Adulterants in crack cocaine in Brazil / Adulterantes no crack vendido na "Cracolândia"

Abstract Introduction Brazil is the world's biggest consumer of crack cocaine, and dependence is a major public health issue. This is the first study to investigate the prevalence of potentially harmful adulterants present in hair samples from Brazilian patients with crack cocaine dependence. Method We evaluated adulterants in hair samples extracted by convenience from 100 patients admitted at the 48 hour-observation unit of Centro de Referência de Álcool, Tabaco e Outras Drogas (CRATOD), Brazil's largest center for addiction treatment. A cross-sectional analysis was performed with the data obtained. Results Adulterants were found in 97% of the analyzed hair samples. The most prevalent adulterant was lidocaine (92%), followed by phenacetin (69%) and levamisole (31%). Conclusion Adulterants were widely prevalent in hair samples from crack users treated at CRATOD: at least one adulterant was present in virtually all the hair samples collected. This points to a need to monitor adverse effects in the clinical setting in order to provide this high-risk group of patients with prompt and effective care related to the acute and chronic complications associated with these adulterants.

Resumo Introdução O Brasil é o maior consumidor mundial de crack, e a dependência é um grande problema de saúde pública. Este é o primeiro estudo a investigar a prevalência de adulterantes potencialmente nocivos presentes em amostras de cabelo de pacientes brasileiros com dependência de crack. Métodos Foram avaliados adulterantes em amostras de cabelos extraídos por conveniência de 100 pacientes internados na unidade de observação de 48 horas do Centro de Referência de Álcool, Tabaco e Outras Drogas (CRATOD), o maior centro de tratamento de dependência do Brasil. Uma análise transversal foi realizada com os dados obtidos. Resultados Foram encontrados adulterantes em 97% das amostras de cabelo analisadas. O adulterante mais prevalente foi a lidocaína (92%), seguida da fenacetina (69%) e levamisol (31%). Conclusão Os adulterantes foram amplamente prevalentes em amostras de cabelo de usuários de crack tratados no CRATOD: pelo menos um adulterante estava presente em praticamente todas as amostras de cabelo coletadas. Isso aponta para a necessidade de monitorar os efeitos adversos no ambiente clínico, a fim de proporcionar a esse grupo de pacientes de alto risco cuidados imediatos e efetivos relacionados às complicações agudas e crônicas associadas a esses adulterantes.

Development and validation of a UPLC-MS/MS method for the quantification of acetaminophen in human plasma and its application to pharmacokinetic studies

We developed an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the determination of acetaminophen concentration in human plasma. Following protein precipitated extraction, the analytes were separated and analyzed using an UPLC-MS/MS in the multiple reaction monitoring (MRM) mode with the respective [M+H]+ ions, m/z 152.06 → 110.16 for acetaminophen and m/z 180.18 → 138.12 for phenacetin (internal standard, IS). The method showed a linear response from 1 to 100 µg/mL (r > 0.9982). The limit of quantitation for acetaminophen in plasma was 1 µg/mL. The intra- and inter-day accuracy ranged in the ranges of 94.40–99.56% and 90.00–99.20%, respectively. The intra- and inter-day precision ranged in the ranges of 2.64–10.76% and 6.84–15.83%, respectively. This method was simple, reliable, precise and accurate and can be used to determine the concentration of acetaminophen in human plasma. Finally, this fully validated method was successfully applied to a pharmacokinetic study of acetaminophen in healthy volunteers following oral administration.

Effects of Ziziphus jujuba fruit extracts on cytochrome P450 (CYP1A2) activity in rats / 中国天然药物

Drug-drug interactions have become a serious problem in the clinic, since plant-based medicines are extensively used. The present study investigated the effects of Ziziphus jujuba fruit (ZJ) extract on the pharmacokinetics of phenacetin, a typical substrate of a cytochrome P450 enzyme CYP 1A2, in rats. The rats were pretreated with the water extract (1.0 g · kg(-1)) or the ethanolic extract (3.6 g · kg(-1)) of ZJ for 10 days, and the pharmacokinetics of phenacetin was investigated after intravenous administration. In an in vitro assay, acetaminophen formation in the hepatic microsomes of ZJ-treated rats was investigated to assess CYP1A2 activity. Our results demonstrated that the treatment with the water and ethanolic extracts of ZJ decreased the plasma concentration of phenacetin and increased the plasma concentration of acetaminophen, resulting in a 43.2% and 15.5% reduction in the AUC0-120 of phenacetin, respectively, and a 53.2% and 64.9% increase in the AUC0-120 of acetaminophen, respectively after intravenous administration. The water or ethanolic extract of ZJ significantly increased the clearance of phenacetin and acetaminophen formation in hepatic microsomes. In conclusion, ZJ extracts displayed effects on the pharmacokinetics of phenacetin and increased the CYP1A2 activity in rats. Therefore, precaution on drug-drug interactions should be taken when ZJ is co-administered with drugs metabolized by CYP1A2, which may result in decreased concentrations of these drugs.

Functional Significance of Cytochrome P450 1A2 Allelic Variants, P450 1A2*8, *15, and *16 (R456H, P42R, and R377Q)

P450 1A2 is responsible for the metabolism of clinically important drugs and the metabolic activation of environmental chemicals. Genetic variations of P450 1A2 can influence its ability to perform these functions, and thus, this study aimed to characterize the functional significance of three P450 1A2 allelic variants containing nonsynonymous single nucleotide polymorphisms (P450 1A2*8, R456H; *15, P42R; *16, R377Q). Variants containing these SNPs were constructed and the recombinant enzymes were expressed and purified in Escherichia coli. Only the P42R variant displayed the typical CO-binding spectrum indicating a P450 holoenzyme with an expression level of approximately 170 nmol per liter culture, but no P450 spectra were observed for the two other variants. Western blot analysis revealed that the level of expression for the P42R variant was lower than that of the wild type, however the expression of variants R456H and R377Q was not detected. Enzyme kinetic analyses indicated that the P42R mutation in P450 1A2 resulted in significant changes in catalytic activities. The P42R variant displayed an increased catalytic turnover numbers (k(cat)) in both of methoxyresorufin O-demethylation and phenacetin O-deethylation. In the case of phenacetin O-deethylation analysis, the overall catalytic efficiency (k(cat)/K(m)) increased up to 2.5 fold with a slight increase of its K(m) value. This study indicated that the substitution P42R in the N-terminal proline-rich region of P450 contributed to the improvement of catalytic activity albeit the reduction of P450 structural stability or the decrease of substrate affinity. Characterization of these polymorphisms should be carefully examined in terms of the metabolism of many clinical drugs and environmental chemicals.

CYP450 enzyme inhibition of berberine in pooled human liver microsomes by cocktail probe drugs / 中国中药杂志

<p><b>OBJECTIVE</b>To investigate the effect of CYP450 enzyme inhibition of berberine in pooled human liver microsomes by cocktail probe drugs.</p><p><b>METHOD</b>Cocktail probe drugs method has been established, an LC-MS/MS analytical method has been established to determine the five probes of midazolam, phenacetin, dextromethorphan, tolbutamide, chlorzoxazone and the internal standard was benzhydramine to evaluate the effect of CYP450 activity following administration of berberine in pooled human liver microsomes.</p><p><b>RESULT</b>Compared with control group, the pharmacokinetics of midazolam, phenacetin and tolbutamide were no significant differences, but the pharmacokinetics of chlorzoxazone was significantly decreased. There were no significant differences for the pharmacokinetics of dextromethorphan when the concentration of berberine was 50 microg x L(-1). The pharmacokinetics of dextromethorphan was significantly decreased when the concentration of berberine was exceed 200 microg x L(-1).</p><p><b>CONCLUSION</b>Berberine has no influence on the activities of CYP3A4, CYP1A2 and CYP2C19 below 2 000 microg x L(-1), but can inhibit the activity of CYP2E1 and CYP2D6 in concentration-dependent.</p>

Thermodinamic aspects of solvation and dilution for acetanilide and phenacetin in some aqueous and organic solvents mutually saturated

Acetanilide (ACN) and phenacetin (PNC) are compounds structurally related with acetaminophen widely used as model drugs in pharmaceutical chemistry. Based on published thermodynamic quantities for dissolution, partitioning and sublimation of ACN and PNC, at 25.0 °C, thermodynamic quantities for drugs solvation in cyclohexane-saturated water (W(CH)) and water-saturated cyclohexane (CH(W)), chloroform-saturated water (W(CLF)) and water-saturated chloroform (CLF(W)), and isopropyl myristate- saturated water (W(IPM)) and water-saturated isopropyl myristate (IPM(W)), as well as the drugs dilution in the organic solvents were calculated. The Gibbs energies of solvation were favourable in all cases. Respective enthalpies and entropies were negative indicating an enthalpy-driving for the solvation process in all cases. Otherwise, the Gibbs energies of dilution were favourable for ACN and PNC in IPM(W) but unfavourable in the other organic solvents, whereas the respective enthalpies and entropies were negative for both drugs in all the organic solvents, except for PNC in CH(W) indicating enthalpy-driving for the dilution process in the former cases and entropy-driving for the later. From obtained values for the transfer processes, an interpretation based on solute-solute and solute-solvent interactions was developed.

Tissue-like cultures of rat hepatocytes in study of phase I and phase II drug metabolism / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To investigate phase I and phase II enzyme activities in drug metabolism with tissue-like cultures of rat hepatocytes.</p><p><b>METHODS</b>The gel entrapment and spheroid culture of hepatocytes were used as tissue-like cultures and the monolayer culture was used as a control. The metabolism of phenacetin and 7-hydroxycoumarin (7-HC) was evaluated as the activities of phase I and phase II enzymes after incubated in medium for a period of time. The metabolites were assayed by HPLC. The hepatocytes were exposed to beta-naphthoflavone (BNF, 50 micromol x L(-1)) before the phase I and phase II enzyme activities were analyzed.</p><p><b>RESULT</b>In monolayer culture, phase I parameters decreased quickly and did not detected at d 5, and the phase II enzyme activities were not detected at d 7. In other two models of tissue-like cultures, the activities of phase I and phase II enzyme maintained at 32%-50% of the initial value at d 7. Paracetamol formation rates in spheroid culture maintained at 96% of that at d 1. The phase I enzyme activities of the spheroid culture were maintained from d 1 to d 3 at a level of 2.7-3.9-fold higher than the monolayer culture. After exposure to BNF the activities on phase I enzyme increased by about 2.5-fold (P <0.05) in all three culture models, while the increase in phase II enzyme was not significant.</p><p><b>CONCLUSION</b>The gel entrapment culture and spheroid culture are superior to the monolayer culture in maintenance of drug metabolic enzyme activities.</p>

A Case of Analgesic Nephropathy Complicated by Transitional Cell Carcinoma of the Ureter / 대한신장학회잡지

Following a report by Hultengren et al. (Acta Chir Scand, 1965), it has been suggested that analgesic abuse predisposes to urothelial neoplasia. Urinary tract malignancy is combined in 8-10% of patients with analgesic nephropathy. Microscopic or gross hematuria can be the first sign leading to the diagnosis of uroepithelial malignanacy in analgesic abusers. Since uroepithelial malignancies found in analgesic abusers tend to be multiple and have a worse prognosis, continued monitoring is essential, and new hematuria should be evaluated with urinary cytology, and cystoscopy with reterograde pyelography. Phenacetin found to be the chief cause of malignancies in analgesic abusers, it has been anticipated to be a human carcinogen and was banned as an OTC drug since 1987. But still there remains a debate whether acetaminophen and other compound analgesic components are carcinogenic. We report the case of a 58-year-old man with a history of analgesic abuse who was diagnosed with transitional cell carcinoma combined with analgesic nephropathy. We also review the literature.

Solubilization of certain Analgesics by cetomacrogol 1000

Solubilization of certain nonsteroidal anti-inflammatory drugs, viz., phenacetin, ibuprofen and indomethacin by Cetomacrogol 1000 [Cetomacrogol] has been investigated. The values of the ratio of mole drug solubilized per mole micellar Cetomacrogol revealed that the solubilizing power of Cetomacrogol towards ibuprofen is higher than that for phenacetin or indomethacin. One Cetomacrogol micelle solubilizes 38, 17 and 6 molecules of ibuprofen, phenacetin and indomethacin, respectively. Spectrophotometry as well as solubility measurements in different solvents have been used to provide evidence on the environment of the solubilizate molecule in the micelle. On the basis of the results obtained, it was concluded that these drugs are solubilized as follows: Phenacetin and ibuprofen are solubilized in the hydrocarbon core and in the polyoxyethylene region adjacent to the hydrocarbon core. Indomethacin is wholly solubilized in the polyoxyethylene layer adjacent to the hydrocarbon core. The ability of the surfactants to accelerate the dissolution rate of the drug was also investigated. The dissolution profiles of these drugs in Cetomacrogol revealed marked enhancement of dissolution and there is a good correlation between the dissolution efficiency of the three drugs and their solubility in Cetomacrogol at the same temperature

Nefropatía por analgésicos / Nephropathy caused by analgesics

El uso crónico de analgésicos puede afectar de varias formas la función renal. La nefropatía por analgésicos es una de estas formas de compromiso renal de causa medicamentosa, la que aún siendo poco frecuente en Chile es la más grave, pues su evolución natural lleva a la insuficiencia renal terminal, con todas sus consecuencias socioeconómicas. El presente artículo es una revisión de la etiología, fisiopatología, presentación clínica, tratamiento y posibles medidas de prevención de este tipo de nefropatía

Carcinoma in situ de pelvis renal / Carcinoma in situ of renal pelvis

Es evidente el efecto carcinógeno de ciertas sustancias sobre el urotelio, tal como se ha demostrado con los analgésicos que contienen Fenacetina. Presentamos un caso dignosticado como Carcinoma "in situ" de pelvis renal y uréter, en donde existía el antecendente de abuso de consumo de analgesicos por tiempo prolongado

Clinical Study of Hospitalized Patients with Drug Eruption During a 10-Year Period (1976~1985) / 대한피부과학회지

The study comprises 127 inpatients with drug eruption, treated at the Department of Dermatology, Seoul National University Hospital, during a 10-year period. The results are summarized as follows: 1. Out of 1,434 dermatologic inpatients, 127(8. 9%) patients were diagnosed as drug eruption. 2. The cutaneous manifestations of drug eruptions in the order of frequency were as follows: exanthematous eruption, urticaria, erythema multiforme, Stevens Johnson syndrome, TEN, exfoliative dermatitis, fixed drug eruption and purpura. 3. Antibiotics and antimicrobials were the most common causative agents followed by antipyretics and analgesics, CNS depressant drugs and herb drugs. 4. The 5 most common drugs causing drug eruptions were ampicillin, acetyl salicylic acid, diphenylhydantoin, sulfonamide and phenacetin.

Valoración mediante estudio doble ciego de la combinación de tartrato de ergotamina, acetofenetidina, ácido acetilortoxibenzoico y trimetilxantina en el tratamiento de cefalea vascular tipo migraña / Evaluation by double-blind study of the combination of ergatomine tartrate, acetophenetidine, acetytorthoxybenzoic acid and trimethylxantine, in the treatment of migraine-type vascular cephalea

En el servicio de neurología del Hospital Central Militar de la ciudad de México, se estudió a 60 pacientes con diagnóstico de cefalea vascular tipo migraña, clásica y común. Se valoró la eficiencia y posibles efectos indeseables, mediante estudio doble ciego, de las siguintes combinaciones de medicamento: 1) mesilato de dihidroergotamina, cafeína, butalbital y propifenazona; 2) tartrato de ergotamina y cafeína; y 3) tartrato de ergotamina, acetofenetidina, ácido acetilortoxibenzoico y trimetilxantina