Tesi sul tema "Pseudoephedrine"

Pseudoephedrine is an over-the-counter drug commonly used as a decongestant, but also thought to have ergogenic effects. The World Anti-Doping Agency (WADA) has prohibited large doses (> 150 μg∙ml-1) of pseudoephedrine, while the National College Athletic Association (NCAA) does not include it on the banned substance list. The purpose of this study was to examine the effect of body weight dosing of pseudoephedrine on 800-m run times of NCAA female runners. Fifteen NCAA female track runners volunteered to participate in the randomized, double blind, crossover design. In trials that were a week apart, participants were given both 2.5 mg∙kg-1 pseudoephedrine and a placebo. Ninety minutes post-ingestion, participants completed an 800-m individual time trial on an indoor track. Finishing time was recorded with an automated video timing device. Heart rate and anxiety state scores were recorded immediately after each trial. Finally, a urine sample was taken from 5 participants about 2 hr post-ingestion. Placebo and pseudoephedrine running times were compared using a iv paired t test. Heart rate and anxiety state scores were also compared using a paired t test. Fourteen runners completed both trials and one was an outlier, giving thirteen participants used for statistical analysis. Despite being dosed (144 mg ± 17 mg) well above normal therapeutic levels, there was no significant difference (p = 0.92) in 800-m times between the placebo (2:39.4 ± 9.6) and pseudoephedrine (2:39.4 ± 9.6) trials, in post-exercise heart rate (p = 0.635, pseudoephedrine = 177.9 ± 14.5 beats∙min-1, placebo = 178.4 ± 18.5 beats∙min-1), or in anxiety state levels (p = 0.650, pseudoephedrine = 38.4 ± 11.6, placebo = 38.1 ± 8.8). A 2.5 mg∙kg-1 dose of pseudoephedrine had no effect on 800-m run times in NCAA female runners, and did not raise urine levels above 150 μg∙ml-1. This raises the question as to why pseudoephedrine is a specified prohibited substance by WADA. (49 pages)

This research evaluates the ability of gas chromatography mass spectrometry (GCMS), isotope ratio mass spectrometry (IRMS) and inductively coupled plasma mass spectrometry (ICPMS) to characterize methylamphetamine hydrochloride synthesised from precursors extracted from proprietary cold medication using three different extraction solvents. Two clandestine routes were utilized in the synthetic phase of the research, (i) Moscow route and (ii) Hypophoshorous route (Hypo). Repetitive batches of samples were prepared and analysed by each analytical technique to provide a robust sample set for data interpretation. Organic impurity analysis was undertaken using a developed and validated GCMS impurity profiling method. The GCMS method discriminated the samples by synthetic route based on the presence of specific target impurities. Carbon, nitrogen and hydrogen stable isotope ratios facilitated the differentiation of samples by route, and precursor source with nitrogen and hydrogen isotopes providing the best results. Inorganic impurities present in the samples were analysed using inductively coupled plasma mass spectrometry (ICPMS). This technique provided meaningful discrimination according to the route and precursor utilized in the synthetic phase. Pattern recognition techniques were applied to the generated data (raw and pre processed) from each of the analytical technique both individually and in combination. Pearson's correlation coefficient, hierarchical cluster analysis, principal component analysis and artificial neural networks (self organizing feature maps) were used to investigate the separation of samples to the individual routes and precursor extracted from the individual solvent systems. The mathematical tools demonstrated that methylamphetamine profiling linking precursors sourced from proprietary grade materials extracted from different solvent systems and synthetic route employed was achievable.

Pseudoephedrine is well established as a chiral auxiliary in the alkylation of amide enolates to form tertiary and quaternary carbon stereocenters. However, due to its facile transformation into the illegal narcotic methamphetamine, pseudoephedrine is either illegal or highly regulated in many countries, which limits its use in academic and industrial settings. To address this issue, pseudoephenamine has been developed as a replacement for pseudoephedrine in organic synthesis. This new auxiliary suffers no regulatory issues and exhibits several practical advantages over pseudoephedrine, including the high diastereoselectivities observed in alkylation reactions forming quaternary carbon stereocenters, the propensity for pseudoephenamine amides to be free-flowing crystalline solids, and the sharp, well-defined peaks that typically compose the 1H NMR spectra of these amides.
Chemistry and Chemical Biology

This thesis conducts a multi-level policy transfer analysis of a governmental response to the problem of pseudoephedrine diversion. Pseudoephedrine is an active ingredient in over-the counter cold and flu medication available from pharmacists and also acts as a precursor chemical in the illicit production of Amphetamine-Type-Stimulants (ATS). ATS are synthetically produced psychotropic drugs that are subject to international and national controls on their production, supply and use. Throughout the late 1990s and mid 2000s there was a large increase in the rates of use and production of ATS in Australia. Between the years of 2001-2005, clandestine production of ATS was particularly pronounced in Queensland where the laboratory detections outnumbered all other states in Australia combined. Over 90% of clandestine laboratories detected in Australia relied upon the diversion of pseudoephedrine from legitimate pharmaceutical products. In 2006, in response to the increased diversion of pseudoephedrine from pharmacies into the illicit drug manufacturing market and as a means for pharmacists to fulfil their record-keeping regulatory obligations, the Pharmacy Guild of Australia developed Project STOP. Project STOP is a tool that assists pharmacists in making an informed decision regarding the supply of products that contain pseudoephedrine. It is supported by a legislative framework that requires a driver’s licence number to be entered into an electronic database for the purchasing history of the customer to be reviewed before a decision regarding supply is made. Following its initial implementation in Queensland, Project STOP was subsequently transferred to all other jurisdictions in Australia as part of a national rollout. This thesis conducts an analysis of the transfer of Project STOP as a governmental response to the problem of pseudoephedrine diversion. It presents three levels of analysis to provide a comprehensive understanding of the conditions of possibility for the development of Project STOP; an assessment of how it came to be identified as the national solution to the problem of pseudoephedrine; and, how Project STOP works in the applied domain following its transfer. It concludes by outlining the broader implications of this study for policy transfer.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Criminology and Criminal Justice
Arts, Education and Law
Full Text

R-phenylacetylcarbinol (PAC) is used as a precursor for production of ephedrine and pseudoephedrine, which are anti-asthmatics and nasal decongestants. PAC is produced from benzaldehyde and pyruvate mediated by pyruvate decarboxylase (PDC). A strain of Rhizopus javanicus was evaluated for its production of PDC. The morphology of R. javanicus was influenced by the degree of aeration/agitation. A relatively high specific PDC activity (328 U decarboxylase g-1 mycelium) was achieved when aeration/agitation were reduced significantly in the latter stages of cultivation. The stability of partially purified PDC and crude extract from R. javanicus were evaluated by examining the enzyme deactivation kinetic in various conditions. R. javanicus PDC was less stable than Candida utilis PDC currently used in our group. A kinetic model for the deactivation of partially purified PDC extracted from C. utilis by benzaldehyde (0?00 mM) in 2.5 M MOPS buffer has been developed. An initial lag period prior to deactivation was found to occur, with first order dependencies of PDC deactivation on exposure time and on benzaldehyde concentration. A mathematical model for the enzymatic biotransformation of PAC and its associated by-products has been developed using a schematic method devised by King and Altman (1956) for deriving the rate equations. The rate equations for substrates, product and by-products have been derived from the patterns for yeast PDC and combined with a deactivation model for PDC from C. utilis. Initial rate and biotransformation studies were applied to refine and validate a mathematical model for PAC production. The rate of PAC formation was directly proportional to the enzyme activity level up to 5.0 U carboligase ml-1. Michaelis-Menten kinetics were determined for the effect of pyruvate concentration on the reaction rate. The effect of benzaldehyde on the rate of PAC production followed the sigmoidal shape of the Monod-Wyman-Changeux (MWC) model. The biotransformation model, which also included a term for PDC inactivation by benzaldehyde, was used to determine the overall rate constants for the formation of PAC, acetaldehyde and acetoin. Implementation of digital pH control for PAC production in a well-stirred organic-aqueous two-phase biotransformation system with 20 mM MOPS and 2.5 M dipropylene glycol (DPG) in aqueous phase resulted in similar level of PAC production [1.01 M (151 g l-1) in an organic phase and 115 mM (17.2 g l-1) in an aqueous phase after 47 h] to the system with a more expensive 2.5 M MOPS buffer.

A successful supercritical fluid extraction method includes removal of the analyte from the matrix into the bulk fluid as well as trapping or concentration of the analyte prior to analysis. In the first phase of this research, the trapping capacities of three solid-phase traps (glass beads, 50/50 (w/w) glass beads/octadecylsilica), 50/50 (w/w) Porapak Q®/glass beads) were determined as a function of trap composition for a mixture of components varying in polarity and volatility. The Porapak Q®/glass beads mixture was found to be the most successful solidphase investigated exhibiting the highest trapping capacity. The use of the Porapak Q®/glass beads as a solid-phase trap was investigated in later extraction studies in this dissertation. The extraction of highly polar, multifunctional analytes may not be completely successful with modified carbon dioxide, therefore, a secondary modifier (i.e. additive) may be added directly to the extraction fluid in hopes of improving the recoveries. In the second phase of this research, the effect of secondary modifiers in the subcritical fluid extraction of lovastatin from in-house prepared tablet powder mixtures and MEVACOR® tablets was investigated. The effect of in-line methanol-modifier percentage, additive type (acidic, basic, neutral) to the in-line methanol, and additive concentration on the extraction efficiency were examined. The extraction recoveries of lovastatin from MEVACOR® tablets were shown to be highly dependent on methanol concentration and additive type. Isopropylamine was shown to be the most successful additive investigated. An optimized and reproducible extraction method was developed. The extraction of ionic compounds with carbon dioxide may be difficult due to the high polarity of the compounds. In the third phase of this research, the addition of ion-pairing additives to the matrix in hopes of forming an ion-pair complex of reduced analyte polarity was investigated. Therefore, a screening study consisting of a fractional-factorial design was performed in order to identify the factors which contribute most to the recovery of an anionic species, triphenylphosphinetrisulfonate (TPPTS), from a spiked-sand surface employing supercritical fluid extraction with carbon dioxide. The experimental parameters investigated were: type of ion-pairing additive (i.e. tetralkylammonium hydrogen sulfates) and its concentration, carbon dioxide density, extraction temperature, static extraction time, CO₂ mass used, liquid CO₂ flow rate, and the volume of methanol spiked into the matrix prior to extraction. Of the eight factors investigated, four factors were identified as significantly affecting the recovery of the anionic species. They were: 1) ion-pairing reagent added to the spiked sand surface and its concentration; 2) static extraction time; and 3) volume of methanol present in the extraction vessel. The experimental parameters and settings identified as influential by the statistical approach were later shown in concert to yield 100% recovery of TPPTS from the spiked-sand. In the fourth phase, the extraction of a cationic species, pseudoephedrine hydrochloride, from spiked-sand and Suphedrine tablets, with pure and methanol-modified CO₂ was examined. Once the extraction was shown to feasible, several strategies were compared in terms of their effectiveness in enhancing the analyte's extractability. The first strategy involved the addition of ion-pairing additives. Several sodium salts of alkylsulfonic acids varying in lipophilicity and concentration were investigated. The addition of 1-heptanesulfonic acid, sodium salt, in methanol, in a 5:1 mole ratio of reagent to analyte was shown to be the most useful in recovering the drug from the spiked-sand. The second strategy considered the influence of acids and bases and other modifier compositions such as a methanol/water mixture with or without 1-heptanesulfonic acid, sodium salt, on the pseudoephedrine recovery. The recoveries obtained from the drug spiked-sand were shown to comparable in the presence of a methanol/water solution, a tetrabutylammonium hydroxide in methanol solution, and a methanol solution with 1-heptanesulfonic acid, sodium salt. Next the extraction of pseudoephedrine hydrochloride from Suphedrine tablets was performed with pure and modified CO₂. Similar to the sand-spike studies, the effect of the addition of the ion-pairing reagent and other in-cell modifiers were examined. Once again, the recoveries obtained when the matrix was in the presence of a methanol/water mixture and a methanol solution containing 1-heptanesulfonic acid, sodium salt were similar. Finally, the identity of the extracted analyte was determined via IR analyses, and it was shown that pseudoephedrine hydrochloride was indeed extractable from the tablets with in-line modified CO₂ in the absence of any in-cell modifier. In the last phase of this research, a supercritical fluid chromatographic separation with evaporative light scattering detection was developed for the separation of five phospholipids varying in polarity and ionic characteristics. Several parameters were investigated and shown to be influential in the separation. They were: 1) stationary phase composition, 2) addition of an acidic additive and its concentration, 3) mobile phase ramp rate, and 4) column outlet pressure.
Ph. D.

Conselho Nacional de Desenvolvimento Científico e Tecnológico
Ebastine is a second generation antihistaminic clinically used for the treatment of allergic rhinitis and chronic urticaria. Pseudoephedrine hydrochloride is a direct- and indirectacting sympathomimetic, commonly combined with other drugs for their decongestant effect. In Brazil, this drugs association is available in capsules. In the literature, as well as in the official compendium, there are no methods for simultaneous analysis of ebastine and pseudoephedrine hydrochloride in pharmaceutical formulations. In the present work, liquid chromatography (HPLC) and derivative spectrophotometry (UVD) methods were developed and validated for quantification of this drugs association, in capsules. The HPLC analysis were performed on a C18 column, using a mobile phase composed of methanol: acetonitrile: ammonium acetate buffer pH 6.8 (85:5:15, v/v), run at a flow rate of 1,0 mL.min-1, with UV detection at 254 nm. In the UVD method, ebastine was quantified in the first derivative (dA/dλ), at 263.5 and 252.8 nm, respectively. All of them were validated in the following parameters: linearity, precision and accuracy. The specificity was evaluated in the HPLC assay by stress testing. The methods showed good linarity (r>0.99), precision (RSD<2%) and accuracy; the results, statistically compared, did not show significant difference (p>0,05).
A ebastina é um fármaco anti-histamínico de segunda geração utilizado clinicamente no tratamento da rinite alérgica e urticária crônica. O cloridrato de pseudoefedrina é um agente simpaticomimético de ação direta e indireta, muito utilizado em associação com outros fármacos pelo seu efeito descongestionante. No mercado brasileiro, encontra-se a associação desses dois fármacos disponível na forma de cápsulas. Na literatura, bem como em compêndios oficiais, não são descritos métodos para análise simultânea de ebastina e cloridrato de pseudoefedrina em formulações farmacêuticas. No presente trabalho, métodos por cromatografia líquida de alta eficiência (CLAE) e por espectrofotometria derivada (UVD) foram desenvolvidos e validados para quantificação simultânea desses fármacos, em cápsulas. As análises por CLAE foram realizadas em coluna C18, utilizando fase móvel composta de metanol: acetonitrila: tampão acetato de amônio pH 6,8 (80:5:15, v/v), eluída isocraticamente a 1,0 mL.min-1, com detecção UV em 254 nm. No método por UVD, a ebastina e o cloridrato de pseudoefedrina foram quantificados na primeira derivada (dA/dλ), em 263,5 e 252,8 nm, respectivamente. Ambos os métodos foram validados frente aos parâmetros de linearidade, precisão e exatidão. A especificidade do método por CLAE foi avaliada através do teste de estresse. Os métodos mostraram boa linearidade (r>0,99), precisão (DPR<2%) e exatidão. Os resultados obtidos por CLAE e UVD foram comparados estatisticamente e não apresentaram diferença significativa (p>0,05).

Pseudoephedrine is a mild stimulant which partially mimics the action of noradrenaline and adrenaline. Recently, pseudoephedrine has been removed from the World Anti Doping Agency (WADA) prohibited substances list. This occurred despite limited research in regards to its effects on sporting performance, and no studies on prolonged exercise performance (>2hrs). There is some evidence to suggest pseudoephedrine may have an ergogenic effect at dosages exceeding therapeutic levels, possibly by masking fatigue. This study investigated the possible ergogenic effects of pseudoephedrine on endurance cycling performance. Using a double blind, randomised cross over design, eight well-trained cyclists (VO2max 69 ± 2 ml×kg-1) performed two self- paced performance time trials at least 6 days apart. Ninety minutes prior to the trial, subjects consumed either placebo or pseudoephedrine (2.5 mg×kg-1) capsules. Diet and exercise were controlled for 48 hrs prior to each trial. The time trial required completion of a set amount of work, equivalent to riding at two and half hours at a power output calculated to elicit 70% VO2 max. Power output was measured using a Powertap system (Cycle Ops Power, Saris Cycling Group, USA). Venous blood samples were collected prior to capsule ingestion, just before starting the trial, and at every 20% increment in completed work until completion and were analysed for glucose and lactate. Heart rate was recorded throughout the trial. There was no significant effect of pseudoephedrine on average performance (p=0.235). Heart rate was significantly higher with pseudoephedrine consumption compared to placebo (p<0.05), but there was no significant difference in glucose or lactate between trials. Pseudoephedrine does not significantly improve self-paced endurance cycling performance, though the individual response was variable. However, exercising heart rate was significantly higher during exercise after ingestion of the stimulant.

Background: Pseudoephedrine (PSE) is a mild central nervous system stimulant that when consumed at a high dosage has the potential to alter physiological and psychophysical responses. PSE is widely accessible as over-the-counter medication and despite limited research into PSE at high dosages or its effects on prolonged exercise (>2 hours) is no-longer on the World Anti-Doping Association’s banned substance list. Currently unrestricted in sport and with no real understanding of the abovementioned responses during endurance exercise there is a high potential for abuse in sport. A recent study performed in our laboratory found PSE to improve self-paced cycling performance in some individuals, however no physiological measurements were taken Purpose: The primary purpose of this study was to determine the physiological effects of PSE at a dosage previously shown to improve performance (2.5 mg/kg) in some individuals during prolonged cycling. A secondary purpose of this study was to assess the effect on endurance cycling performance. Methods: In a randomized, double-blind and counter-balanced design, ten welltrained cyclists participated in two trials, consisting of 120 min of fixed-intensity cycling at 65% VO2max followed by a set work, self-paced time-trial (TT) of ~30 min, following ingestion of either 2.5 mg/kg PSE or visual-matched glucose placebo. Venous blood samples were collected before and during exercise, along with body temperatures and heart rate. Perceived effort and expired gas samples were collected during exercise. Exercise and diet was controlled ~48-hours prior to the trials. Results: Mean heart rate was significantly higher with PSE (P = 0.028) during fixed-intensity exercise. Blood glucose concentrations were significantly lower with PSE (P <0.001) for the first 40 min of fixed-intensity exercise. Respiratory exchange ratio was lower in the final 20-min of fixed-intensity and TT with PSE. Blood lactate, perceived effort, ventilation, and body temperatures were not significantly different between conditions during exercise, nor was TT performance; however individual response was variable. Conclusions: PSE ingestion increased heart rate during endurance cycling and initially suppressed carbohydrate release into the bloodstream while increasing fat oxidation in the later stages of exercise. Despite individual responses, endurance cycling performance remained unchanged with PSE ingestion.

O Brasil ocupa posição de destaque no consumo mundial de anfetaminas, contrariamente à tendência mundial de retração. Devido aos efeitos colaterais e ao alto potencial de abuso, a produção e comercialização de anfetaminas vêm sendo controladas no mundo inteiro. Com a restrição de uso, houve um retorno a procura pelos equivalentes naturais, especialmente as efedrinas presentes em diversas especialidades farmacêuticas, utilizadas no tratamento de doenças respiratórias. São componentes de vários compostos emagrecedores, suplementos alimentares e dietéticos utilizados para perda de peso e ganho de massa muscular. Face ao uso indiscriminado e a grande incidência de resultados falso-positivos nos testes de triagem para anfetaminas por imunoensaio enzimático homogêneo, fazem-se necessários testes confirmatórios. Neste sentido, este trabalho se propôs a desenvolver um método confirmatório simples e rápido para detecção, identificação e quantificação de efedrinas (efedrina/pseudoefedrina) em amostras de urina por por cromatografia a gás / espectrometria de massas-massas (CG/EM/EM), passível de ser adotado na rotina de laboratórios de análises toxicológicas. Devido à complexidade da matriz e as peculiaridades do analito, inicialmente procedeu-se o estudo do tratamento da amostra, considerando as etapas de derivatização, extração, pré-concentração e purificação, de modo a fornecer um extrato límpido, livre de impurezas, interferentes e com melhor sensibilidade, linearidade e seletividade analítica. Os métodos de extração usados foram extração líquido-líquido (ELL), extração em fase sólida (SPE) e microextração em fase sólida (SPME). Os resultados indicaram que o reagente de derivatização ciclohexanona foi o que apresentou melhor desempenho, menor custo e promoveu maior seletividade dos diasterômeros EF/PEF em colunas normais de CG. Sendo que o método mais apropriado para a detecção e identificação de efedrinas/anfetamina por CG/EM é a SPME levando em consideração características como simplicidade, rapidez, custo, recuperação e ausência de interferentes. Entretanto, considera-se valido o uso de SPE para a quantificação, devido à possibilidade de pré-concentração do analito.
Brazil is one of the biggest amphetamine consumers in the world, going against the worldwide retraction tendency. Due to serious adverse effects and high abuse potential, the production and commercialization of amphetamines has been controlled around the world. With the restriction of its use, there was a return in the search of natural equivalents, especially the ephedrines found in many medicines utilized in the treatment of respiratory diseases. Furthermore, they are components of dietary supplements used to lose weight and muscular mass gain. Because of the indiscriminate use and the high incidence of false-positive results in the amphetamines screening tests by enzyme immunoassay technique, it is necessary confirmatory tests. In this way, the aim of this work is to develop a confirmatory simple and quickly method for the detection and quantification of ephedrines (ephedrine and pseudoephedrine) gas chromatography / mass-mass spectrometry (GC/MS/MS), with possibility to be adopted in toxicological analyses laboratorial routine. Due to the complexity of the matrix and analyte peculiarities, initially proceeds the study of sample treatment, considering the derivatization, extraction, pre-concentration and purification steps, obtaining a limpidous extract, free of impurities, interferents and with better sensitivity, linearity and analytical selectivity. The extraction method used were liquid-liquid extraction (LLE), solid-phase extraction (SPE) and solid-phase microextraction (SPME). The results indicate that cyclohexanone was the derivatization agent with the best performance, lower price and good selectivity in diasteromers EF/PEF separation in normal GC columns. The most appropriate method for detection and identification of ephedrines/amphetamine by GC/MS is SPME, considering characteristics as simplicity, speed, cost, recovery and absence of interferents. However, the use of SPE must be considered to quantification, since it allowed analyte pre-concentration.

Goals: Prepare a case study on the transition to the new OTC medicines groups with restrictions. To evaluate the positives and negatives, which brought the introduction of the group - with OTC restrictions. Pick up generally applicable principles and specify non-functional parts of the system. Method: For data processing method was applied theoretical research. Literature was searched in the database of the Czech National Library - Klementinum, WHO database, TRIBUNE and interfaces of News portals. The instrumental case study was processed for a detailed insight into the issues. The case study is also based on the analysis of the legal framework of the Czech Republic. The documents provided by SÚKL are used for financial analysis. As another method the stakeholder analysis was used - analysis of opinions of people involved in the drug policy. Results: The case study shows that switching medicines containing PSE to the limited group of OTC to prevent producers of drugs buing drugs in Czech pharmacies, but it did not reduce the amount of drugs produced in the country. Producers started to import precursors from abroad. The whole new system established in 2009 was correct in principle, but failed in practice. State Institute for Drug Control or other stakeholders in drug policy have not been able to resolve the ensuing complications.

The thesis is focused on the distribution of medicinal products containing the active ingredient pseudoephedrine. These medicines are misused because of its active substance to produce an addictive methamphetamine (meth). The aim is to monitor the development restrictions associated with those drugs in the past, concern and characterize the current status of this issue. In the thesis, the theoretical knowledge of economics and drug problems. The practical part deals with the historical development of restrictions and evaluation of the status quo.

The use of pseudoephedrine as a practical chiral auxiliary for asymmetric synthesis is describe. Both enantiomers of pseudoephedrine are inexpensive commodity chemicals and can be N-acylated in high yields to form tertiary amides. In the presence of lithium chloride, the enolates of the corresponding pseudoephedrine amides undergo highly diastereoselective a1kylations with a wide range of alkyl halides to afford α-substituted products in high yields. These products can then be transformed in a single operation into highly enantiomerically enriched carboxylic acids, alcohols, and aldehydes. Lithium amidotrihydroborate (LAB) is shown to be a powerful reductant for the selective reduction of tertiary amides in general and pseudoephedrine amides in particular to form primary alcohols.

NOTE: Text or symbols not renderable in plain ASCII are indicated by [...]. Abstract is included in .pdf document. The noncatalyzed aldol addition of [...]-methylsilacyclobutane-[...],[...]-ketene acetals to aldehydes and the transformation of alkylated pseudoephedrine amides to highly enantiomerically enriched carboxylic acids and ketones are described. In Chapter 1, constraining of the silicon atom of an [...]-silyl ketene-[...],[...]-acetal within a four-membered ring is shown to greatly accelerate the rate of its noncatalyzed aldol addition to aldehydes and ketones. This reaction is highly syn selective and is proposed to proceed through a boat transition state involving pentacoordinate silicon. In Chapter 2, the preparation of carboxylic acids and ketones from alkylated pseudoephedrine amides is described. Acidic, basic, and slightly acidic metal-mediated hydrolysis conditions have been developed. In addition, the treatment of alkylated pseudoephedrine amides with alkyllithium reagents is shown to be a practical method for the preparation of highly enantiomerically enriched ketones.

The production of methamphetamine in clandestine laboratories presents a particular hazard due to the environmental hazards it poses. In addition to the dangers associated with using caustic and reactive solvents, these clandestine laboratories also have to potential to cause a fire or explosion. This danger has caused some states to redefine arson to include fires caused by the illicit manufacture of drugs. Arson investigation can be challenging due to the destructive nature of the crime. Much of the evidence that existed prior the fire can be consumed and evidence that does survive can be difficult to identify in the rubble. Despite these difficulties, methods have been developed to determine the types of accelerants present in addition to identifying illicit substances such as methamphetamine and the precursor drug pseudoephedrine. This study was designed to determine if solid phase microextraction combined with gas chromatography/mass spectrometry could be used to analyze burned samples of wood to which pseudoephedrine had been applied. In addition, an experiment was designed to determine what concentration of pseudoephedrine must be present before a fire in a controlled laboratory setting, for a detectable amount to remain. Samples were created by adding pseudoephedrine hydrochloride, either in powder form or dissolved in methanol, to blocks of Douglas Fir and exposing the surface to a flame for two minutes. Additional samples were created by adding trace amounts, i.e. microliter quantities, of pseudoephedrine standard to blocks of wood before placing them in a fire for ten minutes. A thermal degradation product of pseudoephedrine was detected in samples containing more than 15 mg of the drug. To verify that the detected product was a result of thermal degradation, 10 mg of pseudoephedrine were heated at 200 °C for one hour. The product of the thermal degradation study and the product detected following two minutes of exposure to a flame had the same retention time and mass spectrum. Therefore, it was concluded that the detected thermal degradation product may be used to indicate the presence of pseudoephedrine in a fire.

碩士
高雄醫學大學
藥學研究所碩士在職專班
92
In study, we tried to find a rapid, sensitive method to qualitative and quantitative of A, MA, EPH, PEPH, MDMA and K these six abuse drugs at the same time by using capillary zone electrophoresis The best result was achieved by used 500 mM Boric acid mix with 20 mM Borax（pH 6.88）then 40 mM Borax buffer（pH 7.23）and applied two steps voltage of 10 kV 13.5 mins and 8 kV 6.5 mins. And UV detection was at 214 nm absorbance. The analytical precision was characterized by relative standard deviation values （R. S. D）<10% for migration times intra-day and inter-day with peak area are producibility <1.60% linearity in the range 0.5 μg/ml~2 μg/ml was acceptable with amphetamine correltion coefficients >0.995；methamphetamine correlation coefficients >0.998 and ephedrine correlation coefficients >0.998；pseudoephedrine correlation coefficients >0.996；MDMA correlation coefficients >0.998；ketamine coreelation coefficients >0.996. The result of this study is suitable for separation of these compounds.

碩士
高雄醫學大學
職業安全衛生研究所
89
Because of the global overcast economy, domestic high unemployment, low work achievement, recession of life standard and illiteracy of teenagers, more and more people attempt to stupefy themselves by using drugs. Drug abuse impacts our society on direct and indirect cost to the medical and custodial care system. Additionally occupational accident and public danger will be occurred when people are working under the influence of drugs. Therefore screen for drug abuse is very important. Amphetamine (A), methamphetamine (MA), ephedrine (EPH), pseudoephedrine (PEPH), morphine (MO) and codeine (CO) are basic components of drugs. On the other hand those elements are also used on medical treatment. To confirm if it is truly drug abuse or not is especially important. The drug testing process is multifaceted. How to get rid of the interruption in analyzing and false positive in testing is very important. Many review papers only determination one kind of designer drug. In our study, we tried to find a rapid, sensitive method to qualitative and quantitative of A, MA, E, PEPH, MO and CO these six abuse drugs at the same time by using capillary zone electrophoresis coupled with electrospray interface (ESI) ion-trap tandem mass spectrometry (CE-ESI-MS2). The best result was achieved with a pH 2.44 2mM ammonium acetate-methanol (80:20,v/v) buffer and applied voltage of 20kV. The flow-rate of sheath liquid and sheath gas was optimized. Because the migration time in MS was different only few seconds, the ion-trap mass detector detected in one segment. All the analyses revealed the [M-H]+ ion mass spectra. Molecular ions of A (m/z 136), MA (m/z 150), EPH (m/z 166), PEPH (m/z 166), MO (m/z 286) and CO (m/z 300) were detected respectively, while product ions of MS2 for each compound were detected almost exactly at the same time.

Zur stereoselektiven Herstellung von α-Hydroxyketonen aus prochiralen Ketonen stellen die Alkoholdehydrogenasen eine ökologische als auch ökonomische Alternative zu den verfügbaren industriellen Syntheserouten dar. Zurzeit stoßen sowohl die Biokatalyse als auch die organische Katalyse bei der Herstellung von sterisch anspruchsvollen α-Hydroxyketonen an ihre Grenzen. Die Synthese von enantiomerenreinem (R)-Phenylacetylcarbinol [(R)-PAC] und S- Phenylacetylcarbinol [(S)-PAC] aus dem prochiralen α-Diketon Phenylpropan-1,2-dion (PPD) stellt eine anspruchsvolle Synthese sowohl für akademische als auch für industrielle Zwecke dar. Diese chiralen Bausteine dienen als Vorgänger bei der Synthese von (‒)-Ephedrin und (+)-Pseudoephedrin. (‒)-Ephedrin und (+)-Pseudoephedrin werden jährlich in großen Mengen hergestellt, was zunehmend ein ernsthaftes ökologisches Problem darstellt. Aufgrund ihrer Toxizität als auch ihre Persistenz in der Umwelt, beispielsweise in Abwasserkläranlagen, wurden sie kürzlich als neu auftauchende Kontaminanten eingestuft. In dieser Arbeit wurde die Biodegradierung der Isomere von Ephedrin untersucht. Dabei wurde der neue Stamm Arthrobacter sp. TS-15 isoliert, welcher mit Ephedrin als einzige Kohlenstoffquelle wachsen kann. Dieser Stamm wurde bei der DSMZ unter der Nummer (DSM 32400) hinterlegt. Das Genom dieses Stammes wurde sequenziert und unter der Zugangsnummer (SDXQ00000000) in der Genbank verwahrt. Anhand verschiedener phylogenetischer Untersuchungen wurde TS-15 als eine Subspezies von Arthrobacter aurescens eingeordnet. Des Weiteren wurde der Einfluss der Isomerie von Ephedrin auf dessen Biodegradierung sowie auf die Wachstumsrate von TS-15 untersucht. Es wurde festgestellt, dass das Isomer (‒)-Pseudoephedrin am langsamsten abgebaut wird und dementsprechend einen negativen Einfluss auf das Kulturwachstum hat. Hingegen zeigte sein Enantiomer (+)-Pseudoephedrin die schnellste Biodegradierung mit einem positiven Effekt auf das Wachstum von TS-15. Anhand der Analyse der Metabolite im Kultivierungsmedium als auch aus den Zellextrakten von TS-15 wurde ein neuer katabolischer einleitender Schritt detektiert, in dem das Ephedrin zu Methcathinon VII oxidiert wird. Zur Bestimmung der oxidierenden Enzyme wurden Proteinanreicherungsverfahren eingesetzt. Mittels Peptidmassenfingerprints wurden 51 Proteinhits ermittelt. Nach einer kombinierten Analyse mittels der Proteinhits und des rationalen Genomminings wurde ein neues Gencluster zum Abbau von Ephedrin identifiziert. Zwei postulierte Dehydrogenasen wurden aus dem Genom isoliert, kloniert und in dem E. coli T7 SHuffle Stamm heterolog exprimiert. Dadurch wurden neue enantiokomplementäre Enzyme entdeckt. Die Pseudoephedrin Dehydrogenase (PseDH) ist enantiospezifisch für (+)-S,(N)-(Pseudo-)-Ephedrin, während die Ephedrin Dehydrogenase (EDH) nur die enantiospezifische Oxidation von (‒)-R,(N)-(Pseudo-)-Ephedrin katalysieren kann. Beide Dehydrogenasen sind NADH-abhängig und der Superfamilie der kurzkettigen Dehydrogenasen untergeordnet. Bei der Charakterisierung dieser Dehydrogenasen konnte gezeigt werden, dass das Substratspektrum wertvolle chirale Produkte umfasst. Beide Dehydrogenasen zeigen strikte Regio- und Enantioselektivität gegenüber dem α-Diketon Phenylpropan-1,2-Dion (PPD). Somit wurde PPD zu (S)-PAC (ee >99%) und (R)-PAC (ee >99%) mittels PseDH bzw. EDH mit vollem Umsatz reduziert. Darüber hinaus wurde die Kristallstruktur der PseDH im Rahmen einer Zusammenarbeit mit der Universität von York mit einer Auflösung von 1,8 Å aufgeklärt. Die Kristallstruktur wurde in PDB unter der Zugangsnummer (6QHE) hinterlegt. Mittels der Kristallstruktur der PseDH und des Homologiemodells der EDH wurden Strukturanalysen durchgeführt und die ersten Hypothesen zur Funktionsweise dieser Enzyme aufgestellt. Des Weiteren wurden über Peptidsequenzanalysen zu diesen Enzymen Rückschlüsse auf ihren evolutionären Ursprung gezogen. Die Stabilität der Dehydrogenasen wurde mit unterschiedlichen Lösungsmitteln bestimmt. CPME wurde als geeignetstes organisches Lösungsmittel für die Biokatalyse mit diesen Enzymen ermittelt. Beide Enzyme wurden mittels eines organisch-wässrigen Zweiphasensystems unter enzymgekoppelter Cofaktorregenerierung getestet. Dadurch wurde der Zugang zur Produktion von (S)-PAC und (R)-PAC aus PPD mittels PseDH bzw. EDH geschaffen.

l-Ephedrine and d-pseudoephedrine are important pharmaceutical products commonly found in anti-asthmatic formulations, nasal decongestant mixtures and sinus preparations. d-Pseudoephedrine is the active ingredient in "Sudafed". l-Ephedrine is currently synthesised in a three step process. The first step utilises fermenting yeast in water to catalyse the acyloin condensation of benzaldehyde and acetaldehyde to form the l-ephedrine precursor, l-phenylacetylcarbinol (l-PAC). The second step involves the reaction of l-PAC with methylamine to form the corresponding N-methyl imine; the final step employs a metal catalyst to facilitate the reduction of the imine with hydrogen. This study is focused on the first step of the synthesis, which suffers from the drawback that two by-products, benzyl alcohol and l-phenylpropan-l,2-diol are always formed. The study aims to improve the efficiency of the l-PAC formation by performing the reaction with dried yeast in an organic solvent.