Identification and Determination of 1-Methylimidazole-4-Acetic Acid in Human Cerebrospinal Fluid by Gas Chromatography-Mass Spectrometry

Abstract: A method for the quantification of 1-methylimidazole-4-acetic acid in human CSF was developed. Methylimidazole-acetic acid was identified and quantitated in CSF. The method involves concentration of the compound on a cation exchanger, extraction of the methyl ester with ethyl acetate, and preparation of a heptafluorobutyryl derivate of the methyl ester, which is finally purified by chromatography on silica gel and quantitated by gas chromatography-mass spectrometry with the deuterated analogue as internal standard. The coefficient of variation at 1 ng/ml was 13%. The limit of sensitivity was about 0.2 ng/ml. The concentration of methylimidazole-acetic acid in lumbar CSF from healthy volunteers was below 1 ng/ml. Ventricular CSF contained higher concentrations than lumbar fluid. The existence of a rostrocaudal concentration gradient was established. There was a correlation between the concentration of methylimidazole-acetic acid and tele-methylhistamine in CSF. The concentration of methylimidazole-acetic acid in lumbar CSF from schizophrenic patients, patients with subarachnoidal haemorrhage, or patients with rheumatic disease was in the range of that in healthy volunteers.     

Using Interorganizational Information Systems to Support Environmental Management Efforts at ASG

We examine use of environmental information systems by ASG AB (hereafter ASG), an international logistics and transport firm headquartered in Stockholm, Sweden, as a case study to illustrate the role of information systems in life-cycle-oriented environmental management. This case provides an example of how a firm can use interorganizational information systems (IOISs) to move toward environmentally sustainable business practices. Through the use of IOISs, ASG has been able to improve its environmental performance and that of its suppliers. Further, this improved environmental performance has been a competitive advantage for ASG and enabled it to attract new business. As such, ASG's experiences illustrate how aggressive practices move environmental management beyond compliance and cost control, at which many firms have been successful, to revenue generation. The case also shows how environmentally sustainable business practices can be integrated into a firm's strategy. In addition to illustrating how ASG has used IOISs to improve environmental performance, we compare their use of environmental ISs with the expected evolution of environmental ISs presented in the Shaft and colleagues (1997) framework. Although some of ASG's experiences verify the expected progression of these types of systems, some developments are not as expected. These differences have implications for the framework.     

Genetic mutation analysis at early stages of cell line development using next generation sequencing

A central goal for most biopharmaceutical companies is to reduce the development timeline to reach clinical proof of concept. This objective requires the development of tools that ensure the quality of biotherapeutic material destined for the clinic. Recent advances in high throughput protein analytics provide confidence in our ability to assess productivity and product quality attributes at early stages of cell line development. However, one quality attribute has, until recently, been absent from the standard battery of analytical tests facilitating informed choices early in cell line selection: genetic sequence confirmation. Techniques historically used for mutation analysis, such as detailed mass spectrometry, have limitations on the sample number and turnaround times making it less attractive at early stages. Thus, we explored the utility of Next‐Generation Sequencing (NGS) as a solution to address these limitations. Amplicon sequencing is one such NGS technique that is robust, rapid, sensitive, and amenable to multiplexing, all of which are essential attributes for our purposes. Here we report a NGS method based upon amplicon sequencing that has been successfully incorporated into our cell line development workflow alongside other high‐throughput protein analytical assays. The NGS method has demonstrated its value by identifying at least one Chinese hamster ovary (CHO) clone expressing a variant form of the biotherapeutic in each of the four clinical programs in which it has been utilized. We believe this sequence confirmation method is essential to safely accelerating the time to clinical proof of concept of biotherapeutics, and guard against delays related to sequence mutations. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:813–817, 2016     

Synthesis and evaluation of 2-pyridylbenzothiazole, 2-pyridylbenzoxazole and 2-pyridylbenzofuran derivatives as 11C-PET imaging agents for β-amyloid plaques

The syntheses and SAR of new series of β-amyloid binding agents are reported. The effort to optimize signal-to-background ratios for these ligands are described. Compounds 8, 21 and 30 displayed desirable lipophilicity and pharmacokinetic properties. Compounds 8 and 21 were evaluated with in vitro autoradiographic studies and in vivo in APP/PS1 transgenic mice. It is shown that it was possible to increase the signal-to-background ratios compared to PIB 1, as demonstrated by compounds 8 and 21.     

Determination of N-Acetylaspartic Acid in Human Cerebrospinal Fluid by Gas Chromatography–Mass Spectrometry

N-Acetyl-L-aspartic acid was identified and determined in human cerebrospinal fluid. The concentration in lumbar fluid was about 2 nmol/ml and about 20 nmol/ml in ventricular fluid. There was no difference between healthy subjects and schizophrenic patients.     

Development of a vaginal gel containing 9-deoxo-16,16-dimethyl-9-methylene PGE2 for cervical dilatation and pregnancy termination

A stable hydrophilic gel for vaginal administration containing 9-deoxo-16,16-dimethyl-9-methylene PGE2 (9-methylene PGE2) was developed and its clinical usefulness for preoperative cervical dilatation and for termination of first and second trimester pregnancy evaluated in 521 pregnant patients admitted to the hospital for therapeutic abortion. Following vaginal administration of 3 mg of 9-methylene PGE2 gel a peak plasma level of between 3.5 and 10 ng/ml was found 3 to 6 hours following treatment. The "bioavailability" of the drug was in the order of 25-30%. 9-methylene PGE2 was found to be equally effective as 1 mg Cervagem for preoperative cervical dilatation. With a pretreatment period of 3 hours side effects were rare with both compounds. If the pretreatment period was extended to 12 hours the degree of cervical dilatation, but also the frequency of side effects increased significantly. Repeated administration of 9-methylene PGE2 was found to be effective (96% complete abortion) in terminating very early pregnancy provided the total dose was 10 mg or more. During second trimester the minimum effective dose was 4.5 mg of the compound repeated every fourth hour. The results of the present study have shown that with the new gel formulation the amount of 9-methylene PGE2 needed to terminate first and second trimester pregnancy was approximately ten times less in comparison with the previously used lipid base suppositories. The treatment was also associated with a low frequency of side effects.