Avaliar a eficácia analgésica da associação de 30mg do fosfato de codeína com 500mg do paracetamol após exodontias de terceiros molares inferiores impactados. Foi realizado um estudo clínico bilateral com uma amostra de 47 pacientes. Em um dos lados, todos os pacientes receberam a dosagem de 30mg do fosfato de codeína em associação com 500mg do paracetamol após exodontia (grupo teste). Para a exodontia contralateral, foi disponibilizado outro frasco contendo cápsulas idênticas, porém com a dosagem de 500mg de paracetamol (grupo controle). 100% dos pacientes do grupo teste não necessitaram utilizar a medicação resgate e não consumiram doses adicionais da medicação após as cirurgias. No grupo controle, 44,7% dos participantes relataram o uso do medicamento resgate. O consumo total de comprimidos no grupo teste foi, em média, inferior quando comparados ao lado contralateral. 80,8% dos pacientes relataram maior conforto, quanto ao critério da dor, no lado em que foi utilizado a dosagem de 30mg de fosfato de codeína associado a 500mg de paracetamol. Os efeitos colaterais estiveram mais presentes no grupo teste, sendo mais comum o relato de sonolência (34%) e tontura (31,9%), não havendo relato de abandono desta medicação por nenhum dos pacientes. Concluímos que a dosagem de 30mg do fosfato de codeína associada a 500mg de paracetamol apresentou resultados favoráveis no controle da dor e uma baixa incidência de efeitos colaterais. / To assess the analgesic efficacy of regular dosage of codeine phosphate 30mg association with paracetamol 500mg after extraction of impacted lower third molars. We performed a bilateral clinical study analyzing a sample of 47 patients. All patients received a 30mg codeine phosphate dosage in combination with paracetamol 500mg after extraction (test group). For the contralateral tooth extraction, we had another bottle available containing identical capsules, with a 500mg paracetamol dosage (control group). 100% of the test group patients did not need to use rescue medication and did not consume additional doses of medication after surgeries. In the control group, 44.7% reported the use of rescue medication. Total consumption of pills in the test group was on average lower than the contralateral side. 80.8% of patients reported greater comfort, as the criterion of pain in the side that was used 30mg codeine phosphate dosage associated with paracetamol 500mg. The adverse effects were more present in the test group, with sleepiness being more common (34%) and dizziness (31.9%), without any patient medication abandonment. We conclude that the 30mg codeine phosphate dosage associated with paracetamol 500mg showed favorable results in controlling pain associated with a low incidence of side effects.

Avaliar a eficácia analgésica da associação de 30mg do fosfato de codeína com 500mg do paracetamol após exodontias de terceiros molares inferiores impactados. Foi realizado um estudo clínico bilateral com uma amostra de 47 pacientes. Em um dos lados, todos os pacientes receberam a dosagem de 30mg do fosfato de codeína em associação com 500mg do paracetamol após exodontia (grupo teste). Para a exodontia contralateral, foi disponibilizado outro frasco contendo cápsulas idênticas, porém com a dosagem de 500mg de paracetamol (grupo controle). 100% dos pacientes do grupo teste não necessitaram utilizar a medicação resgate e não consumiram doses adicionais da medicação após as cirurgias. No grupo controle, 44,7% dos participantes relataram o uso do medicamento resgate. O consumo total de comprimidos no grupo teste foi, em média, inferior quando comparados ao lado contralateral. 80,8% dos pacientes relataram maior conforto, quanto ao critério da dor, no lado em que foi utilizado a dosagem de 30mg de fosfato de codeína associado a 500mg de paracetamol. Os efeitos colaterais estiveram mais presentes no grupo teste, sendo mais comum o relato de sonolência (34%) e tontura (31,9%), não havendo relato de abandono desta medicação por nenhum dos pacientes. Concluímos que a dosagem de 30mg do fosfato de codeína associada a 500mg de paracetamol apresentou resultados favoráveis no controle da dor e uma baixa incidência de efeitos colaterais. / To assess the analgesic efficacy of regular dosage of codeine phosphate 30mg association with paracetamol 500mg after extraction of impacted lower third molars. We performed a bilateral clinical study analyzing a sample of 47 patients. All patients received a 30mg codeine phosphate dosage in combination with paracetamol 500mg after extraction (test group). For the contralateral tooth extraction, we had another bottle available containing identical capsules, with a 500mg paracetamol dosage (control group). 100% of the test group patients did not need to use rescue medication and did not consume additional doses of medication after surgeries. In the control group, 44.7% reported the use of rescue medication. Total consumption of pills in the test group was on average lower than the contralateral side. 80.8% of patients reported greater comfort, as the criterion of pain in the side that was used 30mg codeine phosphate dosage associated with paracetamol 500mg. The adverse effects were more present in the test group, with sleepiness being more common (34%) and dizziness (31.9%), without any patient medication abandonment. We conclude that the 30mg codeine phosphate dosage associated with paracetamol 500mg showed favorable results in controlling pain associated with a low incidence of side effects.

Whole-body PBPK models were developed based on both the intestinal traditional model (TM) and segregated-flow model (SFM) to describe codeine sequential metabolism in man/rat. Model parameters were optimized with Scientist® and Simcyp® simulator to predict literature data after oral (p.o.) and intravenous (i.v.) codeine administration in man/rat. In vivo codeine PK studies on rats were performed to provide more data for simulation. The role of fm’ (fractional formation clearance of morphine from codeine) in model discrimination between the TM and SFM was investigated. A greater difference between the [AUC_M3G/AUC_Morphine]p.o. and [AUC_M3G/AUC_Morphine]i.v. ratio existed for the SFM, especially when the fm’ was low. It was found that our tailor-made PBPK models using Scientist® were superior to those from Simcyp® in describing codeine sequential metabolism. Residual sum of squares and AUC’s were calculated for each model, which demonstrated superiority of the SFM over TM in predicting codeine sequential metabolism in man/rat.

Whole-body PBPK models were developed based on both the intestinal traditional model (TM) and segregated-flow model (SFM) to describe codeine sequential metabolism in man/rat. Model parameters were optimized with Scientist® and Simcyp® simulator to predict literature data after oral (p.o.) and intravenous (i.v.) codeine administration in man/rat. In vivo codeine PK studies on rats were performed to provide more data for simulation. The role of fm’ (fractional formation clearance of morphine from codeine) in model discrimination between the TM and SFM was investigated. A greater difference between the [AUC_M3G/AUC_Morphine]p.o. and [AUC_M3G/AUC_Morphine]i.v. ratio existed for the SFM, especially when the fm’ was low. It was found that our tailor-made PBPK models using Scientist® were superior to those from Simcyp® in describing codeine sequential metabolism. Residual sum of squares and AUC’s were calculated for each model, which demonstrated superiority of the SFM over TM in predicting codeine sequential metabolism in man/rat.

(-) Codeine, (-) morphine, and their semi-synthetic derivatives play an integral role in medicinal analgesia. Due to a complex list of undesirable side effects, their effective use is often complicated and troublesome giving cause for the investigation of novel semi-synthetic analogs for efficacy and side-effect profile. It was envisioned that new and interesting codeine analogs could be synthesized via an opening of a hindered 7,8-[alpha]-epoxide. Classically, hindered epoxides are formed via halohydrin formation and subsequent closure. Interestingly, the 7,8-epoxide formed via bromohydrin closure was resistant to reaction with small nucleophiles, such as oxygen and hydride, but reactive towards large and nucleophilic atoms, such as sulfur and bromide. It was discovered that the epoxide was in fact the less hindered 7,8-[Beta] epoxide via x-ray analysis of various compounds. This hinted at an unexpected rearrangement which most likely occurred during the bromohydrin formation due to the severe steric interactions present in the core structure of codeine. Due to the reversibility of bromonium ion formation, a highly hindered double bond can produce the opposite configuration of what is expected when subjected to aqueous brominating conditions. Many popular alkaloids, including codeine and galanthamine, are biosynthetically formed via a spirocyclic dienone intermediate. In nature these intermediates are formed via an enzymatically driven phenolic oxidation; however in the lab this reaction has proven difficult to reproduce. In a previous Magnus publication, (±) codeine and (-) galanthamine, were synthesized via a common spirocyclic cross-conjugated dienone intermediate similar to the intermediate found in nature. Most importantly, this intermediate was formed without a phenolic oxidation. Instead, a para-alkylation of an appropriately substituted phenol efficiently created the key intermediate. Expanding on this phenolic alkylation strategy, various biaryl systems were built in order to investigate the scope and limitations of this reaction. Multiple para- alkylations proved successful while ortho- alkylations unveiled an interesting rearrangement which occurs during the reaction. Lastly, it was determined that a 7-membered ring could not be set using a phenolic alkylation strategy. / text

A melhora na eficácia do bloqueio sensitivo induzida pela associação ou injeção prévia do opióide tramadol foi comprovada em animais e em humanos, sugerindo potencialização ou sinergismo de efeitos. No entanto, ainda não há estudos sobre a influência da associação da codeína ao anestésico local (AL) injetada concomitante ou previamente ao bloqueio funcional (sensitivo, motor e proprioceptivo) do nervo ciático. Dessa forma, o objetivo deste trabalho foi estudar a influência do analgésico opióide codeína na duração do bloqueio nervoso ciático de rato induzido por lidocaína, através de novos protocolos farmacológicos. Para isso, foi realizada uma análise da função sensitiva, proprioceptiva e motora desse nervo misto, comparando-se os efeitos da injeção prévia ou concomitante da codeína. Foram utilizados 80 ratos machos Wistar para serem avaliados funcionalmente após o recebimento na região do nervo ciático de soluções injetáveis dos diferentes fármacos: lidocaína com epinefrina (AL), AL sem vasoconstritor (AL SV), codeína (COD), tramadol (TRAM), AL + codeína (AL + COD), AL + tramadol (AL + TRAM), codeína 20 min antes do AL (COD 20 + AL) ou tramadol 20 min antes do AL (TRAM 20 + AL). O bloqueio sensitivo foi considerado o período de ausência do reflexo de retirada da pata após estímulo nociceptivo-pressórico (analgesímetro e pinça mosquito), já o bloqueio motor pela duração da claudicação (ausência do reflexo extensor postural) e o proprioceptivo, pela ausência de resposta do salto e tato (escore 0-3). A duração de ação do (AL + COD) foi maior (p<0.01) que a (COD) e que (COD20´+ AL) e os outros grupos (p<0.05). O COD isolado mostrou discreta atividade nociceptiva. Os resultados sugerem sinergismo de atividade entre opióide e AL. O uso concomitante de codeína ao AL melhora a eficácia do bloqueio sensitivo, motor e proprioceptivo, abrindo nova perspectiva no controle da dor a ser estudada em Odontologia. / The improvement in sensitive blockade induced by association or previous tramadol opioid injection was proved in animals and humans suggesting potencialization or sinergism in effects. Nevertheless, there are no experiments about the influence of codeine association to local anesthetics (LA) injected simultaneously or previously to block sciatic nerve functions (sensitive, motor and proprioceptive). The propose of this experiment was evaluate the influence of codeine analgesic opioid on duration of rat sciat nerve blockade induced by lidocaine using new pharmacological protocols. It was anallyzed the nociceptive, motor and proprioceptive functions of this mist nerve comparing the effects of previous or associated injection of codeine. Eighty (N=80) Wistar male rats were functional avaliated after they received differents injected drugs solutions, in sciat nerve region: lidocaine and epinephrine (LA), local anesthetics with no vasoconstrictor (LA NV), codeine (COD), tramadol (TRAM), LA + codeine (LA + COD), LA + tramadol (LA + tramadol), codeine 20 minutes previously to LA (COD 20+ LA) or tramadol 20 minutes previously to LA (TRAM 20 + LA). The sensitive blockade was considered the absence of withdraw reflex after nociceptive and pressoric stimulous (analgesimether and forceps), the motor was evaluated the duration of claudication and proprioceptive by de absence of hopping and tactile response (score 0-3). We concluded that the blockade duration of (LA + COD) was greater than (COD) (p<0.01) and than (COD 20 + LA) and than other groups (p<0.05). Codeine isolated showed discret nociceptive action. Our results suggested sinergism between opioid and LA. The associated use of codeine and LA improves de efficacy of sensitive, motor and proprioceptive blockade guiding to a new prospect in dentistrys pain control.

Šiame darbe nagrinėjami kietazės ekstrakcijos ir skysčių – skysčių ekstrakcijos metodai, bei lyginami jų efektyvumai ekstrahuojant kodeiną iš kraujo plazmos ir šlapimo. Ekstrakcijų efektyvumai buvo nustatinėjami UV spektrometrijos būdu. Darbo tikslas – nustatyti optimalias mėginio ruošimo toksikologinėje analizėje metodikas, tinkamas kodeino išskyrimui iš biologinių terpių – kraujo plazmos, šlapimo, bei palyginti šių metodikų efektyvumą. įvertinus gautus duomenis, galima teigti, kad ekstrahuojant kodeiną iš šlapimo, skysčių – skysčių ekstrakcijos ir kietafazės ekstrakcijos efektyvumai buvo panašūs. Ekstrahuojant kodeiną iš kraujo plazmos – efektyvesnė pasirodė kietafzė ekstrkcija. / In this master’s thesis are examined solid phase extraction and liquid - liquid extraction methods. Codeine has been extracted by using these methotds, efficiencies of extraction methods were determined by UV spectrophotometry. The aim of this this master’s thesis is to determine the optimal sample preparation methodologies for toxicological analysis, codeine proper isolation of biological media - plasma, urine, and to compare the effectiveness of these methods. After assessment of the data, it can be said that the extraction of codeine from urine, efficiencies were similar extracting by using liquid - liquid extraction and solid phase extraction. Codeine is more efficiently extracted from blood plasma by solid phase extraction method than liquid - liquid extraction method.

Darbo tikslas: Optimizuoti plonasluoksnės chromatografijos ir efektyviosios skysčių chromatografijos metodikas, tinkamas alprazolamo, kodeino ir paracetamolio kokybiniam įvertinimui. Tyrimo objektas ir metodai: Optimizuojant PC metodiką, analizuoti etaloniniai 0,2 mg/ml koncentracijos alprazolamo, kodeino, paracetamolio trichlormetaniniai tirpalai ir jų mišinys. Tirpiklių sistemoms buvo naudoti etanolis, trichlormetanas, eteris, 25% amonio hidroksidas, acetonas, izobutanolis. Dėmių ryškinimui naudota UV šviesos (254nm; 365nm) lempa arba Dragendorfo reagentas (modifikuotas pagal Munjė). Optimizuotos metodikos pritaikytos tiriant trichlormetaninius darbinius tirpalus, pagamintus iš vaistinių preparatų „Xanax“, „Paracetamolis Sanitas“ ir „Ultracod“. Siekiant pritaikyti ESC metodiką tiriamųjų junginių analizei, buvo tirti etaloniniai 0,1 mg/ml koncentracijos alprazolamo, kodeino ir paracetamolio metanoliniai tirpalai bei jų mišinys. Medžiagų atskyrimui ir identifikavimui naudotas chromatografas Waters 2695 su fotodiodų matricos detektoriumi Waters 996 (210 – 400 nm bangų ilgio diapazonas). Chromatografavimui naudoti metanolis, 3% acto rūgšties vandeninis tirpalas. Optimizuota ESC metodika pritaikyta tiriant metanolinius darbinius tirpalus, pagamintus iš vaistinių preparatų „Xanax“, „Ultracod“ ir „Solpadeine“. Rezultatai ir išvados: Tinkamiausios tirpiklių sistemos alprazolamo, kodeino ir paracetamolio mišinio kokybiniam vertinimui PC metodu – TS-D (trichlormetanas: acetonas:... [toliau žr. visą tekstą] / Aim: To optimize thin-layer chromatography and high-performance liquid chromatography methods for alprazolam, codeine, paracetamol and their mixture qualitative analysis. Object and methods: For TLC method optimization alprazolam, codeine, paracetamol and their mixture stock solutions (0,2 mg/ml) in trichlormetan were analysed. For mobile phase were used: ethanol, trichlormetan, ether, 25% ammonia hydroxide, acetone, isobutanol. For spots development were used UV light lamp (254nm; 365nm) or Dragendorff reagent (modified by Munje). Optimized methods were tried with pharmaceutical products “Xanax”, “Paracetamolis Sanitas” and “Ultracod” solutions. For HPLC method optimization alprazolam, codeine, paracetamol and their mixture stock solutions (0,1 mg/ml) in methanol were analysed. Chromatograph Waters 2695 with photo diode array detector Waters 996 (210-400 nm wave length) were used for qualitative determination. Analysis was made by using methanol and 3% acetic acid aqueous solution. Optimized method was applied in analysis of pharmaceutical products “Xanax”, “Ultracod” and “Solpadeine” solutions. Results: The best mobile phases for alprazolam, codeine and paracetamol mixture qualitative analysis using TLC is TS-D (trichlormetan: acetone: concentrated ammonia hydroxide (55:40:5)) and TS-F (trichlormetan: ether: isobutanol: concentrated ammonia hydroxide (50:30:15:5)). TS-D and TS-F mobile phases are suitable for examined substances qualitative analysis in mixture and... [to full text]

Diss. (sammanfattning) Uppsala : Univ., 2002. / Härtill 5 uppsatser.

A melhora na eficácia do bloqueio sensitivo induzida pela associação ou injeção prévia do opióide tramadol foi comprovada em animais e em humanos, sugerindo potencialização ou sinergismo de efeitos. No entanto, ainda não há estudos sobre a influência da associação da codeína ao anestésico local (AL) injetada concomitante ou previamente ao bloqueio funcional (sensitivo, motor e proprioceptivo) do nervo ciático. Dessa forma, o objetivo deste trabalho foi estudar a influência do analgésico opióide codeína na duração do bloqueio nervoso ciático de rato induzido por lidocaína, através de novos protocolos farmacológicos. Para isso, foi realizada uma análise da função sensitiva, proprioceptiva e motora desse nervo misto, comparando-se os efeitos da injeção prévia ou concomitante da codeína. Foram utilizados 80 ratos machos Wistar para serem avaliados funcionalmente após o recebimento na região do nervo ciático de soluções injetáveis dos diferentes fármacos: lidocaína com epinefrina (AL), AL sem vasoconstritor (AL SV), codeína (COD), tramadol (TRAM), AL + codeína (AL + COD), AL + tramadol (AL + TRAM), codeína 20 min antes do AL (COD 20 + AL) ou tramadol 20 min antes do AL (TRAM 20 + AL). O bloqueio sensitivo foi considerado o período de ausência do reflexo de retirada da pata após estímulo nociceptivo-pressórico (analgesímetro e pinça mosquito), já o bloqueio motor pela duração da claudicação (ausência do reflexo extensor postural) e o proprioceptivo, pela ausência de resposta do salto e tato (escore 0-3). A duração de ação do (AL + COD) foi maior (p<0.01) que a (COD) e que (COD20´+ AL) e os outros grupos (p<0.05). O COD isolado mostrou discreta atividade nociceptiva. Os resultados sugerem sinergismo de atividade entre opióide e AL. O uso concomitante de codeína ao AL melhora a eficácia do bloqueio sensitivo, motor e proprioceptivo, abrindo nova perspectiva no controle da dor a ser estudada em Odontologia. / The improvement in sensitive blockade induced by association or previous tramadol opioid injection was proved in animals and humans suggesting potencialization or sinergism in effects. Nevertheless, there are no experiments about the influence of codeine association to local anesthetics (LA) injected simultaneously or previously to block sciatic nerve functions (sensitive, motor and proprioceptive). The propose of this experiment was evaluate the influence of codeine analgesic opioid on duration of rat sciat nerve blockade induced by lidocaine using new pharmacological protocols. It was anallyzed the nociceptive, motor and proprioceptive functions of this mist nerve comparing the effects of previous or associated injection of codeine. Eighty (N=80) Wistar male rats were functional avaliated after they received differents injected drugs solutions, in sciat nerve region: lidocaine and epinephrine (LA), local anesthetics with no vasoconstrictor (LA NV), codeine (COD), tramadol (TRAM), LA + codeine (LA + COD), LA + tramadol (LA + tramadol), codeine 20 minutes previously to LA (COD 20+ LA) or tramadol 20 minutes previously to LA (TRAM 20 + LA). The sensitive blockade was considered the absence of withdraw reflex after nociceptive and pressoric stimulous (analgesimether and forceps), the motor was evaluated the duration of claudication and proprioceptive by de absence of hopping and tactile response (score 0-3). We concluded that the blockade duration of (LA + COD) was greater than (COD) (p<0.01) and than (COD 20 + LA) and than other groups (p<0.05). Codeine isolated showed discret nociceptive action. Our results suggested sinergism between opioid and LA. The associated use of codeine and LA improves de efficacy of sensitive, motor and proprioceptive blockade guiding to a new prospect in dentistrys pain control.