LC-MS-MS analysis of the neuroleptics clozapine,flupentixol, haloperidol,penfluridol, thioridazine,and zuclopenthixol in hair obtained from psychiatric patients

Hair samples of psychiatric patients were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS-MS) for the neuroleptics clozapine, flupentixol, haloperidol, penfluridol, thioridazine, and zuclopenthixol. In the study, these neuroleptics were administered to the patients regularly for a minimum of six months. Sample preparation was performed by washing, powdering with a ball mill, extraction of drugs from hair by ultrasonication with methanol, cleanup by solid-phase extraction and subsequent LC-MS-MS analysis using multiple reaction monitoring (MRM). Calibration was performed for all drugs in the range of 0.05 to 10 ng/mg using spiked hair powder and doxepin-d3 as internal standard. Twenty to 50 mg of hair powder was used and the detection limits of LC-MS-MS were below 0.05 ng/mg for all drugs tested. Therapeutic dosage, number of subjects, hair color, and detected amounts of drugs were as follows: clozapine (150400 mg/day; n = 3, light brown, medium brown, black; 0.47-0.92 ng/mg), haloperidol (150 mg/3 weeks; n = 1, black/gray; 12.2 ng/mg), penfluridol (20-30 mg/week; n = 2, medium brown, black; 0.08 ng/mg; not detected in one case), thioridazine (100-400 mg/day; n = 4, light brown, medium brown, black; 0.33-9.91 ng/mg, not detected in one case). Besides the active drugs also the desmethyl-metabolites of clozapine and thioridazine were detected by LC-MS-MS. However, flupentixol (5 mg/day; light brown hair) and zuclopenthixol (350 mg/3 weeks; light brown hair) were not detected by these methods in one case each, although the drugs were administered regularly to these patients. The comparison of dosage and hair color in two cases with thioridazine and penfluridol suggests that other interindividual factors may have an influence on drug concentration in hair.     

Environmental risk assessment of veterinary medicinal products in the EU--a regulatory perspective

The pharmacological nature of veterinary medicinal products, frequent application rates and use on a large scale for livestock production sensitizes regulation authorities for environmental concern. Consequently, in the European Union legal requirements plus guidance for an Environmental Risk Assessment of veterinary pharmaceuticals have been established. Applicants of new veterinary medicinal products have to provide an ecotoxicity report according to a guidance document which rests upon a logical, tiered approach with a cut-off trigger between a basic characterisation of the veterinary medicinal product and an in-depth assessment of its fate and ecotoxic effects. The outcome of this assessment is the establishment of the environmental risk that may arise from the use of the VMP under question. Contamination of the environment can be reduced by appropriate risk mitigation measures, e.g. limiting the application rate, the amount of contaminated manure being spread on agricultural lands or the access of treated pasture animals to surface waters.     

Second derivative spectrophotometric determination of trimethoprime and sulfamethoxazole in the presence of hydroxypropyl-beta-cyclodextrin (HP-beta-CD)

An easy and rapid second-derivative spectrophotometric method for the simultaneous analysis of trimethoprime (TMP) and sulfamethoxazole (SM) is described. These drugs have been used as antibacterial against a wide spectrum of organisms and combinations of these drugs are commonly used for the treatment of a variety of infections. The most advantageous approach of this method is the use of HP-beta-CD, which allows to improve the performance of the second-derivative ultraviolet spectrophotometry. For both compounds, a shift of the absorption bands and variations of their intensity were observed. The calibration graphs were linear in the concentration range of TMP (1.92-19.2 microg ml(-1)) and SM (1.60-16.5 microg ml(-1)), the correlation coefficient for the calibration graphs was better than 0.9994 and the precision was satisfactory (CV%< 4.96) in HP-beta-CD solutions. The proposed method was successfully applied to the assay of commercial tablets. The results were compared to those obtained by second-derivative ultraviolet spectrophotometry in the absence of HP-beta-CD. Thereby, the details of the statistical treatment of the analytical data are also presented.     

Documentation goes wireless: a look at mobile healthcare computing devices

Patient care information often suffers as it travels from handwritten notes, dictation, or the memory of the clinician to the medical record. Hand-held devices equipped with mobile healthcare aplications can bring documentatin to the point of care. In this article, learn how mobile healthcare computing devices can decrease medical errors, increase efficiency, and improve the delivery of care.     

Perceived barriers to medical-error reporting: an exploratory investigation

Medical-error reporting is an essential component for patient safety enhancement. Unfortunately, medical errors are largely underreported across healthcare institutions. This problem can be attributed to different factors and barriers present at organizational and individual levels that ultimately prevent individuals from generating the report. This study explored the factors that affect medical-error reporting among physicians and nurses at a large academic medical center located in the midwest United States. A nominal group session was conducted to identify the most relevant factors that act as barriers for error reporting. These factors were then used to design a questionnaire that explored the likelihood of the factors to act as barriers and their likelihood to be modified. Using these two parameters, the results were analyzed and combined into a Factor Relevance Matrix. The matrix identifies the factors for which immediate actions should be undertaken to improve medical-error reporting (immediate action factors). It also identifies factors that require long-term strategies (long-term strategy factors) as well as factors that the organization should be aware of but that are of lower priority (awareness factors). The strategies outlined in this study may assist healthcare organizations in improving medical-error reporting, as part of the efforts toward patient-safety enhancement. Although factors affecting medical-error reporting may vary between different organizations, the process used in identifying the factors and the Factor Relevance Matrix developed in this study are easily adaptable to any organizational setting.     

4-[6-(Dansylamino)hexylamino]-7-methyl-2-phenyl-1,8-naphthyridine as a new potential fluorescent probe for studying A1-adenosine receptor

A new fluorescent ligand for adenosine receptors, obtained by the insertion of a dansylamino-moiety with a linear hexyl spacer in the N4 position of a 1,8-naphthyridine adenosine receptor ligand, proved to possess a high affinity and selectivity for the A1 receptor subtype.     

Ribose-modified nucleosides as ligands for adenosine receptors: synthesis, conformational analysis, and biological evaluation of 1'-C-methyl adenosine analogues

1'-C-Methyl analogues of adenosine and selective adenosine A(1) receptor agonists, such as N-[(1R)-1-methyl-2-phenylethyl]adenosine ((R)-PIA) and N(6)-cyclopentyladenosine, were synthesized to further investigate the subdomain that binds the ribose moiety. Binding affinities of these new compounds at A(1) and A(2A) receptors in rat brain membranes and at A(3) in rat testis membranes were determined and compared. It was found that the 1'-C-methyl modification in adenosine resulted in a decrease of affinity, particularly at A(1) and A(2A) receptors. When this modification was combined with N(6) substitutions with groups that induce high potency and selectivity at A(1) receptors, the high affinity was in part restored and the selectivity was increased. The most potent compound proved to be the 1'-C-methyl analogue of (R)-PIA with a K(i) of 23 nM for the displacement of [(3)H]CHA binding from rat brain A(1) receptors and a > 435-fold selectivity over A(2A) receptors. In functional assays, these compounds inhibited forskolin-stimulated adenylate cyclase with IC(50) values ranging from 0.065 to 3.4 microM, acting as full agonists. Conformational analysis based on vicinal protonminus signproton J-coupling constants and molecular mechanics calculations using the MM2 force field proved that the methyl group on C1' in adenosine has a pronounced impact on the furanose conformation by driving its conformational equilibrium toward the north, gamma+, syn form.     

Evaluation of the inhibition effect of thiolated poly(acrylates) on vaginal membrane bound aminopeptidase N and release of the model drug LH-RH

The purpose of this study was to evaluate the inhibitory effect of thiolated carbopol 974P (carb-cys) on the enzymatic activity of vaginal aminopeptidase N in-vitro. Mediated by a carbodiimide, L-cysteine was covalently linked to carbopol 974P. Depending on the weight ratio of polymer to cysteine during the coupling reaction, resulting conjugates displayed 31.3-54.4 micromol thiol groups per g polymer. The inhibitory effect of carb-cys conjugates was evaluated towards isolated aminopeptidase N and aminopeptidase-N-like activity of excised vaginal mucosa covered with native mucus, respectively. Enzymatic activity was assayed spectrophotometrically using L-leucine-p-nitroanilide (L-leu-pNA) as a synthetic substrate. Carb-cys thereby showed a significantly higher inhibitory effect than unmodified polymer towards both isolated enzyme and vaginal mucosa. Moreover, enzyme inhibition was strongly dependent on the amount of thiol groups being immobilised. The more thiol groups available the higher was the inhibitory effect. Due to its additional high cohesive properties and the possibility of a sustained drug release, which could be shown for the model drug LH-RH, carb-cys appears interesting for the development of vaginal peptide drug-delivery systems.     

Mitoxantrone and cisplatin in recurrent and/or metastatic salivary gland malignancies

A phase II study was performed to assess the safety and efficacy of mitoxantrone and cisplatin in locally recurrent and/or metastatic carcinomas of the salivary glands. Between May 1997 and March 2001, a total of 14 patients were entered on this trial. All of them had previously undergone radical resection and 10 were subsequently treated with adjuvant radiation therapy with (n=3) or without (n=7) concomitant chemotherapy. Therapy according to the study protocol consisted of mitoxantrone given as i.v. bolus on day 1 at a dose of 12 mg/m2 and cisplatin given as 90-min infusion at a dose of 30 mg/m2 on days 1-3. We observed two partial responses (14.3%) and stabilization of disease in nine patients (64.3%); progression during therapy was noted in only three cases (21.4%). The median time to progression was 15 months (range 2-36) and the median survival time was 27 months (range 4-54). Myelosuppression was commonly observed. Leukocytopenia occurred in all patients, and was grade 3 or 4 in three (21%) and four (29%) patients. WHO grade 3 thrombocytopenia and anemia was seen in three (21%) and four (29%) patients, respectively. Non-hematologic toxicity was in general mild to moderate except for two cases (14%) of grade 3 nausea and vomiting; overall incidence rates were nausea and vomiting (n=14), stomatitis (n=6), diarrhea (n=3), alopecia (n=11), infection (n=7), increase of serum creatinine (n=3), and peripheral neuropathy (n=3). The combination of mitoxantrone and cisplatin seems to be an active and fairly well-tolerated regimen for the treatment of advanced salivary gland cancers. According to the observed high rate of abrogating progressive disease for a long duration, and the resulting promising progression-free and overall survival time, further investigation seems warranted.     

Apolipoprotein-mediated transport of nanoparticle-bound drugs across the blood-brain barrier

Recent studies have shown that drugs that are normally unable to cross the blood-brain barrier (BBB) following intravenous injection can be transported across this barrier by binding to poly(butyl cyanoacrylate) nanoparticles and coating with polysorbate 80. However, the mechanism of this transport so far was not known. In the present paper, the possible involvement of apolipoproteins in the transport of nanoparticle-bound drugs into the brain is investigated. Poly(butyl cyanoacrylate) nanoparticles loaded with the hexapeptide dalargin were coated with the apolipoproteins AII, B, CII, E, or J without or after precoating with polysorbate 80. In addition, loperamide-loaded nanoparticles were coated with apolipoprotein E alone or again after precoating with polysorbate 80. After intravenous injection to ICR mice the antinociceptive threshold was measured by the tail flick test. Furthermore, the antinociceptive threshold of polysorbate 80-coated dalargin-loaded nanoparticles was determined in ApoEtm1Unc and C57BL/6J mice. The results show that only dalargin or loperamide-loaded nanoparticles coated with polysorbate 80 and/or with apolipoprotein B or E were able to achieve an antinociceptive effect. This effect was significantly higher after polysorbate-precoating and apolipoprotein B or E-overcoating. With the apolipoprotein E-deficient ApoEtm1Unc mice the antinociceptive effect was considerably reduced in comparison to the C57BL/6J mice. These results suggest that apolipoproteins B and E are involved in the mediation of the transport of drugs bound to poly(butyl cyanoacrylate) nanoparticles across the BBB. Polysorbate 80-coated nanoparticles adsorb these apolipoproteins from the blood after injection and thus seem to mimic lipoprotein particles that could be taken up by the brain capillary endothelial cells via receptor-mediated endocytosis. Bound drugs then may be further transported into the brain by diffusion following release within the endothelial cells or, alternatively, by transcytosis.