A highly sensitive first derivative synchronous spectrofluorimetric approach for the simultaneous analysis of the anti-breast cancer co-administered drugs, letrozole and tramadol in dosage forms and human plasma at nanogram levels.

Letrozole is an anticancer medication prescribed for the management of estrogen receptor-positive breast cancer in postmenopausal women. Chronic pain is prevalent in patients receiving chemotherapy, leading to the use of adjuvant analgesics such as tramadol. This work introduces the first analytical approach for the concurrent quantification of letrozole and tramadol, two co-administered drugs, employing a rapid, highly sensitive, eco-friendly, and cost-effective first derivative synchronous spectrofluorimetric technique. The fluorescence of tramadol and letrozole was measured at wavelengths of 235.9 nm and 241.9 nm, respectively using a wavelength difference (Δλ) of 60.0 nm. The developed approach demonstrated exceptional linearity (r ˃ 0.999) within the specified concentration ranges for tramadol (10.0-1200.0 ng/mL) and letrozole (1.0-140.0 ng/mL). The results demonstrated that the proposed technique exhibits a high level of sensitivity, with detection limits of 0.569 and 0.143 ng/mL for tramadol and letrozole, respectively, indicating the good bioanalytical applicability. The within-run precisions, both intra-day and inter-day, for both analytes, were less than 0.71 % RSD. The developed approach was effectively applied to simultaneously estimate the mentioned drugs in their tablets and human plasma samples, achieving high percentage recoveries and low % RSD values. In order to assess the environmental sustainability of the developed approach, Analytical GREEnnessNNESS (AGREE) and the Green Analytical Procedure Index (GAPI) metric tools were employed. Both tools revealed that the developed approach is excellent green, suggesting its usage as an environmentally-friendly alternative for the routine assayof the investigated pharmaceuticals. The developed approach was validated according to the ICHQ2 (R1) requirements.

Comprehensive overview of analytical and bioanalytical methodologies for the opioid analgesics - Tramadol and combinations.

Synthetic opioids like Tramadol are used to treat mild to moderate pain. Its ability to relieve pain is about a tenth that of morphine. Furthermore, Tramadol shares similar effects on serotonin and norepinephrine to several antidepressants known as serotonin-norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine and duloxetine. The present review paper discusses the recent developments in analytical methods for identifying drugs in pharmaceutical preparations and toxicological materials, such as blood, saliva, urine, and hair. In recent years, a wide variety of analytical instruments, including capillary electrophoresis, NMR, UV-visible spectroscopy, HPTLC, HPLC, LC-MS, GC, GC-MS, and electrochemical sensors, have been used for drug identification in pharmaceutical preparations and toxicological samples. The primary quantification techniques currently employed for its quantification in various matrices are highlighted in this research.

First derivative synchronous spectrofluorimetric method for the simultaneous determination of tramadol and celecoxib in their dosage forms and human plasma.

One of the most common features of many different clinical conditions is pain; hence, there is a crucial need for eliminating or reducing it to a tolerable level to retrieve physical, psychological and social functioning. A first derivative synchronous spectrofluorimetry technique is proposed for the simultaneous determination of celecoxib and tramadol HCl, a recent coformulation authorized for treating acute pain in adults. The method includes using synchronous spectrofluorimetry at ∆λ = 80 nm where tramadol HCl was determined using first derivative technique at λ = 230.2 nm, while celecoxib was determined at λ = 288.24 nm. The proposed method was successfully applied to their co-formulated dosage forms in addition to spiked human plasma and validated in agreement with the guidelines of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). The linear ranges were found to be 0.50-5.0 and 0.15-0.50, the limits of detection to be 0.088 and 0.011 and the limits of quantification to be 0.266 and 0.032 µg/ml for celecoxib and tramadol, respectively. Statistical analysis revealed no significant difference when compared with previously reported methods as evidenced by the values of the variance ratio F-test and Student t-test. The proposed method was successfully applied to commercial dosage forms and spiked human samples. Moreover, the greenness of the proposed method was investigated based on the analytical eco-scale approach, with the results showing an excellent green scale with a score of 95.

Interpretation of hair and nails findings in an infant death case related to maternal addiction to tramadol.

An 11-month-old boy was found dead. Autopsy findings (cyanosis and polyvisceral congestion) and blood tramadol (TR) concentration of 6240 µg/L were consistent with an acute TR intoxication. In this poisoning situation, owing to the mother's statements (TR addiction leading to daily TR-orange juice mixture preparation accidentally used for the baby bottle preparation by the mother's partner), and the question of possible previous TR administrations to the infant, hair and/or nails (infant, mother, partner, 6-year-old sister) analysis was performed. Hair (2-cm-long hair segments from proximal [S1] to distal [S3]) and nails concentrations (pg/mg; nd: not detected) were as follows: Infant (hair: TR 1420 [S1], 1622 [S2], 2736 [S3]; O-DMT 16-38; N-DMT 34-100 [TR in significant quantities in the hair decontamination bath]-toenails: TR 584; O-DMT 8; N-DMT 15), mother (hair: TR 2340 [S1], 2150 [S2], 2500 [S3]; O-DMT 704-1170; N-DMT 827-1360), mother's partner (fingernails: TR 72; O-DMT nd; N-DMT nd) and sister (hair: TR 261 [S1], 524 [S2]; O-DMT 15 [S1], 16 [S2]; N-DMT 20 [S1], 38 [S2]). Metabolite ratio (infant and sister hair) was comparable to those observed in hair of pharmaceutical industry employees manufacturing tramadol. TR in washing baths, low observed nail concentrations (infant and partner) confirm (i) TR-related mother's addiction and (ii) external contamination issues (TR in sweat of the child at the time of death and in living environment) to explain the infant's keratinized samples results. This case report illustrates the interest of analyzing keratinized matrices of the whole family in such a situation.

Capillary zone electrophoresis in combination with UV detection for simultaneous determination of tramadol and paracetamol in pharmaceutical and biological samples.

The aim of the present study is the development and validation of a simple method based on capillary zone electrophoresis coupled with UV detection for simultaneous determination of tramadol and paracetamol in pharmaceutical and biological samples. The background electrolyte was composed of 50 mM ammonium carbonate, which is a type of a non-conventional electrolyte system. The developed method was characterized by suitable validation parameters, such as linearity (coefficient of determination r2 0,995), selectivity or the limit of detection at the level of 0.25 - 0.5 μg/ml. Acceptable values of accuracy and precision were obtained, which were in good agreement with the recommended validation guidelines for analysis of pharmaceutical and biological samples. Detection was performed at a wavelength of 200 nm. The developed method was successfully applied to determine tramadol and paracetamol in various dosage forms and in urine biological samples. Achieved results indicate a potential of the method to be integrated in the common quality control processes of drugs and/or in bioanalysis.

Temporal patterns of tramadol in hair after a single dose.

This controlled study aimed to measure concentrations of tramadol (TRA) and its two main metabolites, N-desmethyltramadol (NDMT) and O-desmethyltramadol (ODMT), in hair following a single dose ingestion and to investigate the distribution patterns in hair by segmental analysis of hair samples taken at several sampling time points after ingestion. An oral dose (50 or 100mg) of TRA was administered to 17 healthy volunteers. Hair samples were collected prior to drug administration and 14, 30, 60 and 120 days after ingestion. Each sample was segmented in 5mm segments and washed. The analytes were extracted from pulverized hair by incubation in extraction media for 18h at 37°C. A validated UHPLC-MS/MS method was used to quantify the analytes at a LLOQ of 0.001ng/mg. Hair segments corresponding to the time of ingestion were positive for TRA and the metabolites of each sampling time point, although neighboring segments also showed positive results. The highest concentrations for both dosage groups were observed in the proximal segment of hair collected 14 days after ingestion for all subjects: 0.061-0.95ng TRA/mg, 0.012-0.86ng NDMT/mg and 0.009-0.17ng ODMT/mg (n=16). Generally, the TRA concentration was higher than the metabolites concentrations but depended on the CYP2D6 phenotype. The metabolite to TRA ratios were stable within a subject over the sampling time points, however it varied greatly between subjects. No significant differences in hair concentrations were found between the two dosage groups at each sampling time. Several confounding factors were identified such as hair pigmentation and internal sweat. We showed that analysis of 5mm segments improved the determination of the exposure time after a single ingestion of TRA. In addition, in the later sampling time points the analytes were spread more between segments and the total drug amount of each later sampling time point declined up to a 100% (median: 75%) due to wash out. The presented results are important additions to the sparse literature reporting single dose of psychoactive drugs in hair.

US FDA-validated green GC-MS method for analysis of gabapentin, tramadol and/or amitriptyline mixtures in biological fluids.

Background: Mixtures of gabapentin, tramadol and/or amitriptyline are usually recommended for treatment of neuropathic pain. Materials & methods/results: A novel GC-MS/MS method was developed to assess the studied mixture whether in pure forms or human biological fluids (plasma/urine). The chromatographic detection was performed using MS detector applying the selected ion-monitoring mode. An (Agilent, CA, USA) GC-MS with triple axis single quadrupole detector unit was used for the analysis equipped with HP-5MS (5% phenyl methyl siloxane) column. Helium was the carrier gas and positive electron impact ionization mode was applied. Conclusion: The developed method was able to assess the mixture components simultaneously within six minutes. Validation of the method was assured according to US FDA guidelines and Eco-Scale assessment.

Influência do tramadol associado à levobupicavaína epidural sobre a taxa de propofol e variáveis fisiológicas, em cadelas submetidas à mastectomia e à ovário-histerectomia / [Influence of tramadol combined with epidural levobupicavaine, on the propofol infusion rate and physiological variables, in female dogs undergoing mastectomy and ovariohysterectomy]

Objetivou-se avaliar os efeitos fisiológicos e sobre o consumo do propofol, relativos à anestesia epidural com levobupivacaína isolada ou associada a diferentes doses de tramadol. Para tal, 18 cadelas foram pré-tratadas com acepromazina, utilizando-se propofol para indução e manutenção anestésicas. Conforme o protocolo epidural instituído, formaram-se três grupos (n=6) tratados com levobupivacaína isolada (1,5mg/kg) (GL) ou acrescida de 2mg/kg (GLT2) ou 4mg/kg (GLT4) de tramadol, respectivamente. As fêmeas foram submetidas à mastectomia e à ovário-histerectomia (OH), registrando-se as variáveis fisiológicas nos períodos pré (TB e T0) e transanestésicos (T10 a T70), bem como a taxa mínima de propofol necessária. Houve redução da FC para o GL e o GLT4 em relação ao GLT2 (T30 a T70), detectando-se, no GL, redução da PAS e da PAD em relação ao TB. Maiores taxas de infusão do propofol foram necessárias para o GL (0,70±0,12mg/kg/min) em relação ao GLT2 (0,50±0,19mg/kg/min) e ao GLT4 (0,50±0,19mg/kg/min). Conclui-se que o tramadol potencializou o propofol, ao ofertar analgesia, independentemente da dose administrada. Todos os protocolos testados foram seguros e eficazes em cadelas submetidas à mastectomia e à OH.(AU)

The aim of this study was to evaluate the physiological and on propofol-sparing effects related to epidural anesthesia with levobupivacaine alone or combined with different doses of tramadol. For this purpose, 18 female dogs were pretreated with acepromazine, using propofol for induction and maintenance of anesthesia. Based on a previously established epidural (L7-S1) protocol, three groups (n=6) were treated with either levobupivacaine alone (1.5mg.k-1) (GL) or in association with to 2mg.kg-1 (GLT2) or 4mg.kg-1 (GLT4) of tramadol, respectively. These dogs were all undergoing mastectomy and ovariohysterectomy (OH). The physiological data were registered in the pre (TB and T0) and trans-anesthetic periods (T10 - T70), as well as the consumption of propofol. There was a reduction in the HR for GL and GLT4 in relation to GLT2 (T30 - T70) and reductions in SAP and DAP in relation to TB in the GL group. Higher continuous infusion rate of propofol were required for GL (0.70±0.12mg.kg-1.min-1) relative to GLT2 (0.50±0.19mg.kg-1.min-1) and GLT4 (0.50±0.19mg.kg-1.min-1). It was concluded that tramadol potentiated propofol, offering analgesia independently of its administered dose. All protocols tested were safe and effective in female dogs undergoing mastectomy and OH.(AU)

Automated high-throughput analysis of tramadol and O-desmethyltramadol in dried blood spots.

The World Anti-Doping Agency (WADA) and the International Testing Agency (ITA) recently announced the development and implementation of dried blood spot (DBS) testing for routine analysis in time for the 2022 Winter Olympic and Paralympic Games in Beijing. Following the introduction of a ban on the use of tramadol in competition in March 2019, the Union Cycliste International (UCI) started a pilot study for the manual analysis of tramadol in DBS for antidoping purposes. In this context, we present a fully automated LC-MS/MS-based method with automated sample preparation using a CAMAG DBS-MS 500 for the analysis of tramadol and its metabolite O-desmethyltramadol in DBS. The presented approach reduces manual handling in the laboratory to an absolute minimum, only requiring the preparation of calibration and quality control DBS cards. The method was developed, optimized, and validated before performing cross-validation with a liquid blood-based analysis method using authentic samples from forensic cases. During the validation process, the method showed an extraction efficiency of 62%, linearity r2 > 0.99, accuracy and precision (within ± 15% and ± 20% at the LLOQ) for the determination of tramadol and O-desmethyltramadol. Method comparison in liquid blood with 26 samples showed good agreement (90 ± 19% for tramadol and 94 ± 14% for O-desmethyltramadol). In conclusion, automated analysis of tramadol and O-desmethyltramadol in DBS provides a fast and accurate solution for antidoping screening. It is suited for high-throughput analysis, having a run time of about 4 min per sample. Furthermore, with the automated approach, manual sample extraction becomes obsolete.

Long-term stability of an infusion containing paracetamol, alizapride, ketorolac and tramadol in glass bottles at 5±3°C.

Background and objective: Infusion containing paracetamol, alizapride, ketorolac and tramadol is used after a general anaesthesia in order to limit pain, fever and nausea. Currently, these infusions are prepared according to demand in the anaesthesia unit, but the preparation in advance could improve quality of preparation and time management. The aim of this study was to investigate the long-term stability of this infusion in glass bottles at 5°C ± 3 °C. Method: Five bottles of infusion were stored at 5°C ± 3 °C for 60 days. A visual and microscope inspection were performed periodically to observe any particle appearance or colour change. pH and absorbance at three wavelengths were measured. The concentrations were measured by ultra-high performance liquid chromatography - diode array detection. Results: Multiple verifications were performed during the first 35 days and no crystal, impurity or colour change were observed. At the next time point (42nd day), crystals were visible to the naked eye. pH and absorbance at 350 nm and 550 nm were stable. A slight increase in the absorbance at 410 nm was observed during the study, suggesting that a degradation product could be formed and absorb at this wavelength. The infusion was considered chemically stable while the lower one-sided prediction limit at 95% remains superior to 90% of the initial concentration. Concentration measurements demonstrated that ketorolac and alizapride remained stable in the infusion for 35 days. The stability of tramadol was 28 days. However, degradation of paracetamol was much faster given that concentration has fallen below 90% of the initial concentration after 7 days. Conclusion: Infusion of paracetamol, alizapride, ketorolac and tramadol remains stable for 7 days in glass bottles at 5°C ± 3 °C and could be prepared in advance with these storage conditions.

A screen-printed electrochemical sensing platform surface modified with nanostructured ytterbium oxide nanoplates facilitating the electroanalytical sensing of the analgesic drugs acetaminophen and tramadol.

An electrochemical sensing platform based upon screen-printing electrodes (SPEs) modified with nanostructured lanthanide metal oxides facilitate the detection of the widely misused drugs acetaminophen (ACP) and tramadol (TRA). Among the metal oxides examined, Yb2O3 nanoplates (NPs) were found to give rise to an optimal electrochemical response. The electroanalysis of ACP and TRA individually, and within mixtures, was performed using cyclic and differential pulse voltammetry. The ACP and TRA exhibited non-overlapping voltammetric signals at voltages of +0.30 and + 0.67 V (vs. Ag/AgCl; pH 9) using Yb2O3-SPEs. Pharmaceutical dosage forms and spiked human fluids were analyzed in wide linear concentration ranges of 0.25-654 and 0.50-115 µmol.L-1 with limits of detection (LOD) of 55 and 87 nmol.L-1 for ACP and TRA, respectively. The Yb2O3-SPEs offer a sensitive and chemically stable enzyme-free electrochemical platform for ACP and TRA assay. Graphical abstractSchematic presentation of one-shot electrochemical analysis of misused drugs, tramadol (TRA) and acetaminophen (ACP) by utilizing ytterbium oxide nanoplates modified screen-printed electrodes (Yb2O3-SPEs). The Yb2O3-SPEs showed interesting responses for ACP and TRA within pharmaceutical formulations and human fluids.

Disappearance of Tramadol and THC-COOH in Hair After Discontinuation of Abuse. Two Different Profiles.

The retrospective calendar of an individual's drug use requires a multisectional analysis in which the length of hair, corresponding to the full temporal window available, is cut into shorter sections to measure drug use during shorter periods of time (generally 1 cm corresponds to ~1 month). Segmental hair analysis is used to verify both previous drug history and recent enforced abstinence. However, after drug discontinuation, the fresh new hair growth segment cannot be immediately negative, due to the contribution of dormant hair. The objective of the study was to test hair samples from chronic tramadol and cannabis users after the discontinuation of both drugs and to evaluate the delay to wait until the hair will become negative. Hair specimens were obtained from eight subjects with a known history of tramadol abuse. Hair was collected 3-6 months after tramadol discontinuation. Tramadol was tested by liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS) with a LOQ at 5 pg/mg. A second set of hair specimens were obtained from 15 subjects with a known history of cannabis abuse. Hair was collected 6-9 months after cannabis discontinuation. THC-COOH was tested by LC-MS-MS with a LOQ at 0.2 pg/mg. The hair stands were cut into L × 1 cm segments, according to their length (L), and tested for the respective drug. It was asked to each subject to clearly indicate the date of drug discontinuation. Assuming a rate of hair growth of 1 cm/month, the segment corresponding to the time of last drug use was calculated. The older segment just before this one was considered as the 100% of the response. THC-COOH and tramadol concentrations in this segment ranged from 2.3 to 8.9 and 895 to 21,010 pg/mg, respectively. After cessation of drug consumption, the presence of both drugs in new growing hair segments continued for a certain period with a more or less broad transition zone. Negative hair results were obtained ~3-4 and 6-7 months after cessation of tramadol and cannabis abuse.

[Occurrence of Tramadol and Fentanyl Use in Domestic Wastewater in Beijing].

Tramadol (TRA) and fentanyl (FEN) are used as common painkillers in clinical practice, but they have been increasingly abused in recent years due to their addictive nature. Two substances and their metabolites enter wastewater through urine and are collected and treated by wastewater treatment plants (WWTPs) before being discharged into the aquatic environment. In this study, wastewater analysis was performed to examine the patterns of TRA and FEN use in the urban area of Beijing for the first time. Influent and effluent samples were collected from 23 WWTPs during two sampling campaigns. Concentrations TRA in influents were found to range from(10.2±8.7)to(175.3±59.7) ng·L-1, while FEN was not detected in most of the samples, or occurred at very low concentrations. Relatively low TRA removal was observed at plants with activated sludge processes. Moreover, TRA loads in the central area of Beijing were significantly higher than those in the suburban areas. Annual TRA use was estimated through wastewater-based epidemiology. The greatest TRA use, approximately 202.5 kg, was found in Haidian district. Seasonal variation in TRA loads was significant, with greater use in the summer than in winter. The method presented in this study can be used as an important reference for monitoring TRA and FEN use via wastewater-based epidemiology and for assessing the risk of the abuse of these compounds in China.

Tramadol, Methadone and Benzodiazepines added to Alcoholic Beverages.

AIMS: To search for pharmaceutical additives in illicit alcoholic beverages referred to the laboratory of Legal Medicine Organization in Iran in 2017. METHODS: Hundred beverages were sampled. Ethanol content was determined by gas chromatography with flame ionization detection (GC-FID) and then a liquid-liquid extraction combined with reversed-phase high performance liquid chromatography equipped with a photodiode array detector (PAD) was employed for the qualitative analysis. The analysis was confirmed using gas chromatography coupled with mass spectroscopy (GC/MS). RESULTS: In 15% either one or more of the following were detected: tramadol, methadone, diazepam, oxazepam, flurazepam and alprazolam. Tramadol was found with highest frequency. CONCLUSIONS: The wide availability of addictive pharmaceutical is leading to fortification of alcoholic beverages on some countries. The addition of such depressant additives should be better known because of the potentially fatal consequences of the combination with ethanol, as well as the potential for adverse effects on behavior.

Development of air-assisted dispersive micro-solid-phase extraction-based supramolecular solvent-mediated Fe3 O4 @Cu-Fe-LDH for the determination of tramadol in biological samples.

A simple method, air-assisted dispersive micro-solid-phase extraction-based supramolecular solvent was developed for the preconcentration of tramadol in biological samples prior to gas chromatography-flame ionization detection. A new type of carrier liquid, supramolecular solvent based on a mixture of 1-dodecanol and tetrahydrofuran was combined with layered double hydroxide coated on a magnetic nanoparticle (Fe3 O4 @SiO2 @Cu-Fe-LDH). The supramolecular solvent was injected into the solution containing Fe3 O4 @SiO2 @Cu-Fe-LDH in order to provide high stability and dispersion of the sorbent without any stabilizer agent. Air assisted was applied to enhance the dispersion of the sorbent and solvent. A number of analytical techniques such as Fourier transform-infrared spectrometry, field emission scanning electron microscope, energy-dispersive X-ray spectroscopy and X-ray diffraction measurements were applied to assess the surface chemical characteristics of Fe3 O4 @SiO2 @Cu-Fe-LDH nanoparticles. The effects of important parameters on the extraction recovery were also investigated. Under optimized conditions, the limits of detection and quantification were obtained in the range of 0.9-2.4 and 2.7-7.5 µg L-1 with preconcentration factors in the range of 450-472 in biological samples. This method was used for the determination of tramadol in biological samples (plasma, urine and saliva samples) with good recoveries.

Development and validation of an HPLC-UV method for simultaneous determination of sildenafil and tramadol in biological fluids: Application to drug-drug interaction study.

The introduction of sildenafil (SDF) to treat erectile dysfunction has solved a widespread condition with negative on the quality of life. Recently, the co-administration of tramadol (TMD) with SDF to manage premature ejaculation has illegally increased and thus drug-drug interaction studies of these drugs became of great importance. Although certain biological functions have been altered upon co-administration of the two drugs, methods for their determination in vivo to understand their interactions have yet to be published. Herein, therefore, an HPLC method with photometric detection was developed for the determination of a binary mixture of TMD and SDF in rabbit plasma after oral administration. In this study, a reversed-phase chromatography was performed at room temperature on a C18 column with a mobile phase composed of 10 mM Na2HPO4 solution (pH 7.5): acetonitrile (45:55, v/v) at a flow rate of 0.8 mL min-1 using caffeine (CAF) as an internal standard. The detector was set at 220 nm. The total analysis time was 6 min. Calibration graphs were linear in the concentration ranges of 0.1-10 and 0.05-10 µg mL-1 with a detection limit of 0.05 and 0.02 µg mL-1 for TMD and SDF, respectively. The method was validated in terms of accuracy, precision, limit of detection and quantitation, recovery, and stability as per US FDA bioanalytical guidelines. In addition, the metabolites N-desmethylsildenafil (UK-103,320) and O-desmethyltramadol were quantified in rabbit plasma after 2 h of oral administration using LC-MS/MS. The simultaneous administration of TMD with SDF has affected peak plasma concentration (Cmax), Tmax, area under the concentration-time curve (AUC), and the elimination rate constant (Kel) of SDF. The present study is the first to give valuable insights into the drug-drug interaction and the pharmacokinetic implications associated with the co-administration of SDF and TMD.

Disinfection by-Products and Ecotoxic Risk Associated with Hypochlorite Treatment of Tramadol.

In recent years, many studies have highlighted the consistent finding of tramadol (TRA) in the effluents from wastewater treatment plants (WTPs) and also in some rivers and lakes in both Europe and North America, suggesting that TRA is removed by no more than 36% by specific disinfection treatments. The extensive use of this drug has led to environmental pollution of both water and soil, up to its detection in growing plants. In order to expand the knowledge about TRA toxicity as well as the nature of its disinfection by-products (DBPs), a simulation of the waste treatment chlorination step has been reported herein. In particular, we found seven new by-products, that together with TRA, have been assayed on different living organisms (Aliivibrio fischeri, Raphidocelis subcapitata and Daphnia magna), to test their acute and chronic toxicity. The results reported that TRA may be classified as a harmful compound to some aquatic organisms whereas its chlorinated product mixture showed no effects on any of the organisms tested. All data suggest however that TRA chlorination treatment produces a variety of DBPs which can be more harmful than TRA and a risk for the aquatic environment and human health.

Different rates of tramadol infusion for peri and postoperative analgesia in dogs undergoing orthopedic surgery / Comparação de diferentes taxas de infusão de tramadol para analgesia peri e pós-operatória em cães submetidos a procedimentos cirúrgicos ortopédicos sob anestesia geral inalatória

The study aimed to determine the continuous rate infusion of tramadol associated with peri- and postoperative analgesia for orthopedic surgeries in dogs, as well as cardiorespiratory and adverse effects. Thirty dogs aged 4.2±1.2 years and weighing 15.1±0.9kg were enrolled in the study, premedicated intramuscularly with acepromazine (0.04mg kg-1) and tramadol (2mg kg-1); anesthesia was induced with propofol and maintained with isoflurane in oxygen. Three infusion rates were compared, comprising three experimental groups: G2: 2.0mg kg-1 h-1; G2.5: 2.5mg kg-1 h-1; and G3: 3.0mg kg-1 h-1. Surgery was initiated 15 minutes following the start of tramadol infusion. During anesthesia, animals were monitored in predefined time points: immediately after tracheal intubation and start of inhalation anesthesia (T0); surgical incision (TSI); final suture (TFS) and end of tramadol infusion (TEI), which was maintained for at least 120 minutes and prolonged according to the duration of surgery. Postoperative analgesia was evaluated through an interval pain scoring scale and the Melbourne pain scale. The mean time of tramadol infusion was greater than 120 minutes in all groups and no differences were found among them (141±27 minutes in G2, 137±27 minutes in G2.5 and 137±30 minutes in G3). Perioperative analgesia was regarded as short and did not correlate with infusion rates. Tramadol infusion provided adequate analgesia with cardiorespiratory stability Analgesia was not dose-dependent, however, and residual postoperative effects were short-lasting, which warrants proper postoperative analgesia following tramadol infusion. Additional studies are required using higher infusion rates and standardized nociceptive stimulation in order to determine how doses influence tramadol analgesia and whe therthereis a limit to its effect in dogs.(AU)

Objetivou-se determinar a infusão de taxa contínua de tramadol associada à analgesia peri e pós-operatória para cirurgias ortopédicas em cães, além de efeitos cardiorrespiratórios e adversos. Foram utilizados 30 cães, com idade média de 4,2±1,2 anos e pesos médios de 15,1±0,9kg, pré-medicados por via intramuscular com acepromazina (0,04mg/kg) e tramadol (2mg/kg). A anestesia foi induzida com propofol e mantida com isoflurano em oxigênio. Foram comparadas três taxas de infusão, compreendendo três grupos experimentais: G2: 2,0mg/kg; G2,5: 2,5mg/kg1; e G3: 3,0mg/kg. A cirurgia começou 15 minutos após o início da infusão de tramadol. Durante a anestesia, os animais foram monitorados nos seguintes momentos: imediatamente após a intubação traqueal e o início da anestesia inalatória (T0); incisão cirúrgica (TSI); final de sutura (TFS) e final da infusão de tramadol (TEI), que foi mantida por, pelo menos, 120 minutos e prolongada de acordo com a duração da cirurgia. A analgesia pós-operatória foi avaliada por escalas de pontuação de dor, conforme a escala intervalar de avaliação de dor e a escala de contagem variável de avaliação de dor da Universidade de Melbourne, a cada uma hora. O tempo médio de infusão de tramadol foi maior que 120 minutos em todos os grupos, e não foram encontradas diferenças entre elas (141±27 minutos em G2, 137±27 minutos em G2,5 e 137±30 minutos em G3). A analgesia perioperatória foi adequada na maioria dos indivíduos e a pós-operatória foi considerada curta, não correlacionada àquelas com diferentes taxas de infusão. A infusão de tramadol nas taxas estudadas produziu analgesia adequada com estabilidade cardiorrespiratória. A analgesia não foi dose dependente, no entanto os efeitos residuais pós-operatórios foram considerados curtos, o que determina a necessidade de analgesia adequada após infusão contínua de tramadol. Estudos adicionais que utilizam taxas mais elevadas de infusão de tramadol e estimulação nociceptiva padrão são necessários para determinar em que medida as doses influenciam a analgesia de tramadol e se há um limite nos seus efeitos nos cães.(AU)

Development of a novel LC-MS/MS method for detection and quantification of tramadol hydrochloride in presence of some mislabeled drugs: Application to counterfeit study.

Counterfeiting of pharmaceuticals has become a serious problem all over the world, particularly in developing countries. In the present work, a highly sensitive LC-MS/MS method was developed for simultaneous determination of tramadol hydrochloride in the presence of some suspected mislabeled drugs such as alprazolam, diazepam, chlorpheniramine maleate, diphenylhydramine and paracetamol. The prepared samples were analyzed on an API 4000 mass spectrometer using an Eclipse C18 column (3.5 µm, 4.6 × 100 mm). The mobile phase consisting of 0.01% formic acid, acetonitrile and methanol (60:20:20 v/v/v) was pumped with an isocratic elution at a flow rate of 0.7 mL min-1 . The detection was achieved on a triple quadruple tandem mass spectrometer in multiple reaction monitoring mode. The proposed method was successfully validated according to International Conference on Harmonization guidelines with respect to accuracy, precision, linearity, limit of detection and limit of quantitation. The calibration linear range for tramadol hydrochloride, alprazolam, diazepam, chlorpheniramine maleate, diphenylhydramine and paracetamol was 5-500 ng mL-1 . The results revealed that the applied method is promising for the differentiation of genuine tramadol tablets from counterfeit ones without prior separation.

Segmental Hair Analysis-Interpretation of the Time of Drug Intake in Two Patients Undergoing Drug Treatment.

The present study involved segmental testing of hair in two clinical cases with known dosage histories. Hair analysis confirmed the first patient's exposure to the prescribed sertraline and citalopram for several months. Citalopram was generally distributed along the hair shaft in accordance with the drug ingestion period. By contrast, "false" positive results were observed for sertraline in distal hair segments, corresponding to a period of no sertraline exposure, which may indicate incorporation from sweat or sebum, which transport the drugs along the hair surface. The second patient received various drugs during her treatment for brain cancer. Metoclopramide, morphine, oxazepam, paracetamol, sumatriptan, tramadol, and zopiclone, which had been part of the therapy, were all detected in the proximal hair segment. The results of these two cases indicated that results-especially concerning the time of drug intake-must be interpreted with caution and allow for the possibility of incorporation from sweat or sebum.