Inhibition of CYP1A2-mediated drug metabolism in vitro and in humans : With special emphasis on rofecoxib and other NSAIDs

The cytochrome P450 1A2 (CYP1A2) is one of the major metabolizing enzymes. The muscle relaxant tizanidine is a selective substrate of CYP1A2, and the non-steroidal anti-inflammatory drug (NSAID) rofecoxib was thought to modestly in-hibit it. Cases suggesting an interaction between tizanidine and rofecoxib had been reported, but the mechanism was unknown. Also other NSAIDs are often used in combination with muscle relaxants. The aims of this study were to investigate the effect of rofecoxib, several other NSAIDs and female sex steroids on CYP1A2 ac-tivity in vitro and in vivo, and to evaluate the predictability of in vivo inhibition based on in vitro data. In vitro, the effect of several NSAIDs, female sex steroids and model inhibitors on CYP1A2 activity was studied in human liver microsomes, without and with preincubation. In placebo controlled, cross-over studies healthy volunteers ingested a single dose of tizanidine after a pretreament with the inhibitor (rofecoxib, tolfenamic acid or celecoxib) or placebo. Plasma (and urine) concentrations of tizanidine and its metabolites were measured, and the pharmacodynamic effects were recorded. A caffeine test was also performed. In vitro, fluvoxamine, tolfenamic acid, mefenamic acid and rofecoxib potently in-hibited CYP1A2. Ethinylestradiol, celecoxib, desogestrel and zolmitriptan were moderate, and etodolac, ciprofloxacin, etoricoxib and gestodene were weak inhibi-tors of CYP1A2. At 100 µM, other tested NSAIDs and steroids inhibited CYP1A2 less than 35%. Rofecoxib was found to be a mechanism-based inhibitor of CYP1A2. In vivo, rofecoxib greatly increased the plasma concentrations (over ten-fold) and the pharmacodynamic effects of tizanidine. Also the metabolism of caf-feine was impaired by rofecoxib. Despite the relatively strong in vitro CYP1A2 inhibitory effects, tolfenamic acid and celecoxib did not have a significant effect on tizanidine and caffeine concentrations in humans. Competitive inhibition model and the free plasma concentration of the inhibitor predicted well the effect of fluvoxam-ine and the lack of effect of tolfenamic acid and celecoxib on tizanidine concentra-tions in humans, and mechanism-based inhibition model explained the effects of rofecoxib. However, the effects of ciprofloxacin and oral contraceptives were un-derestimated from the in vitro data. Rofecoxib is a potent mechanism-based inhibitor of CYP1A2 in vitro and in vivo. This mechanism may be involved in the adverse cardiovascular effects of rofecoxib. Tolfenamic acid and celecoxib seem to be safe in combination with tizanidine, but mefenamic acid might have some effect on tizanidine concentrations in vivo. Con-sidering the mechanism of inhibition, and using the free plasma concentration of the inhibitor, many but not all CYP1A2 interactions can be predicted from in vitro data.

Studies on new processing aids and other compounding ingredients in special purpose rubbers

In the first part of the study we probed the effectiveness of rice bran oil as a multipurpose compounding ingredient for nitrile (NBR) and chloroprene (CR) rubbers. This oil has already been successfully employed in the compounding of NR and SBR in this laboratory.In this context we thought it worthwhile to try this oil in the polar rubbers viz, NBR and CR also. The principle of like dissolves like as applicable to solvents is equally applicable while selecting a plasticiser, elastomer combination. Because of the compatibility considerations polar plasticisers are preferred for polar rubbers like NBR and CR. Although plasticisation is a physical phenomenon and no chemical reaction is involved, the chemical structure of plasticisers determines how much physical attraction there is between the rubber and the plasticiser. In this context it is interesting to note that the various fatty acids present in rice bran oil have a long paraffinic chain, characteristic of waxes, with an acid group at the end of the molecule. The paraffinic end of the molecule contributes lubricating effects and limits compatibility whereas the acid end group contributes some polarity and is also chemically reactive. Because of absorption of acid group on the surface of pigments, these acids will have active pigment wetting characteristics also. These factors justifies the role of rice bran oil as a co-activator and lubricating agent for NBR and CR. In fact in our study we successfully replaced stearic acid as co-activator and aromatic oillDOP as processing aid for CR and NBR with rice bran oil.This part of the study has got special significance in the fact that rubber industry now heavily depends on petroleum industry for process oils. The conventional process oils like aromatic, naphthenic and paraffinic oils are increasingly becoming costlier, as its resources in nature are fast depleting. Moreover aromatic process oils are reported to be carcinogenic because of the presence of higher levels of polycyclic aromatic compounds in these oils.As a result of these factors, a great amount research is going on world over for newer processing aids which are cost effective, nontoxic and performanance wise at par with the conventional ones used in the rubber industry. Trials with vegetable oils in this direction is worth trying.Antioxidants are usually added to the rubber compound to minimise ageing effects from heat, light, oxygen etc. As rice bran oil contains significant amount of tocopherols and oryzanol which are natural antioxidants, we replaced a phenolic antioxidant like styrenated phenol (SP) from the compound recipe of both the rubbers with RBO and ascertained whether this oil could function in the role of antioxidant as well.Preparation and use of epoxidised rice bran oil as plasticiser has already been reported.The crude rice bran oil having an iodine value of 92 was epoxidised in this laboratory using peracetic acid in presence of sulphuric acid as catalyst. The epoxy content of the epoxidised oil was determined volumetrically by treating a known weight of the oil with excess HCI and back titrating the residual HCI with standard alkali solution. The epoxidised oil having an epoxy content of 3.4% was tried in the compounding of NBR and CR as processing aids. And results of these investigations are also included in this chapter. In the second part of the study we tried how RBO/ERBO could perform when used as a processing aid in place of aromatic oil in the compounding of black filled NRCR blends. Elastomers cannot have all the properties required for a particular applications, so it is common practice in rubber industry to blend two elastomers to have desired property for the resulting blend.In this RBO/ERBO was tried as a processing aid for plasticisation, dispersion of fillers, and vulcanisation of black filled NR-CR blends.Aromatic oil was used as a control. The results of our study indicate that these oils could function as a processing aid and when added together with carbon black function as a cure accelerator also.PVC is compatible with nitrile rubber in all proportions, provided NBR has an acrylonitrile content of 25 to 40%. Lower or higher ACN content in NBR makes it incompatible with PVC.PVC is usually blended with NBR at high temperatures. In order to reduce torque during mixing, additional amounts of plasticisers like DOP are added. The plasticiser should be compatible both with PVC and NBR so as to get a homogeneous blend. Epoxidised soyaben oil is reported to have been used in the compounding of PVC as it can perfonn both as an efficient plasticiser and heat stabilizer.At present DOP constitute the largest consumed plasticiser in the PVC compounding. The migration of this plasticiser from food packaging materials made of PVC poses great health hazards as this is harmful to human body. In such a scenario we also thought it worthwhile to see whether DOP could be replaced by rice bran oil in the compounding of NBR-PVC blends Different blends of NBR-PVC were prepared with RBO and were vulcanized using sulphur and conventional accelerators. The various physical and mechanical properties of the vulcanisates were evaluated and compared with those prepared with DOP as the control plasticiser. Epoxidised rice bran oil was also tried as plasticiser for the preparation of NBR-PVC blends. A comparison of the processability and cure characteristics of the different blends prepared with DOP and ERBO showed that ERBO based blends have better processability and lower cure time values. However the elastographic maximum torque values are higher for the DOP based blends. Almost all of the physical properties evaluated are found to be slightly better for the DOP based blends over the ERBO based ones. However a notable feature of the ERBO based blends is the better percentage retention of elongation at break values after ageing over the DOP based blends. The results of these studies using rice bran oil and its epoxidised variety indicated that they could be used as efficient plasticisers in place of DOP and justifies their role as novel, nontoxic, and cheap plasticisers for NBR-PVC blends.

Indian Mathematics Related to Architecture and Other Areas With Special Reference to Kerala

Department of Mathematics, Cochin University of Science and Technology

Topics of divisibility

The set of integers forms a commutative ring whose elements admit a unique decomposition into primes. In this folder three lecture notes are bound, concerning topics, developed by dropping or replacing special properties of this most natural and most special ring. For short: investigated are groupoids w.r.t the interplay of multiplication - on the one hand - and divisibility, ideal decomposition and residuation, respectively, on the other hand.

Summary of resolutions recently adopted by CDCC and resolutions of ECLAC and other organs of the United Nations which might be of special interest to member countries of ECLAC/CDCC

This paper brings to the attention of member countries of the Caribbean Development and Cooperation Committee (CDCC) resolutions adopted by past sessions of the Committee, since 2000, and the process of their implementation. Resolutions 55 to 66 for the period 2000- 2006 have been extracted from the reports of the eighteenth to twenty first sessions of the CDCC Also included for the information of member countries are selected resolutions recently adopted by the Economic Commission for Latin America and the Caribbean (ECLAC) and other organs of the United Nations. These resolutions greatly influence the preparation of the programme of work and are expected guide the day-to-day functioning of the secretariat. It is a great source of information for delegations, given the perceived special relevance of the resolutions to the membership of the CDCC. The resolutions listed in this document are pertinent to all subprogrammes of ECLAC and indeed the CDCC subprogramme 12 of ECLAC. However, the content of these resolutions either marked no real advance on the outcomes of the corresponding conferences that were held within recent times or were cast in a globally relevant context that did not address specific concerns of Caribbean countries to any significant extent.

The special rights other than shares in cross-border mergers of limited liability companies within the European Union. A perspective from the Spanish Law

The present research aims to study the special rights other than shares in Spanish Law and the protection of their holders in cross-border mergers of limited liability companies within the European Union frame. Special rights other than shares are recognised as an independent legal category within legal systems of some EU Member States, such as Germany or Spain, through the implementation of the Third Directive 78/855/CEE concerning mergers of public limited liability companies. The above-cited Directive contains a special regime of protection for the holders of securities, other than shares, to which special rights are attached, consisting of being given rights in the acquiring company, at least equivalent to those they possessed in the company being acquired. This safeguard is to highlight the intimate connection between this type of rights and the company whose extinction determines the existence of those. Pursuant to the Directive 2005/56/CE on cross-border mergers of limited liability companies, each company taking part in these operations shall comply with the safeguards of members and third parties provided in their respective national law to which is subject. In this regard, the protection for holders of special rights other than shares shall be ruled by the domestic M&A regime. As far as Spanish Law are concerned, holders of these special rights are recognized a right of merger information, in the same terms as shareholders, as well as equal rights in the company resulting from the cross-border merger. However, these measures are not enough guarantee for a suitable protection, thus considering those holders of special rights as special creditors, sometimes it will be necessary to go to the general protection regime for creditors. In Spanish Law, it would involve the recognition of right to the merger opposition, whose exercise would prevent the operation was completed until ensuring equal rights.

Scaling in Soil and Other Complex Porous Media

Scaling is becoming an increasingly important topic in the earth and environmental sciences as researchers attempt to understand complex natural systems through the lens of an ever-increasing set of methods and scales. The guest editors introduce the papers in this issue’s special section and present an overview of some of the work being done. Scaling remains one of the most challenging topics in earth and environmental sciences, forming a basis for our understanding of process development across the multiple scales that make up the subsurface environment. Tremendous progress has been made in discovery, explanation, and applications of scaling. And yet much more needs to be done and is being done as part of the modern quest to quantify, analyze, and manage the complexity of natural systems. Understanding and succinct representation of scaling properties can unveil underlying relationships between system structure and response functions, improve parameterization of natural variability and heterogeneity, and help us address societal needs by effectively merging knowledge acquired at different scales.