4-Bromo-2,5-dimethoxyphenethylamine: identification of a new street drug

The identification of 4-bromo-2,5-dimethoxyphenethylamine as a street drug is described. NMR, UV, and mass spectral data used in the identification of the compound are presented.     

5'-Hydroxycotinine-N-oxide,a new nicotine metabolite isolated from rat urine

1. 5'-Hydroxycotinine-N-oxide, 5-(3-pyridyl-N-oxide)-5-hydroxy-1-methyl-pyrrolidone-2, was identified as a new in vivo metabolite of nicotine. 2. The new metabolite was isolated from the urine of rats treated with S -nicotine and characterized using chemical and spectrometric methods. 3. 5-Hydroxycotinine-N-oxide was synthesized and characterized by MS and by infrared as well as 1H- and 13C-NMR spectroscopy. 4. Identity of the new metabolite with synthetic 5-hydroxycotinine-N-oxide was demonstrated by comparing the MS and 1H-NMR spectroscopy data as well as by cochromatography of a spiked urine sample.     

Initiation to drug injection among street youth: a gender-based analysis

Objective(s)

To estimate the incidence rate of initiation into drug injection and to identify predictors of initiation into drug injection separately among street girls and boys.

Design

Data from two consecutive prospective street youth cohort studies (1995-2001 and 2001-2005) were used to conduct these analyses, stratified by gender.

Methods

Data were collected using semi-annual interviewer-administered questionnaires. Variables from the following domains were considered in Cox regression models: socio-demographic characteristics, early and current substance abuse, marginalization, childhood traumatic sexual events and injection exposure.

Results

Of the 946 youth who had never injected drugs at study entry, 86.4% completed at least two questionnaires representing 243 girls and 574 boys. Incidence rates of injection of 7.0 and 5.9 per 100 person-years were observed among these girls and boys respectively. Among girls, cocaine or crack use (adjusted hazard ratio (AHR) = 1.97), heroin use (AHR = 2.86), homelessness (AHR = 2.49) and hanging out regularly with people who inject (AHR = 4.46) all independently increased risk of first injection. Among boys, age decreased risk of initiating injection (AHR = 0.90/year), while cocaine or crack use (AHR = 2.14), heroin use (AHR = 3.56), homelessness before age 16 (AHR = 1.68), incest or rape before age 14 (AHR = 1.98) and hanging out regularly with people who inject (AHR = 1.66) all independently increased this risk.

Conclusions

Our findings suggest similar rates of initiation among girls and boys; however, factors associated with initiation vary by gender. This might lead to the design of more effective programs to prevent initiation into drug injection.     

5'-hydroxycotinine-N-oxide, a new nicotine metabolite isolated from rat urine.

1. 5'-Hydroxycotinine-N-oxide, 5-(3-pyridyl-N-oxide)-5-hydroxy-1-methyl-pyrrolidone-2, was identified as a new in vivo metabolite of nicotine. 2. The new metabolite was isolated from the urine of rats treated with S-nicotine and characterized using chemical and spectrometric methods. 3. 5'-Hydroxycotinine-N-oxide was synthesized and characterized by MS and by infrared as well as 1H- and 13C-NMR spectroscopy. 4. Identity of the new metabolite with synthetic 5'-hydroxycotinine-N-oxide was demonstrated by comparing the MS and 1H-NMR spectroscopy data as well as by co-chromatography of a spiked urine sample.     

Transition to injection drug use among street youth--a qualitative analysis

OBJECTIVES: To examine social contexts and processes influencing transition to drug injection among street youth. METHODS: 42 street youth participated in in-depth interviews. A typology of experiences was built founded on youth's street life and drug use trajectories. The transition to drug injection was examined through these experiences. RESULTS: We identified five types of mutually exclusive experiences. The "downtowner's" experience is characterised by early street life and drug consumption trajectories, and a strong identification with the downtown milieu. These youth progress from one drug to another and, in a milieu where drug injection is omnipresent, this escalation culminates in transition to injection. The "tripper" street life and substance use trajectories begin later and are less intense. Most "tripper" youth are already chronic hallucinogens users when they arrive in downtown Montréal. Although they judge "junkies" severely, they show some ambivalence towards injection. The "on the go" experience is characterised by trajectories of drug use and street life that are intermingled, leading to a loss of control. These youth, who often have serious delinquent behaviours, come to downtown Montréal to party and consume drugs, mostly stimulants. Their drug use pattern and network make them at high risk of starting cocaine injection. The "hard-luck's" experience is characterised by a lack of identification with the downtown milieu. These youth who use drugs recreationally, end up in the streets accidentally, often because of unemployment. The "alcoholic' experience is related to alcohol misuse. These youth usually end up in the streets due to this dependence. Their street involvement is mostly an experience of solitude. The risk of transitioning to injection for both these types is low. CONCLUSIONS: Some combinations of street life and drug use trajectories seem to contribute to injection among street youth. Some important factors interact and increase the risk of street youth transitioning to injection: poor personal assets; early rupture with primary social institutions; social integration into subcultures where both street life and "drug trips" are fashionable, drug preferences and the local drug market.     

Mephedrone, a new designer drug of abuse, produces acute hemodynamic effects in the rat

Mephedrone (4-methylmethcathinone) is a new and popular drug of abuse widely available on the Internet and still legal in some parts of the world. Clinical reports are now emerging suggesting that the drug displays sympathomimetic toxicity on the cardiovascular system but no studies have yet explored its cardiovascular effects. Therefore we examined the effects of mephedrone on the cardiovascular system using a combination of in vitro electrophysiology and in vivo hemodynamic and echocardiographic measurements. Patch clamp studies revealed that mephedrone, up to 30 μM, had little effect on the major voltage-dependent ion channels of the heart or on action potentials recorded in guinea pig myocytes. Subcutaneous administration of mephedrone (3 and 15 mg/kg) to conscious telemetry-implanted rats produced dose-dependent increases in heart rate and blood pressure which persisted after pre-treatment with reserpine. Echocardiographic analysis demonstrated that intravenous injection of mephedrone (0.3 and 1 mg/kg) increased cardiac function, including cardiac output, ejection fraction, and stroke volume, similar to methamphetamine (0.3 mg/kg). We conclude that mephedrone is not directly pro-arrhythmic, but induces substantial increases in heart rate, blood pressure and cardiac contractility and this activity contributes to the cardiovascular toxicity in people who abuse the drug.     

The pharmacokinetics of a new benzamide drug,clebopride, in the rat and the dog

After intravenous, intramuscular and oral administration of clebopride in the rat and the dog its apparent volume of distribution is high (1·6–3·2 1 kg^?1) and it has a longer biological half-life than metoclopramide in both species. High clearance values and concentrations of metabolites in plasma after oral administration indicate that the drug is subjected to an extensive first pass metabolism in the rat. Thus, clebopride administered orally gives relatively low concentrations in the systemic circulation in rats even though it is rapidly absorbed. The metabolic processes appear to become saturated at high doses which is reflected in dose-dependent kinetics. Linear kinetics were observed in the dog, although enterohepatic recycling could occur.     

Metabolic fate of premazepam, a new anti-anxiety drug, in the rat and the dog

A study of the disposition and metabolism of premazepam, 3,7-dihydro-5-phenyl-6,7-dimethyl-pyrrole[3,4-e][1,4]diazepin-2-(1 H) -one, a new anti-anxiety agent, was carried out in rats and dogs given the 14C-labeled compound iv and po. In both species, after oral administration, both total radioactivity and the unchanged drug are rapidly absorbed and peak plasma levels are reached within 0.5-1 hr in rats and 2 hr in dogs. Unchanged premazepam is cleared faster in rats than in dogs, with half-lives about 1.7 and 2.7 hr, respectively. Following oral dosage, two-thirds of the dose is eliminated in urine. From the urine of the two species, eight metabolites and unchanged premazepam were identified. N-7-Desmethyl premazepam (l) is the major metabolite in rat urine (18% of the dose) but is not present in dog urine, while 6-hydroxymethyl premazepam is the most abundant metabolite in dog urine (25% of the dose) but is absent in rat urine. Metabolites III and IV from rat and dog urine are stable derivatives of the intermediate formed by the cleavage of the imine bond of the diazepine ring. A successive hydrolysis of the amidic bond of the same intermediate originates metabolites V-VIII, which are quantitatively minor ones.     

Rapid simultaneous determination of amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine, 3,4-methylenedioxymethamphetamine, and 3,4-methylenedioxyethylamphetamine in urine by fast gas chromatography-mass spectrometry

The use of fast gas chromatography-mass spectrometry (FGC-MS) was investigated to improve the efficiency of analysis of urine specimens that previously screened presumptively positive for amphetamine (AMP), methamphetamine (MAMP), 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA), and/or 3,4 methylenedioxyethylamphetamine (MDEA) by immunoassay testing. Specimens were pretreated with basic sodium periodate, extracted using a positive-pressure manifold/cation-exchange solid-phase cartridge methodology, and derivatized using 4-carbethoxyhexafluorobutyryl chloride (4-CB). The analytical method was compared to traditional GC-MS analysis and evaluated with respect to assay chromatography, linearity, sensitivity, precision, accuracy, and reproducibility. The limits of detection were 62.5 ng/mL for MDA and 31.25 ng/mL for AMP, MAMP, MDMA, and MDEA. All of the target analytes were linear to 12,000 ng/mL with the exception of MAMP which was linear to 10,000 ng/mL. The intra-assay precision of a 500 ng/mL multiconstituent control (n=15) ranged from 522.6 to 575.9 ng/mL with a coefficient of variation of less than 3.8%. Authentic human urine specimens (n=187) previously determined to contain the target analytes were re-extracted and analyzed by both FGC-MS and the currently utilized GC-MS method. No significant differences in specimen concentration were observed between these analytical methods. No interferences were seen when the performance of the FGC-MS method was challenged with ephedrine, pseudoephedrine, phenylpropanolamine, and phentermine. When compared to traditional GC-MS analysis, FGC-MS analysis provided a dramatic reduction in retention time for amphetamine (1.8 min vs. 4.12 min). For example, the FGC-MS method reduced overall run time for a batch of 56 specimens from 12.0 h to 7.25 h. This reduction in analysis time makes FGC-MS an attractive alternative to traditional GC-MS by allowing a laboratory greater flexibility in the purchase and use of capital equipment and in the assignment of laboratory personnel, all resulting in greater overall efficiency by decreasing reporting times for AMP, MAMP, and designer amphetamine positive specimens.     

Urinary metabolites of felodipine,a new vasodilator drug,in man,dog, rat and mouse

1. The urinary excretion of total ¹⁴C after oral administration of 25 mg (～ 1 μmol/kg) ¹⁴C-felodipine to man, and intragastric administration (5 μmol/kg) to dog, rat and mouse, was 70, 39, 44 and 53% dose, respectively, in 72 h.

2. Metabolites of felodipine were separated and quantified by h.p.l.c. Unchanged felodipine and its oxidized analogue were not excreted by any of the species studies.

3. Three metabolites, present in all species studied, were isolated from urine and identified as products of the oxidation of felodipine to its pyridine analogue followed by hydrolysis of one or both of the pyridine carboxylic acid esters.     

The pharmacokinetics of a new benzamide drug clebopride, in the rat and the dog

After intravenous, intramuscular and oral administration of clebopride in the rat and the dog its apparent volume of distribution is high (1.6-3.2 1 kg-1) and it has a longer biological half-life than metoclopramide in both species. High clearance values and concentrations of metabolites in plasma after oral administration indicate that the drug is subjected to an extensive first pass metabolism in the rat. Thus, clebopride administered orally gives relatively low concentrations in the systemic circulation in rats even though it is rapidly absorbed. The metabolic processes appear to become saturated at high doses which is reflected in dose-dependent kinetics. Linear kinetics were observed in the dog, although enterohepatic recycling could occur.     

Ipsapirone, a new anxiolytic drug, stimulates catecholamine turnover in various regions of the rat brain

Ipsapirone, a new anxiolytic drug with a high affinity to 5-HT1A receptors, given in a dose of 10 mg/kg ip markedly accelerated noradrenaline disappearance after inhibition of tyrosine hydroxylase with alpha-methyl-p-tyrosine (250 mg/kg ip) in the cortex, hippocampus and hypothalamus of male Wistar rats. It also increased disappearance of dopamine and the level of 3,4-dihydroxyphenylacetic acid and homovanillic acid in the striatum. At the same time, the level of 5-hydroxyindoleacetic acid was decreased in the cortex, striatum, hypothalamus, but not changed in the hippocampus. 8-OH-DPAT, a selective agonist of 5-HT1A receptors, used in a dose of 5 mg/kg sc was less effective, having accelerated noradrenaline disappearance in the cortex and hypothalamus, and having increased only the level of homovanillic acid in the striatum. The effect of ipsapirone on catecholamine turnover might be secondary in relation to inhibition of the serotonin neurons. A direct interaction between ipsapirone and its metabolite 1-PP with alpha 1- and alpha 2-adrenoceptors is very likely, too.     

Rapid simultaneous determination of amphetamine,methamphetamine, 3,4-methylenedioxyamphetamine, 3,4-methylenedioxymethamphetamine,and 3,4-methylenedioxyethylamphetamine in urine by solid-phase extraction and GC-MS: a method optimized for high-volume laboratories

To facilitate analysis of high sample volumes, an extraction, derivatization and gas chromatographic-mass spectrometric analysis method was developed to simultaneously determine amphetamine (AMP), methamphetamine (MAMP), 3,4-methylenedioxyamphetamine (MDA) 3,4-methylenedioxymethamphetamine (MDMA), and 3,4-methylenedioxyethylamphetamine (MDEA) in urine. This method utilized a positive-pressure manifold cation-exchange polymer-based solid-phase extraction followed by elution directly into automated liquid sampler (ALS) vials. Rapid derivatization was accomplished using heptafluorobutyric anhydride (HFBA). Recoveries averaged 90% or greater for each of the compounds. Limits of detection were 62.5 ng/mL (AMP and MDEA), 15.6 ng/mL (MAMP), and 31.3 ng/mL (MDA and MDMA) using a 2-mL sample volume. The method was linear to 5000 ng/mL for all compounds using MDMA-d5 and MAMP-d14 as internal standards. Over 200 human urine samples previously determined to contain the target analytes were analyzed using the method. Excellent agreement was seen with previous quantitations. The method was challenged with 75 potentially interfering compounds and no interferences were seen. These interfering compounds included ephedrine, pseudoephedrine, phenylpropanolamine, and phenethylamine. The method resulted in dramatic reductions in processing time and waste production.     

我国一类新药“头孢硫脒”相关文献计量分析

摘要：目的 通过对我国自行研发的一类新药“头孢硫脒”自1978年首次文献报道到2022年5月,近44年的期刊文献计量 分析,探讨学界对“头孢硫脒”在研发和临床使用等阶段的科研关注。方法 以中国知网总库(CNKI)为检索数据来源,通过 CNKI计量分析系统、Citespace可视化分析软件,从发文时间分布,作者合作网络,关键词共现、聚类及时间线路径等层次进 行分析,挖掘“头孢硫脒”的研究热点、知识基础及发展关键路径。结果 共纳入文献280篇,核心作者有19位;关键词共现 分析得到高频词8个;关键词聚类分析显示发表文献的关键词聚类到15个类别;关键词路径分析头孢硫脒的研究主要分为两阶 段,第一阶段是头孢硫脒的研发阶段,研究热点是“合成”“药理”“临床研究”;第二阶段是头孢硫脒临床使用阶段,研究 热点是药品的“不良反应”“临床疗效”和“稳定性”。结论 作者、研究机构的合作比较分散,研究内容主要围绕药物合 成、质量稳定性、临床疗效展开,对头孢硫脒的研究趋势是质量控制、稳定性、耐药性及临床疗效等方面。