system can be operated continuously. If all flow rates and the shift time are determined correctly, raffinate and extract fractions can be withdrawn in high purity 44 , An example of a pharmaceutical compound separated by SMB chromatography is tramadol The scheme of the SMB chromatography is described in the article of Johannsen et al The SMB procedure allows to reduce solvent consumption, and consequently may lower the production cost. To avoid the racemization in situ during chiral drug preparation, an asymmetry synthesis using chiral catalysts has been developed by W. Knowles, R. Noyori and K. Sharpless, the Nobel Prize in chemistry 6 , Most of the available asymmetric chemical catalysts are organometal types including transition metals such as titanium, and noble metals such as osmium, palladium, and rhodium. Chiral catalysts are like enzymes in that both have a high degree of specificity. They allow stereospecific reactions to take place and therefore avoid the formation of racemates. Chiral chemical catalysts are hardier than enzymes, and tolerate higher temperatures. However, the use of chiral chemical catalysts is usually costly. L-Dopa anti-Parkinson agent , naproxen anti-inflammatory drug are some examples of single enantiomer drugs produced by this catalytic asymmetric synthesis 24 , 66 , The analyses of chiral drugs in biological fluids are much more difficult than their quantifications and separations in industry although they can use the same physical techniques. The extraction of drugs and toxics in biological matrices for physical chemical analysis HPLC, GC, MS , a key step of bioanalysis, is used to clean the samples by removing proteins and other interfering biological compounds before analysis. For the extraction of a pair of enantiomer drug from biological samples, two techniques are used: liquid-liquid extraction and solid-phase extraction SPE. For the first technique, the choice of extraction solvent depends on the polarity of the chiral drug. In most cases, a buffer with pH is usually added into the sample before solvent extraction in order to liberate drug from protein. As the two enantiomers have the same chemical and physical properties, in general, the recoveries of two enantiomers are the same for the control samples. The classical liquid extraction is in general time-consuming, but it is cheaper and sometimes it can give high recovery and clean extract. However, some new liquid-phase microextraction techniques recently cited in the literature seem simple and rapid For the solid-phase extraction technique, two kind of sorbents are used: classical reversed-phase silica-bonded with C18 and recent polymeric sorbent. The last extraction technique with polymeric sorbent showed a great advantage about recovery and universal use in comparison with classical reversed-phase cartridge as He et al 69 have recently published. For the bioanalysis of racemic drugs, two kinds of analytical methods have been developed: the physical methods and the enantioselective immunoassays. Chiral analysis by physical methods. In the first group, chiral chromatography including high performance liquid chromatography HPLC , gas chromatography GC , supercritical fluid chromatography SFC and capillary electrophoresis CE is most readily accomplished for the enantiomer resolution. HPLC is the most widely used of the four methods. As in industry, two HPLC techniques are used: indirect and direct. In contrast to industry, the indirect HPLC using chiral derivatization reagent with the formation of two diastereomers is frequently performed in bioanalysis because of its high sensitivity. However, this indirect technique requires a functional group in the analyte drug e. A chiral derivating reagent a pure single enantiomer added in the sample will react with these functions to form two diastereomers that can be separated by a classical reversed-phase column C18 or C8 Because of the limitation of the indirect HPLC, direct chiral separations using chiral stationary phases CSPs are the most used because of its simplicity and its rapidity. Today, nearly a hundred CSPs have been developed and are recently marketed, but some types of chiral HPLC columns following are the most used in bioanalysis: cyclodextrine and its derivatives, carbohydrate cellulose, amylose , Pirkle phases, chirobiotic phases. Antibiotics or chirobiotic phases such as vancomycin-CSP or eremomycin-CSP can also separate thalidomide and amino acids, respectively 76 , Liquid chromatography-mass spectrometry LC-MS , gas chromatography-mass spectrometry GC-MS and capillary electrophoresis CE are other physical methods for the separation of numerous chiral pharmaceuticals 79 - Unfortunately, until today, there is no single CSP that can resolve all classes of racemic compounds in bioanalysis, contrary to achiral reversed- phase C18 or C8. The choice of a chiral column is in general examined on the interaction mechanism between CSP and chiral analyte Enantioselective immunoassays. In contrast to physical methods, immunoassays do not require a preliminary extraction of biosample before analysis. Some techniques such as radioimmunoassays or enzymo-immunoassays ELISA used for the determination of some enantiomer drugs propranolol, methadone, amphetamine, warfarin, atropine, pentobarbital were developed, but still on experimental scale 55 - In recent years, as patent on a successful drug nears expiration, pharmaceutical manufacturers have sometimes marketed a single stereoisomer of the old racemic drug as a new drug chiral switch , often with claims of greater activity, less toxicity or both. Many currently marketed drugs are racemic mixtures of stereoisomers. They may be enantiomers, which are non-superimposable mirror images, or geometric isomers, which are not mirror images, but in either case stereoisomers can differ markedly from each other in bioactivity and pharmacokinetics. The FDA now requires manufacturers to identify and characterize each individual isomer of a new racemic mixture. However, the differences between stereoisomers may not be clinically significant. The levofloxacin, S - isomer of ofloxacin, has an important clinical advantage over racemic ofloxacin, but for some other stereoisomers marketed recently as the patent was expiring on the original racemic mixture such as esomeprazole, levalbuterol, dexmethylphenidate and escitalopram , no such advantage has been clinically demonstrated. Accounting for the growing development of chiral drugs as racemate and single enantiomer worldwide, it is primordial to promote the chiral separation and its development because this operation plays a key role not only in pharmaceutical industry but also in clinical therapeutics. Nowadays, many drugs are still used as racemates with their side-effects, this problem is probably due not only to the difficulty in chiral separation technique but also to the production costs. If a new separation method for chiral drugs will be developed with its large application scale and low cost, the number of racemic drugs could diminish significantly. The direct production of a single drug enantiomer by asymmetric synthesis is useful when its other antipode is found toxic or entirely inactive. However, for the drug discovery process, the obtention of a racemate could give triple informations about the drug to be explored i. Theoretically, the use of a single isomer is ideal, but practically, the decision must be taken after long clinical observation between racemate and single enantiomer actions. In some therapeutic cases, the use of a racemate is more helpful than that of each single isomer because of the complementary effects of each other. Therefore, preparative and analytical HPLC are very useful at the experimental step of drug discovery and also are an invaluable tool for the searcher. The ultimate choice of the separation technique either physical or chemical depends on the nature of each drug to be produced and also on the quantity, the time and the cost of the production. Our body is a great factory of chiral selectors, and could well distinguish the stereoform of a chiral drug, we can ask if it is interesting to transform some old achiral drug into its chiral derivative in order to discover some unexpected pharmacological effect. Thalidomide is a chiral drug with a multitude of pharmacological activities, maybe some of them could be given by one or more of its numerous chiral metabolites. In clinical therapeutics, the use of a chiral assay is still not universally performed. Use of a non-stereoselective determination for a drug administered as a racemate may result in erroneous therapeutic interpretation. For example, for the same dosage of a racemic drug administered to two patients, a non-chiral assay can give the same racemate concentrations for both patients. But, the ratio of the active form and the inactive one can differ in two patients and thanks to the last results, the physician can correctly interpret the difference in clinical observation between them. Therefore, it is important to promote the automatization of some chiral techniques used in clinic such as chiral HPLC and enantioselective immunoassays. It is also helpful to inform their utility to doctors and pharmacists. Besides, drug dictionary and pharmacopeia have to mention the chiral form of a drug i. These informations will be a precious guide for all healthcare professionals. The chiral separation of racemic drugs is a necessary operation in pharmaceutical industry as well as in clinical therapeutics. Therefore, the development of new chiral separation techniques is and will be a topic subject in academic research as well as in industrial advance. However, the use of a single isomer must be seriously taken after long clinical assessments between racemate and single enantiomer actions because in some cases, racemates have more therapeutic advantages than single isomers. It is also important to give more informations about chiral drugs especially racemic form to healthcare professionals in order to help them for finding an optimal treatment and a right therapeutic control. As a library, NLM provides access to scientific literature. Int J Biomed Sci. Find articles by Lien Ai Nguyen. Find articles by Hua He. Find articles by Chuong Pham-Huy. Licensee Master Publishing Group. Open in a new tab. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel. Calcium channel antagonists: verapamil, nicardipine, nimodipine, nisoldipine, felodipine, mandipine etc,. Hypnotics, Sedatives: hexobarbital, secobarbital, mephobarbital, pentobarbital, thiopental, thiohexital. Tranquilizers: 3-hydroxy-benzodiazepines: oxazepam, lorazepam, temazepam.

Kapan buy cocaine