text:
by Jawad Hussain / Wednesday, 23 June 2010 / Published in Crime, Punjab
RAWALPINDI: Five robbers barged into the house of a person on Tuesday night and looted Rs17,000 cash, gold ornaments and a television set besides raping his sister in the Saddar Bairooni area, the Dawn News reported Wednesday. The robbery victim managed to recognise one of the dacoits.
The complete article can be found at Dawn News.
Tagged under: armed robbery, Crime, Crime News, Dawn News, Guarding, rape, Rawalpindi, Risk Assessment, robbery, saddar Bairooni, Security
About Jawad HussainI'm a guy who believes in sheer hardwork and dedication to the tasks in hand. I would be the last person on earth to be disappointed with the world. Hope is the key and for me Honesty is still the best policy.
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UKIP MEP for the South East, Diane James, has been elected as Leader of the Party.
Cllr Lisa Duffy came second, followed by West Midlands MEP Bill Etheridge, Philip Broughton and Liz Jones.
Turnout at the election was 17,970.
The results in full:
Diane James 8,451
Lisa Duffy 4,591
Bill Etheridge 2,052
Philip Broughton 1,545
Liz Jones 1,203
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text: I am having an issue with iZoo and the new version (which has become my favorite game by far and I play it every day). Every time I finish a game, it simply closes and goes back to main screen. Is anyone else experiencing this? Is it trying to save my score and crashing? I will pay $10 for this game once it saves my scores. ps. Is it just me, or do the levels with new animals coming from the top AND bottom at the same time really mess with your brain? pps. first post BTW. yay!


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|Publication number
|Publication type
|Application number
|Publication date
|Apr 23, 2002
|Filing date
|Sep 23, 1999
|Priority date
|Sep 23, 1999
|Fee status
|Also published as
|Publication number
|Richard B. Greenwald, Yun Hwang Choe
|Original Assignee
|Enzon, Inc.
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (11), Non-Patent Citations (16), Referenced by (53), Classifications (14), Legal Events (7)
|External Links: USPTO, USPTO Assignment, Espacenet
The present invention relates to polymeric conjugates of anti-metabolites. In particular, the invention relates to polymeric conjugates of ara-C, gemcitabine and derivatives thereof and methods of preparing the same.
Ara-C (cytosine arabinose, cytarabine, 1-(β-D-arabinofuranosyl)cytosine) is a pyrimidine nucleotide analog and an effective anticancer drug primarily used in the treatment of acute myelogenous leukemia and some other types of non-solid tumors. One of the chief advantages of ara-C is its ability to block the transition of cells from the G-phase to the S-phase. There are, however, a few shortcomings associated with the molecule as well. For example, ara-C undergoes rapid enzymatic deamination in plasma to form the inactive ara-U by deoxycytidine deaminase. The use of ara-C is also associated with development of resistance and severe toxic side effects caused by large cumulative doses of the drug. Moreover, it is generally thought of as being ineffective in treating solid tumors.
One attempt to address some of the drugs shortcomings has been to administer ara-C in combination with a deaminase inhibitor such as tetrahydro-uridine. Other attempts have centered around controlling deamination such as by modifying the 2 -position. Still further proposals have focused on making prodrugs of ara-C. For example, various N4-, 5′- and 3′-acyl derivatives have been proposed as possible ara-C prodrugs.
Prodrugs include chemical derivatives of a biologically-active parent compound which, upon administration, eventually liberate the parent compound in vivo. Prodrugs allow the artisan to modify the onset and/or duration of action of an agent in vivo and can modify the transportation, distribution or solubility of a drug in the body. Typical examples of prodrugs include organic phosphates or esters of alcohols or thioalcohols (thiols).
One type of ara-C prodrug is based on N4-peptidyl derivatives. See, for example, F. M. Menger et al. Bioconjugate Chem. 5, 162 (1994); Wipf, P. et al. Bioorganic & Medicinal Chemistry vol. 4, No. 10, pp 1585-1596 (1996); and Balajthy et al. J. Med. Chem. 35, pp. 3344-3349 (1992). Similarly, U.S. Pat. No. 5,641,758 discloses N4-octadecyl ara-C derivatives which have allegedly improved resistance to enzymatic deamination. Although N4-octadecyl prodrugs release the ara-C in vivo, it would be beneficial if the circulating life and activity against solid tumors could be enhanced.
Polymeric conjugation has been suggested as a means to improve the pharmacokinetic and pharmacodynamic properties of a parent drug compound. For example, U.S. Pat. No. 5,880,131 to Greenwald et al., the contents of which are incorporated herein by reference, discloses ester-based polymeric attachment to temporarily increase the circulating life of a parent drug. Relatively hydrolysis-resistant linkages between the polymer and the parent compound residue are not disclosed.
Although some polymer-ara-C conjugates have been reported, they are believed to have exhibited one or more drawbacks. One approach taken to synthesize polymeric drugs of ara-C is found in J. Cancer Research 44, 25-30, January (1984). The authors conjugated either polyglutamic acid (PLGA) or a related copolymer (PHEG) to the N4 position of ara-C via an amide linkage. The degree of loading onto the pendant groups of the copolymers, however, is unpredictable and can only be estimated. The location of the ara-C molecules on the copolymers is also random. Thus, it is not surprising that the rate of hydrolysis of the ara-C from these polymers is unpredictable and that the amount of ara-C released from the copolymers is also variable. Further, although the authors reported that these compounds had superior in vitro activity in an L1210 (leukemia) cell line when compared to ara-C, no activity was reported with regard to their effectiveness on solid tumors.
Another approach to forming ara-C prodrugs is reported by Ichikawa, H. et al. in Drug Design and Discovery, 1993, Vol. 10, pp. 343-353. In this case, chitosan (a biodegradable polymer with repeating pendant groups) is linked to ara-C via a glutaric anhydride spacer. The reactions, however, are low yield and, like the PLGA and PHEG conjugates of ara-C described above, the chitosan-spacer-ara-C conjugates suffer from the same unpredictable loading on the pendant groups and subsequently hydrolysis of the ara-C.
Thus, in spite of the advances already made with ara-C, there continues to be a need for further improvements. The present invention addresses this need.
In one aspect of the invention, compounds of Formula (I) are provided:
G is a linear or branched terminally functionalized polymer residue;
Y1 is O, S, or NR1;
M is selected from either X or Q;
wherein X is an electron withdrawing group and Q is a moiety containing a free electron pair positioned three to six atoms from C(═Y1);
R1-5 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, substituted C1-6 heteroalkyls;
R6 is OR7 or N3, NH2, NO2 or CN, where R7 is selected from the same group as that which defines R1-5;
R8-9 are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, or R6; and
a and n are each independently zero or a positive integer, preferably from about 1 to about 5.
In preferred embodiments, Y1 is O, G is a poly(ethylene glycol) residue, and M is either NH or oxygen.
For purposes of the present invention, the term "residue" shall be understood to mean that portion of a biologically active compound which remains after the biologically active compound has undergone a substitution reaction in which the prodrug carrier portion has been attached.
For purposes of the present invention, the term "alkyl" shall be understood to include straight, branched, substituted, e.g. halo-, alkoxy-, and nitro-C1-12 alkyls, C3-8 cycloalkyls or substituted cycloalkyls, etc.
For purposes of the present invention, the term "substituted" shall be understood to include adding or replacing one or more atoms contained within a functional group of compound with one or more different atoms. The term "sufficient amounts" for purposes of the present invention shall mean an amount which achieves a therapeutic effect as such effect is understood by those of ordinary skill in the art.
One of the chief advantages of the polymer conjugates of the present invention is the fact that the ara-C residues are only found on the termini of the polymer. The uniform polymeric conjugates are thus easy to analyze and are highly reproducible. The rate of hydrolysis is also predictable and reproducible from batch to batch. Still, a further advantage is that in certain preferred embodiments, in which the polymer portion has a molecular weight of from about 20 to about 50 kDa, the conjugates are believed to passively target tumors and thus enhance the effectiveness of ara-C and related compounds on solid tumors. While applicants are not bound by theory, it is believed that tumor proteases, alone and/or in combination with peptidases, cleave the aromatic amide or carbamate bonds, thus freeing the parent active agent within the tumor. Methods of making and using the compounds and conjugates described herein are also provided.
FIGS. 1-2 schematically illustrates the synthesis of compounds described in the specification.
In formula (I), B is one of:
wherein all variables are as defined above in the Summary of the Invention section. In some preferred embodiments, B is an ara-C residue in which R2-5 are each hydrogen and R6 is OR7, where R7 is also hydrogen. The ara-C residue has the structure:
In other preferred embodiments, B is a gemcitabine residue in which each of R2-5 is hydrogen, and each of R8 and R9 is fluoro-. The residue has the structure:
In alternative aspects of the invention, B is a residue of an ara-C derivative such as those described in "Prodrugs of ara-C", by Wipf, P. et al. in Drugs of the Future. (1994) 19(1): 49-54, the contents of which are incorporated herein by reference. For example, B can be a 5′ or 3′-acyl ara-C derivative residue, a cyclocytidine residue or 2′-deoxycytidine derivative residue. For purposes of the present invention, it will be understood that the residue of the ara-C moiety is designed for covalent attachment via the N4 substituent thereof. It will be further understood by those of ordinary skill that the invention embraces not only the ara-C derivatives specifically mentioned herein but also any others capable of undergoing N4- polymeric substitution reactions.
Within formula (I), G is a linear or branched terminally functionalized polymer residue which is preferably substantially non-antigenic. In preferred aspects of the invention, the polymer residue is based on polyalkylene oxides such as poly(ethylene glycol) (PEG). The general formula for PEG and its derivatives, i.e.
where (x) represents the degree of polymerization (i.e. from about 10 to about 2,300) or number of repeating units in the polymer chain and is dependent on the molecular weight of the polymer, (A) is H or a capping group such as aminoalkyl, carboxyalkyl, haloalkyl, or other activating group and (A′) is the same as (A) or another (A) moiety. In alternative aspects, the polymer residue is a poly(propylene glycol) (PPG). Thus, the G moiety residues are preferably O—(CH2CH2O), or O—(CH(CH3)CH2O)x, wherein x is the degree of polymerization. Also useful are branched PEG derivatives such as those described in commonly-assigned U.S. Pat. No. 5,643,575, "star-PEG's" and multi-armed PEG's such as those described in Shearwater Polymers, Inc. catalog "Polyethylene Glycol Derivatives 1997-1998". The disclosure of each of the foregoing is incorporated herein by reference.
As an alternative to the preferred PAO-based polymers, other effectively non-antigenic, terminally functionalized polymers such as dextran, polyvinyl alcohols and the like can be used if the same type of activation is employed as described herein for PAO's such as PEG. Those of ordinary skill in the art will realize that the foregoing list is merely illustrative and that all polymeric materials having the qualities described herein are contemplated. For purposes of the present invention, "effectively non-antigenic" and "substantially non-antigenic" shall be understood to include all polymeric materials understood in the art as being substantially non-toxic and not eliciting an appreciable immune response in mammals. It will be understood by those of ordinary skill that the water-soluble polymer, e.g. PEG, can be terminally functionalized using standard organic synthesis techniques which are reported in the literature to add the desired spacer-liner moiety and leaving group for facilitating attachment to the ara-C derivative NH group. Alternatively, functionalized PEG's are available from commercial suppliers such as Shearwater Polymers of Huntsville, AL or Aldrich Chemical Company of Milwaukee, Wis. Thus, the PEG can be terminally modified to include moieties of the formula (II):
wherein all of the variables are as set forth above with the exception of Z which is a leaving group, such as an activated carbonate moiety like p-nitrophenyl or succinimidyl carbonate; a thiazolidine thione or other art recognized activating group which is capable of reacting with an unprotected amine. In the final synthesis step, the ara-C moiety is reacted with the polymer to form the conjugate.
In order to provide the desired linkage, activated polymers such as PEG diacids can be used as well as PEG diamines and PEG diols. Suitable PAO acids can be synthesized by first converting PEG-OH to an ethyl ester followed by saponification. See also Gehrhardt, H., et al. Polymer Bulletin 18:487 (1987) and Veronese, F. M., et al., J. Controlled Release 10; 145 (1989). Alternatively, the PAO-acid can be synthesized by converting PEG-OH into a t-butyl ester followed by acid cleavage. See, for example, commonly assigned U.S. Pat. No. 5,605,976. The disclosures of each of the foregoing are incorporated by reference herein. Although PAO's and PEG's can vary substantially in number average molecular weight, polymers ranging from about 2,000 to about 100,000 are usually selected for the purposes of the present invention. Molecular weights of from about 5,000 to about 80,000 are preferred and 20,000 to about 50,000 are particularly preferred. The number average molecular weight of the polymer selected for inclusion in the prodrug must be sufficient so as to provide sufficient circulation of the prodrug before hydrolysis of the linker. Preferably, G is O—(CH2CH2O)x and x is a positive integer selected so that the number average molecular weight is at least about 20,000 Daltons.
1. The M Groups
Within the Formula (I), M is X or Q wherein X and Q are variables which represent electron withdrawing groups. In particular, X and Q can be independently selected from moieties such as O, S, or NR10 wherein R10 is one of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8, cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls and substituted C1-6 heteroalkyls, branched, alkyls, aryls, substituted aryls, C1-6 alkyl aralkyls, heteroalkyls, substituted heteroalkyls or substituted C1-6 alkyls such caraboxyalkyls, aminoalkyls, dialkylaminos, hydroxyalkyls or mercaptoalkyls, to name but a few. Preferably, X is either O or NR10 and R10 is preferably H.
2. Q Portion of the Linker
When M is Q, the polymer residue G is preferably attached to Q via a heteroatom such as oxygen. Q is a moiety containing a free electron pair positioned three to six atoms from the C(═Y1) moieties. In a preferred embodiment, the free electron pair is five atoms from the C(═Y1) moieties. Q can be selected from the non-limiting list of cycloalkyls, aryls, aralkyl groups substituted with O, S or NR11, where R11, is defined as the same group as that listed above with regard to R10. Preferably, R11 is H, a C1-6 alkyl or substituted C1-6 alkyl. The free electron pair can be anywhere along the Q moiety as long as the defined spacing between the free electron pair and the C(═Y1) is maintained. Thus, Q assists hydrolysis of the prodrug linkage by anchimeric assistance because the free electron pair can generate a three- to six-membered, but preferably five-membered, ring intermediate upon hydrolysis preferably of the ester linkage.
The prodrugs of the present invention can be prepared using standard organic synthesis techniques. If necessary, the spacer is attached to the polymer and activated by attaching a terminal leaving group. The activated polymer portion can be obtained from either commercial sources or synthesized by the artisan without undue experimentation. For example, PEG-diacids are available from Shearwater Polymers of Huntsville, AL or Aldrich Chemical Company of Milwaukee, Wis. They can also be synthesized as described in commonly assigned U.S. Pat. No. 5,605,976, the contents of which are incorporated herein by reference. When amide linkages are sought, an activated PEG such as a bis-thiazolidine-2-thione-activated PEG (T-PEG) such as that described in commonly assigned U.S. Pat. No. 5,349,001 can be used. Alternatively, when a carbamate linkage is sought, a suitably activated PEG such as PEG-di-chloroformate or bis-SC-PEG, prepared as described in commonly assigned U.S. Pat. No. 5,122,614, or a bis-p-nitrophenyl chloroformate-activated PEG can be used. The disclosure of each of the two mentioned U.S. patents are incorporated herein by reference. The urea-linked ara-C can be prepared using bis-PEG-isocyanate generated by reacting bis-PEG-NH2 with phosgene or triphosgene and a tertiary base such as diisopropylethylamine (DIEA). Regardless of the source, the activated polymer is then reacted with the ara-C derivative to form the conjugate.
For purposes of illustration, the methods include reacting a compound of the structure (III)
with a bis terminally activated polymer of the formula (IV)
to form the compositions of formula (I). See also FIGS. 1 and 2 for reaction schemes related hereto.
Attachment of the B moiety, i.e. the ara-C derivative, can also be carried out in the presence of a coupling agent. A non-limiting list of suitable coupling agents includes 1,3-diisopropylcarbodiimide DIPC), any suitable dialkyl carbodiimides, 2-halo-1-alkyl-pyridinium halides, (Mukaiyama reagents), 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (EDC), 1-propanephosphonic acid cyclic anhydride (PPACA) and phenyl dichlorophosphates, etc. which are available, for example, from commercial sources such as Sigma-Aldrich Chemical, or synthesized using known techniques. Preferably EDC is used in pyridine to couple the ara-C derivative with PEG-carboxylic acid. Alternatively, a PEG-carboxylic activated imide, T-PEG, is reacted with ara-C in pyridine to produce the desired conjugate (prodrug). Other inert solvents such as methylene chloride, chloroform, toluene, DMF or mixtures thereof can also be used. The reaction is also preferably conducted at a temperature from 20� C. up to about 45� C., in the presence of a base, such as 4-(dimethylamino)pyridine, diisopropylethylamine, pyridine, triethylamine, etc. to neutralize any acids generated. Regardless of the synthesis selected, some of the preferred compounds which result from the synthesis techniques described herein include:
where x represents the degree of polymerization.
Another aspect of the present invention provides methods of treatment for various medical conditions in mammals. The methods include administering to the mammal in need of such treatment, an effective amount of a polymer conjugate, such as an ara-C-PEG conjugate, which has been prepared as described herein. The compositions are useful for, among other things, treating neoplastic disease including leukemias, reducing tumor burden, preventing metastis of neoplasms and preventing recurrences of tumor/neoplastic growths in mammals.
The amount of the polymer conjugate administered will depend upon the specific ara-C molecule included therein. Generally, the amount of prodrug used in the treatment methods is that amount which effectively achieves the desired therapeutic result in mammals. Naturally, the dosages of the various prodrug compounds will vary somewhat depending upon the parent compound, rate of in vivo hydrolysis, molecular weight of the polymer, etc. In general, however, prodrug ara-C is administered in amounts ranging from about 5 to about 5,000 mg/m2 per day, based on the amount of the ara-C moiety. Gemcitabine polymer conjugates prodrugs are also administered in amounts ranging from about 5 to about 2,000 mg/m2 per day. The range set forth above is illustrative and those skilled in the art will determine the optimal dosing of the selected prodrug based on clinical experience and the treatment indication. Actual dosages will be apparent to the artisan without undue experimentation.
The prodrugs of the present invention can be included in one or more suitable pharmaceutical compositions for administration to mammals. The pharmaceutical compositions may be in the form of a solution, suspension, tablet, capsule or the like, prepared according to methods well known in the art. It is also contemplated that administration of such compositions may be by the oral and/or parenteral routes depending upon the needs of the artisan. A solution and/or suspension of the composition may be utilized, for example, as a carrier vehicle for injection or infiltration of the composition by any art known methods, e.g., by intravenous, intramuscular, subdermal injection and the like.
Such administration may be also be by infusion into a body space or cavity, as well as by inhalation and/or intranasal routes. In preferred aspects of the invention, however, the prodrugs are parenterally administered to mammals in need thereof.
The following examples serve to provide further appreciation of the invention but are not meant in any way to restrict the effective scope of the invention. The underlined and bold-faced numbers recited in the Examples correspond to those shown in the Figures.
All reactions were run under atmosphere of dry nitrogen or argon. Commercial reagents were used without further purification. Ara-C was obtained from Sigma Chemical Compound (Madison, Wis.) and t-Boc protected amino acids were from Advanced ChemTech (Louisville, Ky.). All PEG compounds were dried under vacuum or by azeotropic distillation from toluene prior to use.
The HPLC Method
Analytical HPLC's were performed using a C8 reverse phase column (Beckman, ultrasphere) under isocratic conditions with a 80:20 mixture (v/v) of methanol-water as the mobile phase. Peak elutions were monitored at 254 nm using UV detector. To detect the presence of any free PEG and also to confirm the presence of PEGylated product, an evaporative light scattering detector (ELSD), Model PL-EMD 950 (Polymer Laboratories), was employed. Based on ELSD/uv analysis, all the final PEGylated products were free of native ara-C and were ≧95% pure by HPLC.
Analysis of Ara-C Contents in PEG Derivatives
For the determination of ara-C contents in PEG derivatives, N4-acetylcytidine was used as the standard because of the absorbance change due to the acylation of ara-C. The UV absorbance of N4-acetylcytidine in water was determined at 257 nm for six different concentrations ranging from 0.01 μmol/mL to 0.05 μmol/mL. From the standard plot of absorbance vs. concentration, the absorption coefficient, ε, of N4-acetylcytidine was calculated to be 36.4 (O.D. at 257 nm for 1 mg/mL with 1.0 cm light path). PEGylated ara-C derivatives were dissolved in water at an approximate concentration of 0.015 mmol/mL (based on MW of 40 kDa) and the UV absorbance of these compounds at 257 nm was determined. Using this value and employing the absorption coefficient, ε, obtained from the above, the concentration of ara-C in the sample was determined. Dividing this value by the sample concentration provided the percentage of ara-C in the sample.
A mixture of ara-C (1, 20 mg, 0.082 mmol) and T-PEG (2, 40 kDa, 0.5 g, 0.013 mmol) in anhydrous pyridine (10 mL) was stirred at 40� C. overnight. The reaction mixture was concentrated in vacuo and the residue was recrystallized from 2-propanol (IPA, 100 mL) to give 0.48 g (96%) of product as a white solid. The amount of ara-C present in this compound as measured by UV assay was 1.07% by weight: 13C NMR (67.80 MHz, CDCl3) δ61.06, 69.77-70.74 (PEG), 74.36, 85.21, 87.30, 94.63, 146.35, 153.58, 161.35, 169.23.
DIEA (60 μL, 0.35 mmol) is added to a mixture of SC-PEG 40 kDa (4, 1.0 g, 0.025 mmol) and 1 (0.15 g, 0.5 mmol) in DCM (10 mL) and DMF (10 mL) and the mixture is stirred overnight at room temperature. The solvent is removed in vacuo and the residue is recrystallized from IPA to give PEG-carbamate-Ara-C (5).
A solution of PEG-diamine dihydrochloride (6), (3.0 g, 0.08 mmol) in 80 mL of toluene is azeotroped for 2 hours. The solution is cooled to 30� C. followed by the addition of triphosgene (0.02 g, 0.06 mmol) and DIEA (0.07 g, 0.5 mmol). This mixture is stirred for 3 hours at 70-80� C. followed by cooling to room temperature and addition of 60 mL of ethyl ether. PEG-isocyanate (7) is collected by filtration under nitrogen, and immediately added to a solution of 1 (0.27 g, 1.1 mmol) and DMAP (0.14 g, 1.1 mmol) in anhydrous pyridine (30 mL) and the reaction is stirred at 45� C. overnight. The solvent is removed in vacuo, and the residue is crystallized from IPA to yield PEG-urea-Ara-C (8).
A mixture of gemcitabine (9, 261 mg, 0.99 mmol) and 2 (40 kDa, 5 g, 0.13 mmol) in anhydrous pyridine (50 mL) was stirred at 40� C. overnight. The reaction mixture was concentrated in vacuo and the residue was recrystallized from IPA (400 mL) to give 4.8 g (96%) of product as a white solid. The amount of gemcitabine present in this compound as measured by UV assay similar to the ara-C assay was 0.93% by weight: 13C NMR (67.80 MHz, CDCl3) δ58.62, 67.73, 68.23, 69.91-70.84 (PEG), 71.93, 78.36, 81.00, 95.79, 122.04, 144.66, 154.34, 161.22, 169.59.
Athymic nude mice were implanted subcutaneous with a 4-5 mm3 tissue fragment of LX-1 collected from donor mice. The tumor trocar site was observed twice weekly and measured once palpable. The tumor volume for each mouse was determined by measuring two dimensions with calipers and calculated using the formula: tumor volume=(length�width2)/2. When tumors reached the average volume of 300 mm3, the mice were divided into their experimental groups, which consisted on untreated control, unmodified Ara-C and PEG-Ara-C. The mice were sorted to evenly distribute tumor size, grouped into 6 to 7 mice per group, and ear punched for permanent identification. Drugs were administered intravenously every 3 days�4 doses (day 1, 4, 7 and 10) via the tail vein at an approximate rate of 0.5 mL per minute. Due to volume constraints Ara-C and its conjugated derivative were not given on an equal molar basis (absolute amount of active). Instead, the PEG conjugate was administered at individual doses of 20 mg/kg, while the parent compound was given close to its maximum tolerated dose (MTD) of 100 mg/kg/dose. Therefore, this study compares the PEG-conjugate at one fifth the native dose, and presumably much less than its MTD. Mouse weight and tumor size were measured at the beginning of study and twice weekly through week 4. Drug effectiveness were determined by comparing tumor growth in treated versus untreated (no vehicle) control mice. Five types of endpoints were used as the basis for comparison: (a) mean tumor volumes at day 24; (b) mean percent change in individual tumor volumes from initial; (c) percent difference in tumor volume (%T/C), measured when the control group's median tumor volume reached approximately 800-1100 mm3 (exponential growth phase); (d) percent difference in tumor volume (%T/C) at day 24 and (e) the number of tumor regression (smaller tumor volume on day 24 compared to day 1) per group.
Native ara-C appeared ineffective in this solid tumor model. In contrast, at one fifth of the unmodified or native dose, PEG-ara-C caused significant tumor growth inhibition (Table 1). PEG-ara-C treatment resulted in lower mean tumor volumes, smaller increases in tumor size and more tumor regressions as compared to both control and native ara-C.
Efficacy comparison between Ara-C and PEG-AraCα against subcutaneous human non-small cell lung
carcinomaβ (LX-1) in Nude mice
Mean Vol. �
% Change �
T/C (%)δ
T/C (%)δ
at Day 24
at Day 24
at Day 24
at Day 7
at Day 24
3131.8 �
1035.8 �
3192.5 �
1514.8 �
2205.0 �
557.4 �
αAll PEG compounds were given 2�/week for 2 weeks, i.v.
βMean baseline tumor volume was 300 mm3.
δThe median tumor volume of treatment and control groups were measured and compared when the control group's median tumor volume reached approximately 1000 mm3 (day 7) and 2400 mm3 (day 24).
*Significant (P < 0.05) vs Ara-C
Cell Lines and Cytotoxicity Assays. Studies using P388/0 cell lines for IC50 (drug concentration inhibiting growth of cells by 50%) were maintained and conducted using standard procedures. Briefly, for IC50 determination, cells were seeded into the microwell plates at a density of 2�103 cells per 50 μL per well. Plates were incubated at 37� C. in a humidified incubator with 5% CO2 for 3 days. Cell growth was measured by the addition of 10 μL/well of Alamar Blue (Alamar Biosciences, Inc., Sacramento, Calif.) and the plates were incubated a further 4 hours at 37� C. The IC50 values for each compound were determined from absorbance versus dilution factor plots. All cell cultures for animal implantation were maintained at 37� C. in a humidified atmosphere of 5% CO2/95% O2 and subcultured once a week. All cell lines were periodically tested for Mycoplasma and were Mycoplasma free. The results are shown in Table 2.
In vitro result of Ara-C, Gemcitabine and Their PEG Derivatives.
IC50 (P388/0, nM)
While there have been described what are presently believed to be the preferred embodiments of the invention, those skilled in the art will realize that changes and modifications may be made without departing from the spirit of the invention. It is intended to claim all such changes and modifications as fall within the true scope of the invention. Numerous references are cited in the specification, the disclosures of all of which are incorporated by reference in their entireties.
|Cited Patent
|Filing date
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|Jun 16, 1992
|Enzon, Inc.
|Active carbonates of polyalkylene oxides for modification of polypeptides
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|Ohya, Y., et al., Synthesis and Cytotoxic Activity of Conjugates of Monomethoxy-Poly-(ethylene glycol) End-Capped with Doxorubicin via Ester, Amide, or Schiff's Base Bond, Journal of Bioactive and Compatible Polymers, vol. 10, p. 51-64 (Jan. 1995).
|Ouchi, T., et al., Syntheses of 5-Flourouracil-Terminated Monomethoxypoly (Ethylene Glycol)s, their Hydrolysis Behavior, and their Antitumor Activities, Copyright 1987 by Marcel Dekker, Inc.
|Ouchi, T., et al., Synthesis and Antitumor Activity of Poly(ethylene glycol)s Linked to 5-Fluorouracil via a Urethane or Urea Bond, Drug, Design and Discovery, vol. 9, p. 93-105 (1992).
|Wipf, P., et al., Prodrugs of ara-C, Drugs of the Future, vol. 19(1), p. 49-54 (1994).
|Wipf, P., et al., Synthesis of Chemoreversible Prodrugs of ara-C with Variable Time-Release Profiles. Biological Evaluation of Their Apoptotic Activity, Bioorganic & Medicinal Chemistry, vol. 4, No. 10, p. 1585-1596 (1996).
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|U.S. Classification
|514/43, 536/28.4, 536/27.4, 536/28.5, 536/28.1, 514/49
|International Classification
|Cooperative Classification
|European Classification
|Oct 12, 1999
Owner name: ENZON, INC, NEW JERSEY
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:GREENWALD, RICHARD B.;CHOE, YUN H.;REEL/FRAME:010303/0568
Effective date: 19990923
|Oct 7, 2003
|Certificate of correction
|Sep 30, 2005
|Fee payment
Year of fee payment: 4
|Oct 7, 2009
|Fee payment
Year of fee payment: 8
|Nov 29, 2013
|Maintenance fee reminder mailed
|Apr 23, 2014
|Lapse for failure to pay maintenance fees
|Jun 10, 2014
|Expired due to failure to pay maintenance fee
Effective date: 20140423


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Re: Affirmativ
e Action: Yay or Nay?
Some days only the bus driver and I are the only ones speaking English on the bus...
I think Afirmative action should go, everyone should have a fair chance if they are a US citizen.
Thanks Asuka424 for the Signature
Re: Affirmativ
e Action: Yay or Nay?
bob-maul wrote:
wais_45 wrote:
bob-maul wrote:
wais_45 wrote:
I think Spanish should be one of the official languages in America (or secondary language).
That is not ideal at all. One official language is the best way to go in our nation. In third world nations, where you cannot standardize learning or assimilate groups, this would make sense and help, but not in this nation. Everything is built with English at its heart and, as was mentioned earlier, it would be cumbersome to accomodate Spanish speakers. The number of people that ONLY speak Spanish is too small to warrant it, and if a state or county within said state has a massive immigrant population, they can deal with it a local level.
I thought there was a lot of spanish speaking people in America? And with America's history with Spain/Mexico it would make sense to at least make it a Secondary langauge. In Canada, French-Canadians are the minority but it's still one of the official languages.
Hispanics/Latin origin make up around 17% of our population. But the majority of them are not first generation and speak English (and many do not even speak Spanish...). If you are Canadian, you should know that the French-Canadians in Quebec are prideful as a whole and have laws to ensure that French is a main language (such as equal representation of the language on signs). They essentially force it to be a language because they try to be their own little nation-state (luckily for Canda, the pro-secession party recently lost big in the elections).
Only a small amount of people ONLY speak French in Canada- with French speakers who learned it as their primary language making up a little over 20% of the Canadian population. It is more the older generations that do not know English, and that is only because of Quebec's insistence on maintaining their heritage in the past.
And it proves my point. Leave it to the individual states and provinces that require it. The national government in Canada should not have to deal with Quebec's separatist culture. That is Quebec's problem. Same in the US. If Southern California cities want to be a safe-haven for illegal immigrants, they can handle the work in assimilating them.
I guess you're right that English was the foundation of America and everything was built around that. I guess it would be comparing apples to oranges when talking about the culture/language of Quebec. I just assumed that there was a lot of spanish speaking peoples in America and I assumed the language itself has had a long history with America.
Also, it wouldn't have mattered if the Parti-Quebecois (the pro-seperatists that lost in the provincial election) won because the youth in Quebec don't really care about the seperatist movement of the past.
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text:
Sweet & Spicy Asian Cucumber Salad
s s
This sweet and spicy Asian cucumber salad is a quick and easy side dish. It's cool and refreshing, cucumbers are the perfect accompaniment to anything intensely spiced (not necessarily hot). Sliced cucumber and paired with Asian seasonings like mirin, rice vinegar, and sesame oil, all of which should be available in your local super market. Serve your sweet and spicy Asian cucumber salad with grilled meat for a delicious meal.
Shared with permission of Foodista.com - foodista.com/...asian-cucumber-salad
Shared with permission of Foodista.com - foodista.com/...asian-cucumber-salad
Featured Pinch Tips Video
- 1 large
- cucumber, sliced
- 1/2 c
- green onions, chopped
- 2 Tbsp
- rice vinegar
- 1 Tbsp
- mirin (asian seasoning)
- 1/2 Tbsp
- sesame oil
- 1/4 Tbsp
- chili garlic sauce
Directions Step-By-Step
1Combine ingredients in a bowl and marinade for 30 minutes. Serve chilled.
About this Recipe
Course/Dish: Vegetables, Other Salads
Regional Style: Asian
Dietary Needs: Vegetarian
Other Tags: Quick & Easy, For Kids, Healthy
Hashtag: #spicy


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Product Info
- Straight from the regal streets of Hyderabad, this exclusive collection has timeless pieces that are cultural masterpieces.
- Perfect to adorn with exquisite ethnic ensemble, the styles are created keeping in mind the royal splendour.
- Fashion earrings.
- Use of semi precious stones and pearls.
- GPC plating.
- Stud post closure.
- Ideal for formal outings.
- COLOUR : Gold and Multi.
- MATERIAL : Alloy, Semi Precious Stone, Pearls.
- SIZE : 1.3 Inch(Approx.)
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The Frozen Throne (25 player)
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|The Frozen Throne (25 player)
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The Lich King is the final boss of Icecrown Citadel, located at the Frozen Throne.


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Shimano Blackmoon Fishing Backpack, Medium
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Chapleau is a township in Sudbury District, Ontario, Canada. It is home to one of the world's largest wildlife preserves called the Chapleau Crown Game Preserve that spans more than 7,000 square kilometers. This protected wildlife preserve is attracts nature enthusiasts for its sheer range of wildlife species and is an absolute must on any wildlife enthusiast's itinerary. The Chapleau Crown Game Preserve is a safe haven to numerous moose, black bears, pygmy shrews, bald eagles, loons among other animals. Another similar place here is the Potholes Provincial Nature Reserve. It is home to thousands of birds and offers a hiking trail that would take you through the plentiful potholes and pools that were created by glaciers here over many millennia. Informative signage would follow you everywhere on this trail to give you an insight about the local topography and wildlife.
Places of Interest in Chapleau
Chapleau Crown Game Preserve
The Chapleau Crown Game Preserve is a protected wildlife sanctuary located in the hinterland of the native Canadian tribes. It offers spectacular viewing opportunities of regional wildlife and includes moose, American black bears, red foxes, Canada lynx, timber wolves, marten, beavers, otters, minks, ruffed and spruce grouses, bald eagles and loons.
Missinaibi Provincial Park
Missinaibi Provincial Park is spread across from the Missinaibi River to the Moose River. It is immensely popular among canoeing enthusiasts and also offers exceptional hiking, fishing, camping and hunting facilities.
The agent provided exceptional services i ever received in 33 years. She surpassed my expectations in resolving the issue
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Married 31 Year Old English Teacher Arrested For Having Sex With Student
December 22, 2013 10:22am PST
A 31 year old high school English teacher has been arrested after a boy's parents had found sexually explicit conversations between the teacher and their son on his computer. Lauren Harrington-Cooper, was a married, 9th grade English teacher at the Wyoming Valley West High School where she has confessed to having a sexual relationship with a senior student.
(See also: "Bikini Teacher" Gets Payback On School, Poses For Hustler Magazine Cover)
The parents of the boy had seen a sexual conversation between the two on his computer and went to the high school to inform the principal. As short while later, Harrington-Cooper was arraigned on a single count of institutional sexual assault.
The teacher had apparently obtained the boy's phone number from his sister and was then able to talk via text message. She was even reported to have told the boy that he was "hot."
(See also: Teacher's Aide Avoids Jail Time After Raping Student)
Starting in mid-December, the two met on several occasions near the boy's house where they engaged in sexual intercourse. The teacher had also performed oral sex on the boy in his car.
After being arrested, Harrington-Cooper, "admitted having sexual relations with the boy, whom she knew was a high school senior to investigators."
(See also: Choir Teacher Caught Having Sex With Teen Student "At Least 5 Times")
Harrington-Cooper was released on $25,000 but not without the warning by District Judge Martin Kane, that if she were to miss "her preliminary hearing on December 26, she would be incarcerated."
The woman has since been hospitalized requiring medical supervision after attempting suicide.
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Quilted Jacket Mens
Guide price: $220
Last updated on 16th Mar 2016
Tags: quiltedjacketmens mensjacket menswear blackleat
Quilted Jacket Mens
Men's 100% Real Lambskin Black Leather Biker Quilted Jacket at Discounted Price $219.00 Buy Online Now made from genuine leather get free shipping worldwide.
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- Worldwide Rank #71,983,241
- Follower/Following Ratio 0.62
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I always do what I want, if it's good for me and good for the people around me.
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@007_MrBottle has 53 followers on Twitter.
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@007_MrBottle is following 86 Twitter accounts.
Last month this account stopped following 3 users.
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FMP would like to present Sepke imported 10 year old gelding who thinks the best!! We have been hard at work to find a sweet boy just like Sepke and we…SOLD
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SKILCRAFT Rubberized Barrel Retractable Ballpoint Pens - Ballpoint pens feature a rubberized barrel with gripper rings for easy grip comfort. The ink cartridge contains ink that won't fade or smear. Color of the cap and clip matches the ink color. Each ballpoint pen writes 2,460'. Refillable ballpoint pens contain 83 total percent recycled material with at least 80 percent post-consumer material.View Product Specs
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4164 Inverrary Dr # 903 Lauderhill, Florida 33319
FABULOUS NEWLY RENOVATED 2 BEDROOM, 2 BATHROOM CONDO AT THE MANORS OF INVERRARY. This is a beautifully remodeled unit. Completed with brand new kitchen cabinets, granite counter tops, newly tiled flooring and newly replaced appliances. All rooms boast new laminate wood flooring, new bathroom cabinets with granite counter tops and new fixtures. Entire unit freshly painted and patio beautifully tiled for outdoor use. No Pets! Ready to move in!
EWM is not responsible for the accuracy of the information listed above. The data relating to real estate for sale on this web site comes in part from the Internet Data Exchange Program and the South East Florida Regional MLS and is provided here for consumers personal, non-commercial use, It may not be used for any purpose other than to identify prospective properties consumers may be interested in purchasing. Real Estate listings held by brokerage firms other than the office owning this web site are marked with the IDX logo. Data provided is deemed reliable but not guaranteed.


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Extreme Weather
Extreme weather events, such as these multiple tornadoes, are more likely as a…
Camille Seaman is a photographer, born in 1962 in the USA, chasing extreme weather across the country and capturing it at its peak. Some of her clients include National Geographic Magazine & Newsweek.
A lighthouse in St. Joseph, Michigan, pulls double duty as an icicle-bearing sentinel. This type of ice is similarly formed like rime ice.
Mammatus Phenomenon = Bubble Clouds,Regina,Canada
Storm chasing photographer captures stunning images of extreme weather http://www.invigor8teasaus.com.au/
Russia's frozen Lake Baikal is covered in naturally occurring formations called ice hummocks. Created by the area's extreme weather conditions, these picturesque blocks can reach a height of 50 feet.
I remember watching the storms roll in back in Louisiana like it was just yesterday... it always made me think of impending doom approaching, lazily drifting through the sky, over encumbered with the liquid of life... thundering in the distance, warning the world of the mayhem in the sky above... beautiful.
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tornados | Picture of a tornado heading toward two cars on a country road in ...
Extreme weather reports! These reports are easy to write with this step by step guide. A favorite of my students!


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Rudolph Hits The Big AppleRudolph the red-nosed reindeer comes to New York City this holiday season.
NYC's Can't-Miss Christmas Trees Beyond Rockefeller CenterA roundup of our favorite Christmas trees in New York City, besides the Rockefeller Center Christmas tree.
NYC Weekend Events: Festivals, Shows, Things To DoA roundup of the best events and things to do in New York City this weekend.
NYC's Best Holiday Movie ScreeningsPopular holiday movie screenings in NYC this season, from holiday classics like "White Christmas," to "Home Alone," "Elf," and "It's A Wonderful Life."
'Phantom Of The Opera' Hits Broadway Milestone With 12,000th Performance'Phantom of the Opera' opened on January 26, 1988 -- almost 29 years ago. It is the longest-running show in Broadway history.
NYC's Holiday Nostalgia Train Comes To Life Along Second Avenue LineThe historic train will take riders between Lower Manhattan and Queens Plaza every Sunday until the week before Christmas -- all for the price of a standard MetroCard swipe.
5 Best Activities For Subway Buffs In NYCHere's our five favorite activities designed to bring out the subway lover in even the most cynic of riders.
Macy's Thanksgiving Day Parade Guide: Street Closures, Where To WatchWith millions of people expected to attend this year's Thanksgiving Day Parade in NYC, you'll want to check our guide and create a game plan before you head out the door.
Macy's Thanksgiving Day Parade Guide: Street Closures, Where To WatchEverything you need to know about this year's Macy's Thanksgiving Day Parade, from street closures, to watch points and more.
Native American Sites, Memorials In NYCExplore the rich cultural and historic connections New York City has to Native American heritage.
9 NYC Activities That Are Fun For GroupsRound up your friends and family, and check out these activities that are particularly good for groups.
Dwayne 'The Rock' Johnson Named People Magazine's 'Sexiest Man Alive'The 44-year-old tells the magazine that the honor means he has "pretty much reached the pinnacle.''


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text: Item is not available Find Another One Others Looked At... Browning Pigeon 12 gauge O/U SELLER: GulfCoastGuns 1 $2,100.00 Browning GTI 12ga 30" SELLER: Southwest Shooter Supply 1 $2,695.00 Browning Pigeon Grade 3bbl Set SELLER: Southwest Shooter Supply 1 $5,500.00 BRN 017-054401 BT99 CONV 12 34 SELLER: 82 Sellers 1 $1,154.52 BRN 017-054402 BT99 CONV 12 32 SELLER: 82 Sellers 1 $1,154.52 Browning XT Trap 12ga. 32" SELLER: Rick Hemingway 1 $2,400.00 Guns Shotguns Browning Shotguns Over Unders Other OU Trap Skeet Browning B Superposed Standard Shotgun g | 121 | 80 | Lc | 140.607ms Browning B- 25 Superposed Standard Shotgun 12g 26 1/2" For Sale from Colegunsmithing | Positive feedback: 100% View | Verified Seller | 15 Completed Sales View Sellers Items This item is no longer available. /UserImages/178445/992648544 7174137.jpg /UserImages/178445/992648544 7174138.jpg /UserImages/178445/992648544 7174139.jpg /UserImages/178445/992648544 7174140.jpg /UserImages/178445/992648544 7174141.jpg Description Shipping and Payment More Info Browning B- 26 Superposed Standard Shotgun 12g 26 1/2" 1C/ M chocked, bright bores, tight action Blueing is 99%, forend has typical crack on left at rear 1 1/2 X 2 3/8 14 3/8 over pachmayr 325 1" pad is well fitted and correct for period Wood finish is in very good condition and original Great clean shooter! This gun is located in our Florida store, please call for more information. Buyer pays shipping and handling to FFL. Trades Accepted: No Established in 1985, Cole Gunsmithing is one of only five (5) Beretta Warranty Service Centers nationwide and is also skilled in the general service of Perazzi and Caesar Guerini Shotguns. Owner Rich Cole and his team are well-known as the Beretta experts here in the United States. Trained by the Beretta factories, Cole Gunsmithing knows Italian shotguns. We are the exclusive dealer for both Beretta Premium and Perazzi shotguns in both Maine and Florida. In addition, we are stocking dealers for Benelli, Caesar Guerini, and FabArm. Our company is a full-time facility offering best-quality gunsmithing services in two modern shops equipped with state of the art machinery and tooling. So, whether you are a beginner looking for a standard shotgun, a competitive clay sports shooter demanding the utmost in quality and performance, a collector looking for something unique, a hunting enthusiast or anywhere in between, Cole Gunsmithing is committed to the highest levels of customer satisfaction. Condition: Used, Minor Wear Brand: BROWNING Caliber: 12 Gauge Location: FL Share Item Item #: 992648544 Stock No.: 7416957 This item is no longer available. Price: Shipping: See Description (or Arrange local transfer) Accepted Payment Methods: Returns: No Returns Colegunsmithing Seller Since: Jan. 2015 Seller Level: Trusted Seller This seller is an FFL City: State: More Items from this Seller ( 129 items total | View All ) Fabarm XLR5 Velocity LR 1... $2,000.00 Full Details Add To Cart Renato Gamba Safari Expre... $8,500.00 Full Details Add To Cart Fabarm XLR5 12ga 32" Pre-... $2,400.00 Full Details Add To Cart Mc | 15.6205ms -- 178445 Your Recently Viewed Items


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June 2, 2010
SWAYSEY RANKIN #20090005972, PLAINTIFF,v.TOM DART, ET AL., DEFENDANTS.
Three doctor defendants in this 42 U.S.C. §1983 ("Section 1983") action brought pro se by Swaysey Rankin ("Rankin") have filed a joint Answer to Rankin's Complaint. On the constructive side, defense counsel has separated Rankin's uninterrupted narrative in his Complaint Part IV ("Statement of Claim") into consecutively numbered sentences, thus facilitating the ability of the reader to follow Rankin's allegations and the doctors' responses.
But that said, what has emerged in the Answer is simply not credible in one or more respects. All but one of the 22 allegations in the Complaint has been met with an outright denial, while the 22d has drawn a Fed. R. Civ. P. ("Rule") 8(b)(5) disclaimer. Even apart from the obvious fact that the denial of an allegation as to which a defendant has had no personal involvement is necessarily based on hearsay plus a ratification of the informant's credibility, any answer in those stark terms portrays the Complaint as a total fabrication--an outright lie. That may be so, but it seems very unlikely in light of the particularized nature (including specific dates) of a number of Rankin's allegations.
If it were to turn out that it is defendants' blanket denials rather than the entirety of those allegations that are a fabrication, this Court would have to entertain the possibility of Rule 11 sanctions against defendant or their counsel or both. This Court is of course not making any findings as to Rankin's believability--but the constant stream of defendants' denials as to all of his allegations seems highly problematic. For example:
1. There appears to be no way in which these doctors, assigned as they are to the County Jail, have personal knowledge as to the allegation in Complaint ¶3, which relates to something that assertedly happened while Rankin was in custody at the Illinois Department of Corrections. Nor, by the same token, could they have personal knowledge of the allegations in Complaint ¶¶14 and 22, which appear to refer to "staff" other than these three doctors.
2. Allegations with specific dates attached (see, e.g., Complaint ¶¶4, 5, 8 and 19) sound plausible, rather than being fabricated out of whole cloth.
3. Just how can defendants deny allegations about Rankin's condition (see, e.g., Complaint ¶¶11 and 20) if they haven't attended to his asserted ailments, as their other denials suggest?
4. Complaint ¶17 alleges Rankin's treatment at the Cermak Medical Facility, something that is normally recorded as part of such a facility's recordkeeping practices. Does the doctors' denial mean to say that nothing of the sort occurred?
This order could go on to look at other allegations, but what has been said should suffice to demonstrate a serious doubt whether this Answer--with 21 of its 22 responses being flat-out denials of the Complaint's allegations--has been advanced in the objective good faith demanded of every litigant and lawyer under Rule 11(b).
There is, however, one aspect of the response that calls for prompt input from Rankin. AD 3 asserts his failure to have exhausted all administrative remedies, a requirement that is made a precondition to any prisoner lawsuit under 42 U.S.C. §1997e(a)(a statutory provision that has been miscited by defense counsel). Rankin is ordered to provide an appropriate showing of his efforts (if indeed there were any) to obtain administrative relief before he brought this action. If no such submission were to be filed on or before June 21, 2010, this Court would be constrained to dismiss the action on that ground.
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My Town Videos, Articles, Pictures
Briel Back in Town. Back to Business. Alright Everyone Back Up!
Going clubbing with my TORSOPLEGIC friend Bent
Shades of my Father
My Brother the Curse of the Fart Waffle
This Is My Song (get your own)
11 great smiles from my hometown
There's A New Sheriff In Town
Missing My Bestie
My Brother, The Opera Phantom
Cover of my comedy DVD
My Having Dinner With, Nikola Sainovic, Slobodan Milosevic's, Deputy Prime Minister in Butler New Jersey
Billy Ray's in Town!
NOODLES ( YONG KIM ) : " I grew up in the bad part of Koreatown, we called it North Korea-town. "
Pleasurable Textures
Santa Claus Ain't Coming to Town
Where Are My Dragons
Billy on the Street premiere


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Explora Retiro De Desintoxicação, Retiro De Ioga e outros!
We are so excited to bring you new online yoga classes with this lovely lady! Check out @heatherlilleston at yogavibes.com/heatherlilleston. Her first class, filmed @yogavidanyc, is a 50-minute Fall Detox Flow. If you're feeling all over the place (or vata-deranged) practice this flow for some serious grounding!
Online yoga classes. Request invite. #yoga #video #online #classes #yogi #yogapose #ashtanga #asana #meditation #namaste #om #yogateacher
1965, yoga, exercise, class, America, Vintage, Photo
1956, group yoga class in the garden (vintage yoga style photo)…
Christmas Tree Yoga Card by WalkingSatellite on Etsy | Come to Clarkston Hot Yoga in Clarkston, MI for all of your Yoga and fitness needs! Feel free to call (248) 620-7101 or visit our website www.clarkstonhotyoga.com for more information about the classes we offer!
A beautiful morning flow (video) - YogiApproved.com. I hope to be that flexible to do a whole routine without instructions just like this video!
What do you get out of your yoga practice?
Daily dose of inspiration for yogis. #yoga #video #online #classes #yogi #yogapose #ashtanga #asana #meditation #namaste #om #yogateacher
When you are into your practice fully, you are fully present, riding your breath into a peaceful place. The more you do it, the longer you stay in the peaceful place with less gaps of non-peace. It's really beautiful.
5 Minute Yoga Challenge: Roll your feet on a tennis ball to loosen your hamstrings. I've done this all January and at last night's Bikram class I touched my forehead to my knee for the first time!


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Your scent lingers in my thoughts causing me to break from reality and seek comfort in a corner of my mind where only you hide . Your laugh , your eyes , your kiss , pleasantly haunt my memories causing you to be a sweet distraction. That thing I think of when the world is displaying it's harsh reality and truth. I know that in thinking of you, I'm reassured that life isn't all bad , and in that moment I lose myself to that corner of my mind where you and I can be together. Thanks for the moment of bliss , my sweet distraction.
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Because Knetbooks knows college students. Our rental program is designed to save you time and money. Whether you need a textbook for a semester, quarter or even a summer session, we have an option for you. Simply select a rental period, enter your information and your book will be on its way!
China's rapid economic advancement has resulted in vast and unprecedented changes, among which opportunities and challenges coexist. As power is redistributed globally, China is finding itself at a crossroads. And as a socialist nation, China's economic rise presents unique challenges.
By comparing possible modes of the rise of great powers, Reconstructing China explains why it is absolutely essential that China take a path of peaceful development and growth, and how the nation can achieve it in the most effective way possible.
Written by international relations expert Li Jingzhi--a professor at Renmin University of China--Reconstructing China gives policymakers, global investors, business leaders, and anyone else interested in the rise of Chinaa perspective of China's growth they will find nowhere else.


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A mix of fable and history
Recipe for good theatre
Pick a colourful historical character (preferably Tipu Sultan).
Get a renowned playwright to pen the script (preferably Girish Karnad).
Bring in an outstanding cast.
Throw in some fabulous lighting and background music.
Add a shimmer with brilliant period costumes.
Get a seasoned director (preferably Arundhati Raja) to blend it to perfection.
Serve at The Hindu Metroplus Theatre Fest 2012 and watch the awestruck audience savour it to the
last bite.
Elvis D'Cruz
10C, The Orchard, Mather, Vidyanagar
Back in time
In The Dreams of Tipu Sultan the stage was lit up with soft lights and the dark background with a picture was also lighted.
When the play started, I felt the characters were pushing me into history. I felt I was with them but unseen. The whole play was lovely and there was some nice music in between. I felt joy, sadness and patriotism and many other feelings which have no words. When the play was over I felt I came back in a time machine. It was indeed a nice experience.
Udisha Plakkot (VI-A, Bhavan's Vidya Mandir, Giri Nagar)
6A, Cears mid town
K.P Vallon Road, Kadavanthara
The other side of Tipu
The play depicts the Sultan's dreams seen through the narrative of a historian. Set during the last days of his reign, Tipu Sultan is faced with the wrath of the British Raj. As the play progresses, we see a side to Tipu Sultan often overlooked- he wasn't only a king but a husband and a father as well.
While Tipu Sultan's journal seems a convenient narrative device, the play does effectively tell his story and a message. It also leaves the question of his competency as king open for debate. The play could be accessible to a larger audience, if the introduction of the characters was given more context.
Some minor audio issues were present- dialogues were occasionally inaudible due to the low volume of the microphones.
Excellent performances (notably Tipu Sultan) and a convincing ensemble of characters, makes this play a pleasurable experience.
Dr. Hormese Chakola
Shared history
Truth be told, I didn't know what to expect when we headed out to watch this play, but Abhijeet Shetty's powerful and majestic portrayal of a multifaceted, never before seen Tipu Sultan left us in awe.
The range of characters from the plotting British officers, to the duty bound princes, and even Tipu's Maratha counterparts, with their rich attire and outstanding performance, ave the audience a peek into a crucial time of our shared past. The events of which had repercussions in the decades that followed. In the end we left, sharing Tipu's dreams and wondering how things would have turned out if they did come true.
Though there was a short instance of inaudible lines during a portion of the play, that hardly bothered us since the lighting, sound and stage settings were excellent. Kudos to the cast and crew.
Nellikkappillil House,
Mukootil Road,
Poonithura P.O.
The Winner
A document in history
Master playwright Girish Karnad's play The Dreams of Tipu Sultan truly sketches the humane side of the warrior king. Jagriti's presentation of the play, directed by Arundhati Raja, excelled in truly capturing the ethos, culture and temperament of the times. Unlike the historical representation of Tipu as a valiant king, here we see a troubled soul, ready to make compromises, and even send two of his own children as hostages. Abhijeet Shetty scored well in depicting the inner turmoil of the Mysore king. The costumes were most authentic and the props, though minimal, conveyed the sombre mood. The unvarying sober tone and treatment could have given in to a few lighter moments. It was a big cast and each of the actors fitted their roles to the T. The play could very well be a document in history, with a valid objective interpretation.
Sharath K.S.
Kalathiparambil House, Kumbalam


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