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Corporation created or organized under the laws of the United States or a state thereof, iii ; an estate the income of which is subject to U.S. federal income taxation regardless of its source, or iv ; a trust subject to primary supervision of a U.S. court and the control of one or more U.S. persons. This discussion assumes that each obligation in the Deposit Agreement and any related agreement will be performed in accordance with its terms. For purposes of this discussion, U.S. Holders of ADRs will be treated as owners of the ADSs evidenced by such ADRs and the shares represented by such ADSs. Dividends. For U.S. federal income tax purposes, you will be required to include the full amount unreduced by any Withholding Tax ; of a dividend paid with respect to our shares or ADSs as ordinary income. For this purpose, a ``dividend'' will include any distribution paid by us with respect to our shares or ADSs other than certain distributions of our capital stock or rights to subscribe for shares of our capital stock ; , as the case may be, but only to the extent such distribution is not in excess of our current and accumulated earnings and profits as defined for U.S. federal income tax purposes. Such dividend will constitute income from sources outside the United States. Subject to the limitations and conditions provided in the Code, you may deduct from your U.S. federal taxable income, or claim as a credit against your U.S. federal income tax liability, the 15% withholding tax withheld pursuant to the Treaty. Under the Code, dividend payments by us on the shares or ADSs are not eligible for the dividends received deduction generally allowed to corporate shareholders. Any distribution that exceeds our earnings and profits will be treated as a nontaxable return of capital to the extent of your tax basis in the shares or ADSs and thereafter as capital gain. In general, a U.S. Holder will be required to determine the amount of any dividend paid in Swiss francs by translating the Swiss francs into U.S. dollars at the spot rate on the date of receipt. The tax basis of Swiss francs received by you if you are a U.S. Holder generally will equal the U.S. dollar equivalent of such Swiss francs at the spot rate on the date such Swiss francs are received. Upon subsequent exchange of such Swiss francs for U.S. dollars, or upon the use of such Swiss francs to purchase property, you will generally recognize exchange gain or loss equal to the difference between your tax basis for the Swiss francs and the U.S. dollars received or, if property is received, the fair value of the property on the date of the exchange. Sale or Other Disposition. Upon a sale or exchange of shares or ADSs, you generally will recognize capital gain or loss in an amount equal to the difference between the amount realized on the disposition and your tax basis in the shares or ADSs. This capital gain or loss will be long-term capital gain or loss if your holding period in the shares or ADSs exceeds one year. The deductibility of capital losses is subject to limitations. If you are an individual, any capital gain generally will be subject to U.S. federal income tax at preferential rates if you meet the specified minimum holding periods. Such gain or loss, if any, generally will be U.S. source gain or loss. United States Information Reporting and Backup Withholding. Dividend payments with respect to shares or ADSs and proceeds from the sale, exchange or redemption of shares or ADSs may be subject to information reporting to the Internal Revenue Service ``IRS'' ; and possible U.S. backup withholding at a 31% rate. Certain exempt recipients such as corporations ; are not subject to these information reporting requirements. Backup withholding will not apply, however, to a holder who furnishes a correct taxpayer identification number or certificate of foreign status and makes any other required certification or who is otherwise exempt from backup withholding. Any U.S. persons required to establish their exempt status generally must file IRS Form W-9 ``Request for Taxpayer Identification Number and Certification'' ; . Non-U.S. holders are generally not subject to U.S. information or backup withholding. However, such holders may be required to provide certification of non-U.S. status in connection with payments received in the United States or through U.S.-related financial intermediaries. Amounts withheld as backup withholding may be credited against a holder's federal income tax liability, and a holder may obtain a refund of any excess amounts withheld under the backup withholding rules by filing the appropriate claim for refund with the IRS and furnishing any required information. Finalized Treasury regulations have generally expanded the circumstances under which U.S. information reporting and backup withholding may apply. Holders should consult their own tax advisors regarding the application of the U.S. information reporting and backup withholding rules, including the finalized Treasury regulations and tamsulosin. | Vepesid dosingTrade Name Zinecard Adriamycin, Rubex Doxil Vepesid, VP-16 FUDR 5FU, Adrucil Ifex Mesnex Folex, Mexate Taxol, Onxol Thioplex Velban, Velsar, Alkaban-AQ Oncovin, Vincasar, Vincrex Paraplatin Platinol Taxol, Onxol Blenoxane Paraplatin Platinol Zinecard 183.9.
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Cytoplasm to the nucleus to a similar extent as the known CAR activator PB, whereas RIF, a known PXR activator, does not. These observations indicate that PHY can initiate the first required step of CAR activation in primary hepatocytes, leading to eventual up-regulation of CYP2B6 gene expression. To further evaluate the role of hCAR in the regulation of PHYinduced CYP2B6 gene expression, CAR mice were transiently transfected with CYP2B6 reporter vectors alone or in combination with hCAR expression vector. Results from these in vivo experiments demonstrated that CAR is required for PHY activation of CYP2B6 reporter gene expression. In the absence of hCAR, PHY and other known CAR activators failed to increase the expression of the transfected CYP2B6 reporter gene, indicating that other endogenous transcription factors in mice, including PXR, are not capable of mediating PHY-induced CYP2B6 reporter gene expression in vivo. Using CARnull mice, a recent study by Jackson et al.2 identified PHY as a new mCAR activator involved in the induction of murine Cyp2b10 and Cyp2c29. PHY induces both Cyp2b10 and Cyp2c29 expression in wild-type mice, but the induction was dramatically reduced in CAR mice. These results suggest that PHY induces murine Cyp2b10 and Cyp2c29 primarily via the nuclear receptor CAR. Confocal microscopic analysis using fluorescence-tagged hCAR further confirmed that the majority of transfected hCAR is expressed in the cytoplasm in the absence of CAR activators, but that PHY and PB can induce efficient translocation of hCAR into the nucleus. Therefore, PHY appears to be a selective activator for both human and mouse CAR. On the contrary, CITCO, previously reported as a potent human CAR activator 23 ; , demonstrated a moderate capacity for fluorescence-tagged hCAR nuclear translocation compared with PHY and PB. About 11% of the nuclei expressed fluorescence-tagged hCAR in the control animals, which may have contributed to the higher basal expression of CYP2B6 reporter gene activity compared with mice that received the CYP2B6 reporter gene alone. In contrast to PXR, which requires direct ligand binding for activation, CAR can be activated directly by compounds such as TCPOBOP and CITCO, or indirectly by compounds such as PB 8 ; vitro ligand binding assay indicated that PHY does not bind hCAR or with very weak affinity, 3 suggesting that PHY activates hCAR through an indirect pathway in a manner similar to PB. PHY is a widely prescribed anticonvulsant drug used for the prevention and treatment of seizures. Because it often is prescribed chronically and co-administered with other therapeutics, drug-drug interactions associated with PHY are common 32, 33 ; . In humans, PHY is predominantly metabolized by the cytochrome P450 2C isozymes 80% by CYP2C9 and 20% by CYP2C19 ; and is a recognized inducer of CYP2B6, CYP2C9, and CYP3A4 34 36 ; . Because more than 40% of patients with brain tumors experience disease-related seizures 37, 38 ; , drugdrug interactions between anticancer agents and antiepileptic drugs such as PHY can have significant clinical consequences 39 ; . It has been reported that PHY induction of CYP2B6 results in altered pharmacokinetics of the antineoplastics cyclophosphamide and ifosfamide, which are frequently co-administered with PHY 40, 41 ; . Thus, PHY induction of liver cytochrome P450 expression can result in decreased efficacy of co-administered chemotherapeutics metabolized by CYP2B6. However, to date, the mechanisms underlying PHY induction of CYP2B6 have not been elucidated. Based on the results of these studies, PHY is the first drug identified to cause drug.
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