Postmortem distribution of tapentadol and N-desmethyltapentadol

Postmortem distribution concentrations of the pain medication tapentadol and its metabolite N-desmethyltapentadol are reported. Tapentadol (Nucynta?) is a synthetic mu-opioid receptor agonist that also has norepinephrine reuptake inhibitor action. The laboratory received two cases. Case 1: a 19-year-old, morbidly obese male with sudden unexpected death. Toxicology results revealed tapentadol (femoral blood: 0.77 mg/L, liver: 1.65 mg/kg), N-desmethyltapentadol (femoral blood: 0.07 mg/L, liver: 0.19 mg/kg), diazepam (femoral blood: 0.04 mg/L), nordiazepam (femoral blood: 0.06 mg/L) and amiodarone (femoral blood: 5.30 mg/L). Case 2: a 60-year-old female who died from complications following hip replacement. Only tapentadol (femoral blood: 0.26 mg/L, liver: 0.52 mg/kg) was found in the toxicology results. Quantitative results of tapentadol/N-desmethyltapentadol were achieved using liquid chromatography-tandem mass spectrometry in multiple reactions monitoring mode. This is the first known distribution study of tapentadol and N-desmethyltapentadol values in postmortem cases.     

Postmortem blood ketamine distribution in two fatalities

Despite the reported increased use of ketamine as a recreational drug, relatively few fatalities attributed to ketamine poisoning have been documented. Two recent fatalities in which ketamine was detected are described and compared with cases previously reported in the scientific literature. Concentrations of ketamine were measured in the heart and femoral blood samples using gas chromatography with nitrogen phosphorus detection. Ketamine concentrations in a 26-year-old man whose death was attributed to ketamine intoxication were 6.9 and 1.8 mg/L in heart and femoral blood, respectively. In this case, the ketamine concentration detected in the heart blood is in agreement with the lowest concentration reported in the literature, in which ketamine intoxication was ruled as the cause of death and no other drugs were present. Ketamine concentrations in a 20-year-old man, whose death was attributed to asthma and ketamine was considered an incidental finding, were 1.6 and 0.6 mg/L in heart and femoral blood, respectively. Marked differences between heart and femoral blood ketamine concentrations were observed in both of the reported cases. This may be indicative of incomplete distribution prior to death and/or postmortem redistribution of ketamine.     

氯氮平及其代谢产物在兔体内的死后分布

目的建立氯氮平的新西兰大白兔染毒致死模型,观察氯氮平（CLP）及其代谢物在兔体内的死后分布规律。方法按LD50（270 mg.kg-1）与4 LD50（1 080 mg.kg-1）氯氮平给新西兰大白兔灌胃,待实验动物心跳呼吸等生命体征全部消失后,在死亡当时,迅速解剖动物,提取心血、尿、脑、心、肝、脾、肺、肾等组织,样本冷冻保存,经固相萃取提取后,LC/MS/MS定性、定量检测其中氯氮平（CLP）及其代谢物去甲氯氮平（DMCLP）、N-氧化氯氮平（CLP-NO）的含量。结果氯氮平及其代谢物的死后分布存在器官的依存性,肺、肝、肾等器官的分布浓度高,而玻璃体液及下肢肌分布浓度较低。随着染毒剂量的增加,CLP及其代谢物在组织中浓度（尿液除外）有所升高,CLP代谢物与原体浓度的比值随剂量的增加有所下降。结论氯氮平及其代谢物在新西兰大白兔分布不均匀,除常规的尿和血液可以作为分析的检材以外,肝、肺、肾等氯氮平及其代谢物富集的器官亦可作为检案的分析样本。氯氮平及其代谢物浓度与染毒剂量成正比,代谢物与原药浓度的比值与染毒剂量成反比。     

Postmortem distribution of the novel antipsychotic drug quetiapine

The objective of this research was to determine the concentrations and distribution of the atypical antipsychotic drug, quetiapine, in postmortem tissues from eight Medical Examiner cases. Quetiapine was isolated from liquid specimens and tissue homogenates by extraction at an alkaline pH into 1-chlorobutane. The 1-chlorobutane was decanted, and quetiapine, plus the internal standard (prochlorperazine), was back-extracted into 0.1N sulfuric acid. The acid layer was made basic, and quetiapine, plus the internal standard, was re-extracted into 1-chlorobutane. Quantitation was by gradient, high-pressure liquid chromatography on a C-8 ODS (2.1 x 150 mm, 5 mu) column with acetonitrile/0.1M ammonium hydroxide (pH 10) mobile phase and a photodiode array detector set at 258 nm. The apparent linear range of the assay was from 0.05 to 5.0 microg/mL. At known concentrations of 0.1 and 0.5, interday accuracy (n = 5) was 103.8 and 107.2%, respectively. Interday precision (% cv) at the same concentrations was 9.8 and 9.0, respectively. In the cases where quetiapine was not considered to have contributed to the death, the postmortem concentrations in blood, liver, and bile ranged between 0.15 and 2.7 mg/L (n = 6), 1.3 and 9.5 mg/kg (n = 8), and 10 and 46 mg/L (n = 5), respectively. In the one case involving a quetiapine overdose, concentrations in blood (19.8 mg/L), liver (12.6 mg/kg), and bile (161 mg/L) exceeded the ranges of concentrations determined in specimens from the quetiapine-unrelated deaths.     

Postmortem distribution of tramadol, amitriptyline, and their metabolites in a suicidal overdose

A case report involving a 34-year-old white male who was found dead at home by his roommate is presented. At the time of his death, he was being treated with tramadol/acetaminophen, metaxalone, oxycodone, and amitriptyline. The decedent's mother stated that he had been taking increasing amounts of pain medication in order to sleep at night. There were no significant findings at autopsy; however, toxicology results supported a cause and manner of death resulting from suicidal mixed tramadol and amitriptyline toxicity. This case reports the tissue and fluid distribution of tramadol, amitriptyline, and their metabolites in an acutely fatal ingestion in an effort to document concentrations of these analytes in 12 matrices with respect to one another to assist toxicologists in difficult interpretations.     

西地那非的合成工艺改进

以丁酰丙酮酸乙酯 (2 )为原料 ,经肼解环合 ,甲基化 ,水解 ,硝化 ,酰化 ,还原 ,酰胺化 ,氯磺化 ,环合制得西地那非 ,总收率为 2 8%。改进了重要中间体 4 氨基 1 甲基 3 正丙基吡唑 5 酰胺(6 )的合成工艺。     

Postmortem tissue distribution of morphine and its metabolites in a series of heroin‐related deaths

The abuse of heroin (diamorphine) and heroin‐related deaths are increasing around the world. The interpretation of the toxicological results from suspected heroin‐related deaths is notoriously difficult, especially in cases where there may be limited samples. To help forensic practitioners with heroin interpretation, we determined the concentration of morphine (M), morphine‐3‐glucuronide (M3G), and morphine‐6‐glucuronide (M6G) in blood (femoral and cardiac), brain (thalamus), liver (deep right lobe), bone marrow (sternum), skeletal muscle (psoas), and vitreous humor in 44 heroin‐related deaths. The presence of 6‐monoacetylmorphine (6‐MAM) in any of the postmortem samples was used as confirmation of heroin use. Quantitation was carried out using a validated liquid chromatography–tandem mass spectrometry (LC–MS/MS) method with solid‐phase extraction. We also determined the presence of papaverine, noscapine and codeine in the samples, substances often found in illicit heroin and that may help determine illicit heroin use. The results of this study show that vitreous is the best sample to detect 6‐MAM (100% of cases), and thus heroin use. The results of the M, M3G, and M6G quantitation in this study allow a degree of interpretation when samples are limited. However in some cases it may not be possible to determine heroin/morphine use as in four cases in muscle (three cases in bone marrow) no morphine, M3G, or M6G were detected, even though they were detected in other case samples. As always, postmortem cases of suspected morphine/heroin intoxication should be interpreted with care and with as much case knowledge as possible.     

Postmortem distribution of heroin metabolites in femoral blood, liver, cerebrospinal fluid, and vitreous humor

The presence of 6-monoacetylmorphine (6-MAM) is often used to distinguish between heroin (diacetylmorphine) and morphine exposures. 6-MAM, however, is rapidly metabolized to morphine and may not be present in detectable quantities in blood following heroin exposure. Recent studies have shown that 6-MAM may persist in cerebrospinal fluid (CSF) and this specimen may be preferable for establishing heroin exposure. This study reports postmortem distribution of 6-MAM, unconjugated morphine, and codeine in different tissues from 25 deceased individuals. In all cases, 6-MAM was detected in vitreous humor, and in CSF in 16 of the 25 cases (64%). When 6-MAM was detected in blood (13 of 25 cases), the level of 6-MAM in vitreous humor and CSF was higher than in blood, with a mean concentration ratio of 11.3 (range: 1.7-27) for vitreous humor and 6.6 (range: 2.6-17.3) for CSF. 6-MAM was not detected in liver in any of the cases examined. Free morphine levels were highest in liver, followed by blood, CSF, and vitreous humor. The concentration ratios (mean +/- standard deviation) for free morphine in vitreous humor, CSF, and liver to that in blood were 0.36 +/- 0.18, 0.64 +/- 0.27, and 2.99 +/- 2.12, respectively. The liver/blood ratio was consistent with previously reported values for morphine in heart and femoral blood. Codeine levels following heroin overdose were consistently low relative to the morphine concentration. For blood, liver, and CSF, the ratio of codeine to morphine was essentially the same (0.06), whereas the vitreous codeine/morphine concentration ratio was slightly higher (0.19). These results characterize the distribution of heroin metabolites in postmortem tissues. Vitreous humor appears to be a useful specimen for determining 6-MAM and establishing the morphine was derived from heroin.     

Physicochemical properties of sildenafil citrate (Viagra) and sildenafil base

Sildenafil citrate (Viagra) [I] and sildenafil base [II] are easily and unequivocally characterized by a set of physicochemical methods that include X-ray diffractometry, infrared spectroscopy, and thermal analysis. Monoclinic lattice constants: [I]: a = 26.98 A; b = 11.95 A; c = 16.68 A; beta = 106.97 degrees. [II]: a = 8.66 A; b = 34.27 A; c = 8.93 A; beta = 96.63 degrees. Both compounds decompose at 189.4 degrees C [I] and 251.9 degrees C [II]. Densities and refractive indices are given.     

西地那非研究进展

西地那非（商品名万艾可），是一种特异性环磷酸鸟苷（cGMP)磷酸二酯酶5型（PDE5）抑制剂，通过抑制第二信使cGMP的代谢，促进海绵体动脉平滑肌舒张，进而改善勃起功能障碍（ED）症状的口服药物。本文对国外1999－2001年有关本品对心，肺，肾，眼和神经系统等方面的影响的研究进展作一介绍。     

Postmortem toxicology of carbamazepine

The study focuses on a series of 16 fatal cases in which carbamazepine and its two major metabolites (10,11-epoxide and 10,11-dihydroxycarbamazepine) were detected in body fluids and tissues collected at autopsy. The drug may be implicated in a number of deaths; however, most of these are multiple-drug intoxications with a particular contribution of ethanol. The investigations concerning toxicological findings are a source of toxicological postmortem data and show the differences in metabolism rate as depending on the concentration level of carbamazepine and xenobiotics found in the autopsy specimen during the postmortem investigation of a body.     

Long-term use of sildenafil

The treatment of erectile dysfunction (ED) has been revolutionised by new agents to inhibit the enzyme PDE5. The scientific basis of this treatment of ED includes relaxation of the corpus cavernosum smooth muscle tissue by inhibition of PDE5 that breaks down cGMP, the key pathway for the production of erectile function in humans. Many clinical studies, both pre- and post-marketing, have demonstrated the clinical efficacy and safety of sildenafil (Viagra, Pfizer) - the first approved selective PDE inhibitor for the treatment of ED. Sildenafil is inhibitory of PDE5 at a rate tenfold higher than for the next PDE (PDE6), which produces visual changes through the retinal rods. Its clinical effectiveness has been well documented in the majority of men with ED irrespective of aetiology. The aetiology of ED, also, does not appear to effect the function of sildenafil in relaxing corpus cavernosum smooth muscle tissue. Adverse events are usually associated with the vascular changes from PDE5 inhibition. These include headache and flushing. Each of these adverse events, however, declines with medication use. With the use of sildenafil, it has been clearly, clinically demonstrated that the selective inhibition of PDE5 is an appropriate, effective, safe method for the treatment of ED of all aetiologies and severities.     

柠檬酸西地那非的合成

目的合成磷酸二酯酶Ⅴ抑制剂柠檬酸西地那非。方法以 2 戊酮和草酸二乙酯为原料 ,经十步反应合成得到柠檬酸西地那非 ,省却了文献中的水解及成酰氯反应 ,在制备 3 丙基吡唑 5 甲酸乙酯中 ,采用了“一勺烩”的制备工艺。结果合成了柠檬酸西地那非 ,反应步骤由文献中的十二步缩短为十步 ,总收率由文献中的 4 %提高到 1 9%。结论柠檬酸西地那非的合成方法经改进后 ,反应总收率有所提高 ,证明本合成路线可行。     

Postmortem redistribution of morphine in rats.

Because morphine is often found in the postmortem (PM) blood samples of patients treated with or abusing the drug, its causation in death has to be considered. The possibility of PM redistribution of the opioid drug has not been studied previously. We treated adult Wistar rats with 4 mg/kg of morphine i.m. and measured cardiac cavity levels at the time of death, by killing (2 h postdose) 24 and 96 h PM. Morphine concentrations rose from 41.4 +/- 13.2 ng/ml at death to 111.9 +/- 66.6 ng/ml at 24 h (p = 0.00036), with no additional increase at 96 h (98.7 +/- 21.7 ng/ml). After death there was accumulation of endogenous substances cross-reacting with the morphine radioimmunoassay. Although these attribute only 3% to total accumulation of morphine, they may complicate interpretation of morphine "readings" in patients who had not received the drug. Our study suggests that after death there is substantial redistribution of morphine. Elevated PM levels cannot necessarily by interpreted as representing antemortem concentrations.     

Ocular adverse effects of sildenafil

(1) Abnormal colour vision and brightness were two adverse effects of sildenafil observed during pre-marketing studies. Both effects are dose-dependent and reversible, and led to sildenafil being contraindicated in patients with hereditary degenerative retinal disturbances such as pigmentary retinitis. (2) Several cases of anterior ischaemic optic neuropathy have been reported since the marketing release of sildenafil. These are potentially serious adverse effects that can have permanent sequelae, such as a reduced field of vision.     

Cardiovascular safety of sildenafil.

Initial reports of myocardial infarction and sudden death in men with erectile dysfunction who had taken sildenafil (sometimes in conjunction with nitrates) raised concerns that sildenafil may increase the risk of cardiovascular events in men with erectile dysfunction and vascular disease. A significant body of evidence now indicates that sildenafil generally has a good safety profile in men with erectile dysfunction and cardiovascular disease. Sildenafil therapy does not appear to be associated with ischaemic events either at the time of introduction of therapy or during longer-term use. Rates of discontinuation from sildenafil therapy due to adverse events are similar to placebo in men with cardiovascular disease. Sildenafil does not interact in a potentially hazardous way with antihypertensive or antianginal therapy, with the exception of nitrates. Nitrates should not be administered within 24 hours of sildenafil therapy, and care should be taken to determine whether sildenafil may have been used before nitrates are administered to patients. Sildenafil appears to be generally well tolerated in most patients with chronic, stable cardiovascular disease.     

Pharmacology of sildenafil citrate.

Erectile dysfunction is a common and multi-factorial disease that strongly impairs the quality of life in men. During the past decade, many new therapeutic strategies have become available. But the need for oral treatment was strongly felt. This need appears to have been fulfilled with the introduction of sildenafil. The drug acts by enhancing smooth muscle relaxant effect of nitric oxide. A number of clinical studies have now proved its safety and efficacy. The drug has shaken social life all over the world and to accept this "magic pill" or not remains the question of individual choice.     

Utilization and cost of sildenafil in a large managed care organization with a quantity limit on sildenafil

OBJECTIVE: Erectile dysfunction (ED) affects approximately 30 million men in the United States. The objectives of this study were to (1) assess the cost and utilization of sildenafil citrate (Viagra), an oral therapeutic agent for ED, in a large managed care organization (MCO) with a quantity limit of 6 units per 30-day supply and (2) describe the incidence of comorbid conditions and the severity of cardiovascular disease in adult male users of sildenafil. METHODS: Pharmacy claims for sildenafil were identified from an administrative database of claims with dates of service in calendar year 2001 for male members aged 18 years or older. Medical claims for MCO members who had sildenafil claims were used to identify comorbid diseases and categorize patients by degree of cardiovascular risk. High risk was defined as having at least 1 medical claim with a diagnosis of diabetes mellitus, ischemic heart disease, abdominal aortic aneurysm, or peripheral arterial disease, and medium risk was defined as not having any diagnosis in the high-risk category but at least 1 cardiovascular risk factor that included smoking, hypertension, hypercholesterolemia, family history of premature coronary heart disease, or being aged 45 years or older. RESULTS: There were 67,914 pharmacy claims for sildenafil during 2001 for 20,281 MCO members, an average of 3.3 pharmacy claims per patient. The prevalence of sildenafil use was 54.1 per 1,000 male MCO members aged 18 years or older. The total allowed charges for sildenafil pharmacy claims in 2001 were 3.56 million US dollars, of which patients paid 26.6% in average cost-share, and the net MCO cost per member per month (PMPM) was 0.18 US dollars. A total of 1,681 patients (8.3%) exceeded their quantity restrictions for sildenafil tablets in 2001, of which 1,362 (81.0%) paid cash and 319 (19.0%, or 1.6% of all sildenafil users) appealed and received approval from the MCO for additional sildenafil tablets beyond the restriction of 6 tablets per month. Medical claims were available for 15,644 sildenafil patients (77.1%), and 12,720 sildenafil users (81.3% of those with medical claims) were judged to be at high or medium cardiovascular risk. CONCLUSIONS: A quantity limit of 6 tablets of sildenafil per 30-day period was associated with a drug cost to users and the MCO of 0.25 US dollars PMPM. Sildenafil users paid an average cost-share of 26.6%, resulting in a net drug cost of 0.18 US dollars PMPM to the MCO.