Evaluation of Sustained Release Matrix Tablets of Cilostazol

Evaluation of Sustained Release Matrix Tablets of Cilostazol Development and in Vitro-in Vivo Evaluation of Sustained Release Matrix Tablets of Cilostazol Keywords:Cilostazol; Pharmacokinetics; ER Matrix Tablet; In Vitro Kinetics; ABSTRACT The objective of this research had to manufacture extended release matrix tablet of Cilostazol and to evaluate its in vitro drug release and in vivo absorption. The dosage form was designed by selection of various polymers such as Hypromellose, Kollidon SR, Xanthan gum, Ethyl cellulose, Eudragit Polymers. Microcrystalline cellulose and lactose as dilutents to build matrix tablets and povidone as granulating binders. The tablets were prepared by Direct compression, wet granulation and Melt extrusion techniques. Optimized formulation of Cilostazol matrix tablets was prepared by using 7% HPMC K100M polymer, 39 % MCC, 3% of povidone as binder. Matrix tablets were compressed with optimized free flowing granules of uniform drug content. This in vitro drug release showed the extended the release period up to as per desired specifications. The matrix formed by HPMC, MCC and Povidone had been showed satisfactorily with the controlled resistance. Bioavilability study of this wet granulation do sage formulation in rabbit model showed 24 h sustained drug release in vivo. A correlation (R2= 0.9833) was founded between the in vitro drug release and the in vivo drug absorption. The results suggested that wet granulation with is a satisfactory method to develop a sustained release Cilostazol and it can be Performed therapeutically better than conventional IR dosage form. 1. Introduction In this study the Cilostazol sustained release matrix tablet was developed with various polymers. Since the IR dosage form produces and side effect head of ache due to drug oscillation in plasma. The challenge become to develop a matrix tablets are due to drug morphology and highly insoluble in nature . In the present study, a sustained release dosage form of Cilostazol has been developed that enables less frequent administering of drug . Matrix tablets of Cilostazol were formed by appropriate combination of HPMC and Povidone and lactose monohydrate,MCC and Kollidon K30 was chosen for matrix tablet to extend duration of drug release. Cilostazol and its metabolites are inhibit the platelet aggregation and exert vasodilatory action by inhibiting phosphodiesterase activity and cAMP degradation with a resultant increase in cAMP in platelets and blood vessels The objectives of research were: 1) To analyze the physical and chemical characters of prepared Tablets 2) To elucidate the effect of polymers and to study the release kinetics, 3) in-vivo study for the stable formula. 2. Materials and Methods 2.1. Materials Cilostazol was obtained from IPCA lab, Mumbai, India. Hypermellose (Methocel K100M CR), Povidone K30 received as a gift sample from Colorcon Pvt Ltd. Kollidon K30 was obtained from BASF. All other Reagents were purchased from local suppliers, India and were of analytical grade. 2.2. Drug and Excipient Interactions Drug Excipient interaction study was investigated by DSC (differential scanning calorimeter). The DSC Thermo gram of only drug and Drug+Excipient mixtures were noted. The samples were separately packed in aluminum cells and kept a set in Metler TA 4000 Thermal analyzer. 2.3. Formulation 1. Dispensing: All the ingredients were dispensed accurately as per formula quantity. 2. Sifting: Measured quantity (refer table no.4.5) of Cilostazol, Microcrystalinecellulose (Avicel PH-101), HPMC K100M, were passed through 30#, Microcrystalinecellulose(PH-102), Aerosil-200, through 40#, yellow oxide of iron and Magnesium stearate were passed through 60# . 3. Mixing: Measured quantity (refer table no.4.5) of Cilostazol, Microcrystalinecellulose (Avicel PH-101), were mixed in polybag for 15 min, to it added yellow oxide of iron and mixed for 5 min. in RMG at 2.4 RPM . 4. Preparation of Binder solution: Measured quantity (refer table no.4.5) of IPA and Water were poured in stainless steel beaker, to it added PVPK-30 with stirring continuously by glass rod till dissolved completely and clear solution is obtained. 5. Wet Granulation: Granules were prepared by wet granulation method in RMG at 2.4 RPM for 15 min, using step 4 binder solution. Prepared granules dried at 60  ºc till LOD reaches less than 2.5% and finally sifted through 30#. 6. Mixing: Mixed the measured quantity (refer table no.4.5) of Microcrystaline cellulose (Avicel PH-102), HPMC K100M, Aerosil-200, in polybag for 15 min with granules obtained in step 5. 7. Lubrication: Above granules are lubricated with measured quantity of magnesium stearate In the trial 5 concentration of HPMC K100M is reduced from 10% to 8% and trials 6,7,8 from 10% to 7% . 2.4. Physical Characterization of Tablets The prepared tablets were subjected to various physical characterization studies. Weight variation test was performed with 20 tablets with an electronic balance. Tablets hardness was determined using Monsanto (Standard type) tablet hardness tester. Thickness was measured by a venier caliper (Mitutoyo, Japan). Friability was calculated using a Roche friabilator (Basel, Switzerland) 2.5. Drug Content of Tablets (Assay by HPLC) Cilostazol USP: Chromatographic Conditions: The drug content of the formulated tablets was estimated by HPLC method. Column: Stainless steel column packed with octadecylsilane silica gel for chromatography ,c18 ,150Ãâ€"4.6 mm,5 µm(Inertsil ODS-3 is suitable) Mobile phase::Acetonitrile:Mthanol:Water(7:3:10by volume), filter and degas. Flow rate: 1.0ml / min Wavelength: 254nm Diluent: Methanol Injection Volume: 10 µl Temperature: 270C ± 10C Retention time: Cilostazol- about 9.4 minutes. Cilostazol was analyzed by HPLC at a wavelength of 254 nm. 2.6. In Vitro Dissolution Studies In-Vitro dissolution Studies (Dissolution analysis by HPLC) Dissolution testing for the amount of drug-substances released was studied using the following dissolution parameters: Table : Dissolution parameters and specifications for Cilostazol Acceptance criteria : As given table no.4.15 Dissolution Parameters:Medium: 900 ml, 0.3% SLS in 6.8 Phophate bufferApparatus: USP Apparatus 2Paddle Speed: 75 RPM Temperature:370C  ± 0.50c. Duration:1,4,8,12,24 hours Chromatographic Conditions: Instrument: HPLC(Hitachi) Column: Stainless steel column packed with octadecylsilane silica gel for chromatography, C-18, 150cmÃâ€" 4.6mm, 5 µm (Inertsil ODS-3 is suitable) Mobile Phase: Acetonitrile:Mthanol:Water(7:3:10 by volume) filter and degas. Flow rate: 1.0 ml/min Wavelength: 254nm Injection Volume: 20 µl Diluent: Methanol, Dissolution Medium Temperature: 270C  ± 10C. The release studies were conducted in duplicate. Mean % cumulative drug release was plotted against time (hours). 2.7. Drug release Kinetics and Mechanism Kinetics of drug release was determined by fitting data to Table 1. Composition of extended release matrix tablet of Cilostazol different models such as zero order (M = kt), first order equation (M = lnM0+ kt), Higuchi model (M = k√t) and KorsemeyerPeppas equation (M = ktn). The value of n = 0.5 denotes case I diffusion (Fickian), 0.5 n = 1, for case II transport and n > 1 for super case II transport. Where M is the amount of drug (%) released after time t; Where M0is the amount of drug released at (0) zero time; k is the release rate constant, n is the exponent. Drug release following particular mechanism is judged by the linearity of plot 2.8. Stability Studies Stability studies were conducted on SR Tablets of select batch to assess their stability with respect to their physical appearance, drug content and release characteristics after storing at 25ËÅ ¡C under 60% relative humidity (RH) and 40ËÅ ¡C under 75% RH for 6 months [8]. 2.9. Pharmacokinetic Evaluation The animal studies were performed as per guidelines for the Care and Use of Animals that were approved by the Animal Ethics Committee. Male rabbits (Albino) with average weight of 2.5 kg were housed in standard cage individual, which well ventilated with air, humidity and temperature control. 50 mg equivalent weight of Cilostazol sustained Release Tablets with and 50mg equivalent weight of Cilostazol 50mg IR tablet was administered to 2 groups orally (N = 4) via silicone rubber gastric intubation tube. A wooden rod was kept between the jaws of rabbit’s mouth. A gastric tube was centrally placed over the hole in mouth (21.22). With the help of gastric intubation tube the tablets were administered in to the stomach of rabbit by set on the tip in it. After administered the oral dose, 5 ml of water was given to facilitate the admittance of the tablets. Rabbits were kept fasting over night but access to water ad libitum; In a heparin zed branule (G22, G24) 2 ml of blood samples were collected, which placed in the marginal ear vein , at each of the pre determined times i.e., 0.25 Hr, 0.5 Hr, 1 Hr, 2 Hr, 4 Hr, 6 Hr, 8 Hr and 24 Hr after administration:Samples were transferred to eppendrof centrifuge tube and centrifuged at 3000 rpm for 10 min. The separated organic layer will be collected and evaporate to dryness under a gentle steam of nitrogen gas. The obtained residues will be reconstituted in organic solvent with vortex mixing, from which aliquot will be injected to HPLC system . supernatant plasma was separated and transferred and stored at –20ËÅ ¡C until Analyzed. in to 96 well plate 2.10. In Vivo Data Analysis The maximum plasma concentration (Cmax) and the time to reach the maximum concentration (tmax) were directly obtained from the observed values. The area under the curve up to 24 h after administration (AUC) was calculated by the trapezoidal rule from the observed values. 3. Results and Discussion In this study, the matrix tablets were prepred using various types of polymers and different composition. of polymers (Table 1) of matrix forming polymers (HPMC, sodium CMC and MCC) with the help of granulating agent, PVP was used as Binder. In vitro studies conducted for all the formulations. Extended release of drug was in the order of CW1 Figure 1). Rate of drug release was significant (p Figure 1, CW5). It seems the mechanism is by diffusion method. Physical characteristics of matrix tablets were shown in Table 2. There was no any significant burst effect in the optimized HPMC matrix tablets that showed a low possibility of dose dumping and avoids toxicity (in vivo). The Release kinetics of matrix tablets was determined by fitting the drug release data in different established models they are zero order, first order, Higuchi model, Korsemeyer-Peppas equation.Table 3shows values of regression coefficient, release constant and exponent n. First order release data was not satisfactory. The data suggested that kinetics of drug release of DVF5 was best explained by Korsemeyer-Peppas equation (R2= 0.991, n = 0.60). This indicated combined effect of diffusion and erosion mechanism on the release of drug. The stability results of storing at 25ËÅ ¡C/60% RH and 40ËÅ ¡C/75% RH for 6 months as per ICH guidelines evidenced any change in physical parameters and appearance and very slight change in dissolution pattern. Based on the available stability data 2 years shelf life can be provided. Figure 1. In vitro release profile of Cilostazol SR tablets. Table 2. Drug release kinetic of Cilostazol SR tablet formulations. Next, the stable formula were designated for its in vivo test in rabbit. Plasma concentration and pharmacokinetic parameters after oral administration of formulated ER matrix tablet CW5 and Cilostazol IR tablets 50mg were summarized inFigure 2andTable 3. No sustained blood level was observed after oral administration of the IR formulation. The formulated matrix Tablet (CW5) showed significant lowerCmaxthan the IR formulation (P max(tmaxis 6 hr) as compared with immediate release formulation (tmaxis 0.55 hr). The AUC increased from 11190.30 hr*ng/ml to 295396.49 hr*ng/ml for ER tablets. Values of Cmaxand tmaxclearly indicated that the drug release was sustained to about 24 hours after oral administration in rabbits (n = 4). CW5 Tablets maintained prolonged plasma concentration up to about 24 hours. The sustained plasma concentration of new formulation (CW5) indicates its extended drug release in vivo absorption. The Results demonstrated that the hydrophilic polymers were successfully utilized for formulating Cilostazol extended release matrix tablets. By wet granulated with povidone . Moreover the extended release matrix tablets have a unique advantage of lessening chance of dose dumping and to avoid side effects. The investigated extended release matrix tablets were adequate to maintaining constant plasma level of Cilostazol up to 24 hours in rabbits. Figure 2. Profile shows mean plasma concentration of Cilostazol against time, following oral administration of IR tablets and SR Tablets (CW5) to rabbits. Data are represented as mean  ± SD (n = 4). Table 3. Mean ( ±SD) pharmacokinetic parameters of Cilostazol in Rabbits (n = 4) orally administered with IR tablets and ER tablets CW5 (50 mg). 4. Conclusion A new sustained release formulation of Cilostazol has been developed for its in-vitro drug release and in-vivo absorption. Extended release matrix tablet were found to be an effective to maintain the drug level in plasma. Bioavailability studies can be carried out to assess the usefulness of this formulationand in comparison with existing IR products in the market formulations on healthy human volunteers.

Night World : Spellbinder Chapter 2

The crowd erupted in panic. Everything was happening at once; Thea couldn't sort out the different impressions. Half the people in front of her were running. The other half were yelling. â€Å"Call nine-one-one-â€Å" â€Å"It got Eric-â€Å" â€Å"I told you to kill it!† The red-headed boy was darting forward with his stick. Other kids were rushing around, looking for rocks. The group had become a mob. The snake was rattling wildly, a terrifying sizzling sound. It was in a frenzy, ready to strike again at any moment-and there was nothing Thea could do. â€Å"Hey!† The voice startled her. It came from Eric, the boy who'd been bitten. â€Å"Calm down, you guys. Josh, give me that.† He was talking to the redhead with the forked branch. â€Å"It didn't bite me. It just struck.† Thea stared at him. Was this guy crazy? But people were listening to him. A girl in baggy shorts and a midriff top stopped hefting her rock. â€Å"Just let me get hold of it†¦ then I can take it out into the brush where it won't hurt anybody.† Definitely crazy. He was talking in such a matter-of-fact, reasonable way-and he was going to try to pin the snake down with that stick. Somebody had to act fast. A flash of ruby-color caught Thea's eye. Blaise was in the crowd, watching with pursed lips. Thea made her decision. She dove for the snake. It was watching the stick. Thea grabbed for its mind before grabbing its body-which kept it immobilized for the instant she needed to seize it just below the head. She hung on while its jaws gaped and its body lashed. â€Å"Grab the tail and we'll get it out of here,† she said breathlessly to Eric the crazy guy. Eric was staring at her grip on the snake, dumbfounded. â€Å"For God's sake, don't let go. It can twist in a second†¦.† â€Å"I know. Grab it!† He grabbed it. Most of the crowd scattered as Thea wheeled around with the snake's head held tightly at arm's length. Blaise didn't run, she just looked at the snake as if it smelled bad. â€Å"I need this,† Thea whispered hastily as she passed her cousin. She snatched at Blaise's necklace with her free hand. The fragile gold chain broke and Thea's fingers closed around a stone. Then she was heading out into the scrub brush, the weight of the snake dragging on her arm. She walked fast, because Eric didn't have much time. The grounds behind the school sloped up and then downward, getting wilder and more gray-brown. When the buildings were out of sight, Thea stopped. â€Å"This is a good place,† Eric said. His voice was strained. Thea glanced back and saw that he looked pale. Brave and very, very crazy, she thought. â€Å"Okay, we let go on three.† She jerked her head. â€Å"Throw it that way and back up fast.† He nodded and counted with her. â€Å"One†¦ two†¦ three.† Giving it a slight swing, they both let go. The snake flew in a graceful arc and landed near a clump of purple sage. It wriggled immediately into the brush without showing the slightest hint of gratitude. Thea felt its cool, scaly mind recede as it thought, That smell†¦ that shade†¦ safety. She let out the breath she hadn't realized she'd been holding. Behind her, she heard Eric sit down abruptly. â€Å"Well, that's that.† His own breathing was fast and irregular. â€Å"Now could I ask you a favor?† He was sitting with his long legs straight out, his skin even paler than before. Perspiration beaded on his upper lip. â€Å"You know, I'm not really sure it didn't bite me,† he said. Thea knew-and knew Eric knew-that it had. Rattlers did sometimes strike without biting, and did sometimes bite without injecting venom. But not this time. What she couldn't believe was that any human would care enough about a snake to let a bite go untreated. â€Å"Let me see your leg,† she said. â€Å"Actually, I think maybe you'd better just call the paramedics.† â€Å"Please let me see.† She kept her voice gentle, kneeling in front of him, reaching slowly. The way she'd approach a scared animal. He held still, letting her roll up his jeans leg. There it was, the little double wound in the tanned skin. Not much blood. But surrounded by swelling already. Even if she ran back to the school, even if the paramedics broke every speed law, it wouldn't be fast enough. Sure, they'd save his life, but his leg would swell up like a sausage and turn purple and he'd have days of unbelievable pain. Except that Thea had in her hand an Isis bloodstone. A deep red carnelian engraved with a scarab, symbol of the Egyptian Queen goddess, Isis. The ancient Egyptians had put the stones at the feet of mummies; Blaise used it to heighten passion. But it was also the most powerful purifier of the blood in existence. Eric groaned suddenly. His arm was over his eyes, and Thea knew what he must be feeling. Weakness, nausea, disorientation. She felt sorry for him, but his confusion would actually work to her advantage. She pressed her hand to the wounds, the carnelian hidden between her tightly closed fingers. Then she started to hum under her breath, visualizing what she wanted to happen. The thing about gems was that they didn't work on their own. They were just a means of raising psychic power, focusing it, and directing it to a certain purpose. Find the poison, surround it, dispel it. Purify and eliminate. Then encourage the body's natural defenses. Finally, soothe away the swelling and redness, sending the blood back where it belonged. As she knelt there, feeling the sun on the back of her head, she suddenly realized that she'd never done this before. She'd healed animals-puppies with toad poisoning and cats with spider bites-but never a person. Funny how she'd known instinctively that she could do it. She'd almost felt that she had to do it. She sat back on her heels, pocketing the bloodstone. â€Å"How are you feeling?† â€Å"Huh?† He took his arm away from his eyes. â€Å"Sorry-I think I sort of blanked out there for a minute.† Good, Thea thought. â€Å"But how do you feel now?† He looked at her as if he were struggling under pressure to be gentle. He was going to explain to her that people who got bitten by rattlesnakes felt sick. But then his expression changed. â€Å"I feel†¦ it's weird†¦ I think maybe it's gone numb.† He peered doubtfully at his calf. â€Å"No, you were just lucky. You didn't get bitten.† â€Å"What?† He scrambled to roll his jeans leg up higher. Then he just stared. The flesh was smooth and unmarked, with just the slightest trace ot redness left. â€Å"I was sure†¦Ã¢â‚¬  He lifted his eyes to hers. It was the first time Thea had really gotten a chance to look at him. He was a nice-looking guy, lean and sandy-haired and sweet-faced. Long legs. And those eyes†¦ deep green with gray flecks. Just now they were both intense and bewildered, like those of a startled kid. â€Å"How'd you do that?† he said. Thea was shocked speechless. He wasn't supposed to respond like this. What was wrong with him? When she could talk again, she said, â€Å"I didn't do anything.† â€Å"Yes, you did,† he said, and now his eyes were clear and direct, full of an odd conviction. Suddenly his expression changed to something like wonder. â€Å"You†¦ there's something so different about you.† He leaned forward slowly, as if entranced. And then†¦ Thea experienced an odd duality. She was used to seeing herself through the eyes of animals: a big, hairless creature in false skins. But now she saw herself as Eric saw her. A kneeling girl with yellow hair falling loose over her shoulders and soft brown eyes. A face that was too gentle, with a very worried expression. â€Å"You're†¦ beautiful,† Eric said, still wondering. â€Å"I've never seen anybody†¦ but it's like there's a mist all around you. You're so mysterious†¦.† A huge quivering stillness seemed to hang over the desert. Thea's heart was beating so hard that it shook her body. What was happening? â€Å"It's like you're part of everything out here,† he said in that wise, childlike voice. â€Å"You belong to it. And there's so much peace†¦.† â€Å"No,† Thea said. There was no peace at all in her. She was terrified. She didn't know what was going on, but she knew she had to get away. â€Å"Don't go,† he said, when she shifted. He had the stricken expression of a heartbroken puppy. And then†¦ he reached for her. Not roughly. His fingers didn't close on her wrist. They just brushed the back of her hand, sliding away when she jerked. But it didn't matter. That light touch had raised all the hairs on Thea's forearm. And when she looked back into the gray-flecked green eyes, she knew he'd felt it, too. A sort of piercing sweetness, a dizzying exhilaration. And-a connection. As if something deeper than words was being communicated. I know you. I see what you see†¦. Almost without knowing what she was doing, Thea raised her hand. Fingertips slightly outspread, as if she were going to touch a mirror or a ghost. He brought his hand up, too. They were staring at each other. And then, just before then- fingers made contact, Thea felt a jolt of panic like ice water. What was she doing? Had she lost her mind? Suddenly everything was clear-too clear. Her future stretched out before her, every detail sharp. Death for breaking Night World law. Herself centered in the Inner Circle, trying to explain that she hadn't meant to betray their secrets, that she hadn't meant to†¦ to get close to a human. That it was all a mistake, just a moment of stupidity because she'd wanted to heal him. And them bringing the Cup of Death anyway. The vision was so clear it seemed like a prophecy. Thea jumped up as if the ground had lurched underneath her, and she did the only thing she could think of to do. She said scathingly, â€Å"Are you nuts? Or is your brain just overheated or something?† He got the stricken look again. He's a human. One of them, Thea reminded herself. She put even more scorn in her voice. â€Å"I'm part of everything; I did something to your leg†¦ yeah, sure. I bet you believe in Santa Claus, too.† Now he looked shocked-and uncertain. Thea went for the coup de gras. â€Å"Or were you just trying to put the moves on me?† â€Å"Huh? No,† he said. He blinked and looked around. The desert was the ordinary desert, gray-green and parched and flat. Then he looked at his leg. He blinked again, as if getting a fresh grip on reality. â€Å"I†¦ look, I'm sorry if I upset you. I don't know what's wrong with me.† Suddenly he gave a sheepish smile. â€Å"Maybe I'm kind of weird from being scared. I guess I'm not as brave as I thought.† Relief trickled through Thea. He was buying it. Thank Isis that humans were stupider than chickens. â€Å"And I wasn't trying to move in on you. I just-† He broke off. â€Å"You know, I don't even know your name.† â€Å"Thea Harman.† â€Å"I'm Eric Ross. You're new here, aren't you?† â€Å"Yes.† Stop talking and go, she ordered herself. â€Å"If I can show you around or anything†¦ I mean, I would like to see you again†¦.† â€Å"No,† Thea said flatly. She would have liked to have kept it to that monosyllable, but she wanted to crush this new idea of his completely. â€Å"I don't want to see you,† she said, too rattled to think of any more subtle way to put it. And then she turned and walked away. What else was there to do? She certainly couldn't talk to him anymore. Even if she would always wonder why he'd been crazy enough to care about the snake, she couldn't ask. From now on she had to stay as far away from him as possible. She hurried back to the school-and realized immediately that she was late. The parking lot was quiet. Nobody was walking outside the adobe buildings. On my first day, too, Thea thought. Her backpack was on the ground where she'd dropped it, a notebook lying beside it on the asphalt. She grabbed them both and all but ran to the office. It was only in physics class, after she'd handed her admission slip to the teacher and walked past rows of curious eyes to an empty seat in the back, that she realized the notebook wasn't hers. It fell open to a page that had Introduction to Flat-worms scribbled in sloping, spiky blue ink. Below were some pictures labeled Class Turbellaria and Class Trematoda. The worms were beautifully drawn, with their nervous systems and reproductive organs shaded in different colors of highlighter, but the artist had also given them big goofy smiling faces. Grotesque but lovable in a cross-eyed way. Thea turned the page and saw another drawing, the Life Cycle of the Pork Tapeworm. Yum. She leafed back to the beginning of the notebook. Eric Ross, Honors Zoology I. She shut the book. Now how was she going to get it back to him? Part of her mind worried about this through physics and her next class, computer applications. Part of it did what it always did at a new school, or any new gathering of humans: it watched and cataloged, keeping alert for danger, figuring out how to fit in. And part of it simply said, I didn't know they had a zoology class here. The one question she didn't want to ask herself was what had happened out there in the desert? Whenever the thought came up, she pushed it away brusquely. It must have had something to do with her senses being too open after merging with the snake. Anyway, it hadn't meant anything. It had been a weird one-time fluke. In the main hallway at break, Blaise came rushing up, quick as a lioness despite the high heels. â€Å"How's it going?† Thea said, as Blaise drew her into a temporarily deserted classroom. Blaise just held out her hand. Thea fished in her pocket for the carnelian. â€Å"You ruined the chain, you know,† Blaise said as she shook back midnight hair and examined the stone for damage. â€Å"And it was one I designed.† â€Å"Sorry. I was in a hurry.† â€Å"Yes, and why? What did you want with it?† Blaise didn't wait for a response. â€Å"You healed that boy, didn't you? I knew he got bitten. But he was human.† â€Å"Reverence for life, remember?† Thea said. † ‘An ye harm none, do as you will.† She didn't say it with much conviction. â€Å"That doesn't mean humans. And what did he think?† â€Å"Nothing. He didn't know I was healing him; he didn't even realize he got bitten.† It wasn't exactly a lie. Blaise looked at her with smoky, suspicious gray eyes. Then she glanced heavenward and shook her head. â€Å"Now if you'd been using it to heat his blood, I'd understand. But maybe you were doing a little of that, too†¦.† â€Å"No, I was not,† Thea said. And despite the warmth that rose in her cheeks her voice was cold and sharp. The horror of that death vision was still with her. â€Å"In fact, I don't ever want to see him again,† she went on jaggedly, â€Å"and I told him so, but I've got his stupid notebook, and I don't know what to do with it.† She waved the notebook in Blaise's face. â€Å"Oh.† Blaise considered, head on one side. â€Å"Well†¦ I'll take it to him for you. I'll track him down somehow.† â€Å"Would you?† Thea was startled. â€Å"That's really nice.† â€Å"Yes, it is,† Blaise said. She took the notebook, handling it carefully, as if her nails were wet. â€Å"Okay, well, I'd better get to my next class. Algebra.† She made a face. † ‘Bye now.† Suspicion struck as Thea watched her go. Blaise wasn't usually so accommodating. And that † ‘bye now†Ã¢â‚¬ ¦ too sweet. She was up to something. Thea followed the ruby of Blaise's shirt as Blaise went back into the main hallway, then turned without hesitation into a locker-lined corridor. There, searching through one of the lockers, was a lean figure with long legs and sandy hair. Fastest tracking I've ever seen, Thea thought sourly. She peered around the Mediterranean-blue door of a broken locker. Blaise walked up behind Eric very slowly, hips swaying. She put a hand on his back. Eric jumped slightly, then turned around. Blaise just stood there. It was all she needed to do. Blaise reeled guys in just by being. It was the glorious dark hair, the smoldering gray eyes†¦ plus a figure that could stop traffic on the freeway. Curves galore, and clothes that emphasized every one. On another girl it might have been too much, but on Blaise it was just breathtaking. Guys who thought they liked the waif look dropped everything to follow her just as fast as guys who thought they liked blonds. Eric blinked at her, looking hazy already. He didn't seem to know what to say. That wasn't unusual. Guys always got tongue-tied around Blaise. â€Å"I'm Blaise Harman.† The voice was low and liquid. â€Å"And you're†¦ Eric?† Eric nodded, still blinking. Yes, he's dazed all right, Thea thought. The jerk. She was surprised at her own vehemence. â€Å"Good, because I wouldn't want to give this to the wrong person.† Blaise produced the notebook from behind her back like a magician. â€Å"Oh-where'd you get that?† Eric looked relieved and grateful. â€Å"I've been looking everywhere.† â€Å"My cousin gave it to me,† Blaise said carelessly. She held onto the notebook as he tried to take it, and their fingers touched. â€Å"Wait. You owe me something for bringing it back, don't you?† Her voice was a purr. And now Thea knew, without a doubt, what was going to happen. Eric was doomed.

Love Medicine Study Guide Questions

Note: You should also write at least four of your own questions about the book as you read. These can be either things that confused you or aspects of the text that you would like to see us explore in class. HINT: HERE IS YOUR CHANCE TO AFFECT THE FINAL EXAM. You can list more on the reverse if they occur to you while reading. Love Medicine YOUR QUESTIONS: 1. 2. 3. 4.Use this space to connect any relevant cultural information you find to aspects of the text:________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________ ______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________ Discussion Questions 1. The novel deals extensively with the love-hate relationships between family members. What are some of the different kinds of familial bonds, positive and negative? What themes are explored through these relationships? What does this novel suggest about the nature of families? 2.One theme of the novel is the unavoidable impact of the non-Indian world (for instance, Catholicism, alcohol, intermarriages, the Vietnam War, capitalism, the legal system) on the Chippewa. How does the interaction with outsiders affect specific characters? What does the novel suggest about the difficulties and consequences of dealing with a mixed world? 3. Why do you thin k Erdrich chose to write her novel in the way she did, using time leaps and a series of different narrators to recount their own tales? What do you think is gained by this form of narrative? How might the form's emphasis on individual storytelling relate to the novel's larger themes? 4. Why do you think the section â€Å"Love Medicine† was chosen as the title story of the novel?Would you have chosen another section on the basis of a strength or unifying theme? (Above questions from http://www. harpercollins. com/authors/2905/Louise_Erdrich/index. aspx) 5. Analyze the family relationships in Louise Erdrich’s novel. What does this novel suggest about relationships between parents and children, grandparents and grandchildren, siblings, extended relatives, etc.? Pay attention to both blood relations and those that are â€Å"taken† or adoptive, such as Nanapush and Lulu or Marie and Lipsha. 6. Analyze the depictions of gender in Love Medicine, giving at least some at tention to differences in gender concepts and gender relations in traditional Native and mainstream colonizing culture. 7.Analyze the romantic relationships in the novel, both within the institution of Catholic marriage, within traditional culture, and those outside of both. What do these relationships suggest about the concept of romantic love? 8. Compare and contrast the depictions of traditional Ojibwe spirituality and Catholicism within the novel. 9. Examine how the novel depicts the effects of colonization on the Ojibwe people and their world. 10. Analyze relatedness and relationships between Native and non-Native people in this novel, both community and familial. In other words, in responding to this question, you might include the relationship between King

Essay Smoking Should NOT Be Banned in Public Places

Smoking Should Not Be Banned in Restaurants In the perfect situation, smoking policy would be set by bar or restaurant owners, and customers would patronize the establishments with the policy they prefer. Customers would decide-without the governments help-if they want to avoid smoke-filled rooms or enter them. They might even choose to sit in an area sectioned off for smokers or non-smokers, but the ultimate issue is choice (Ruwart 1). When the government starts telling restaurant owners what their customers can and cannot do, the government is overstepping its boundaries. Our government aims to protect us-to save us from societys evils. However, in an attempt to protect the public from the effects of passive smoking†¦show more content†¦The plight of restaurant and bar owners is often ignored, but it is a serious issue for them and for their employees. While the argument rages over the effects of smoking on public health, the question that remains is this: How much is society entitled to penalize smokers for their decisions because-in societys view-those decisions are unhealthy? (Samuelson). Smoking tobacco is not an illegal act, yet the 25 percent of Americans who do smoke are often treated as if they were criminals. They are incessantly nagged, blamed for numerous illnesses and unpleasantries, and made to feel guilty by self-righteous nonsmokers (Bork 28). The Environmental Protection Agency estimates that living with a smoker increases your chance of lung cancer by 19 percent. What they fail to tell you is that, in contrast, (firsthand) smoking increases your chance 1,000 percent (Buckley). Why is the act of smoking tobacco, which merely injures oneself, so scrutinized and shunned by society, while drinking alcohol, which is by far more deadly to innocent bystanders, is accepted by society and virtually unregulated? (Krauthammer ). One may not wish to be seated near an extremely obese person in a restaurant, but it would certainly be unconstitutional to deny service to these patrons. In modern society, the government knows better than to discriminate against minorities, senior citizens, or the physically handicapped; it does not hesitate, however, toShow MoreRelatedThe Effects of Environmental Tobacco Smoke Among Children with Asthma1644 Words   |  7 Pagesthe effects that has among children living in contaminated environment by Second Hand Smoke. One of the health effects can be Asthma, which is provoked by their parents who smoke in their vicinity. Furthermore, there will be a discussion where as a public health practitioner trying to improve the health of these children and to educate their parents to lessen their cigarette consumption near children. First of all, I would like to define Environmental Tobacco Smoke (ETS). According to the UnitedRead Moreunethical advertising14492 Words   |  58 PagesGenerally speaking, advertising is the promotion of goods, services and ideas, usually by an identified sponsor. Marketers see advertising as part of an overall promotional strategy. Other components of the promotional mix include publicity, public relations, personal selling and sales promotion. Advertisement Advertising is a form of communication whose purpose is to inform potential customers about products and services and how to obtain and use them. Many advertisements are also designed toRead MoreCaso Warner Lambert6498 Words   |  26 Pagesthat promised to help the thou-sands of smokers who attempted to quit smoking each year. More commonly known simply as the patch, Niconil was a transdermal skin patch that gradually released nicotine into the bloodstream to alleviate the physical symptoms of nicotine withdrawal. Now in October of 1989, Dixon and his staff had to decide several key aspects of the product launch. There were different opinions about how Niconil should be priced and in what quantities it would sell. Pricing deci-sionsRead MoreHotels Analysis3906 Words   |  16 PagesWe are passionate about delivering exceptional guest experiences. I Integrity – We do the right thing, all the time. L Leadership – We are leaders in our industry and in our communities. T Teamwork – We are team players in everything we do. O Ownership – We are the owners of our actions and decisions. N Now – We operate with a sense of urgency and discipline. (Hilton Worldwide, 2010) The vision and mission have a large effect on staff in Hilton Singapore Hotel and supply a strong power forRead MoreStrategic Marketing Management337596 Words   |  1351 Pagesand Patents Act 1988 or under the terms of a licence issued by the Copyright Licensing Agency Ltd, 90 Tottenham Court Road, London, England W1T 4LP. Applications for the copyright holder’s written permission to reproduce any part of this publication should be addressed to the publisher Permissions may be sought directly from Elsevier’s Science Technology Rights Department in Oxford, UK: phone: ( 44) 1865 843830, fax: ( 44) 1865 853333, e-mail: permissions@elsevier.co.uk. You may also complete yourRead MorePorn and Censorship15240 Words   |  61 PagesPornography and Censorship Should the government be allowed to legitimately prohibit citizens from publishing or viewing pornography, or would this be an unjustified violation of basic freedoms? Traditionally, liberals defended the freedom of consenting adults to publish and consume pornography in private from moral and religious conservatives who wanted pornography banned for its obscenity, its corrupting impact on consumers and its corrosive effect on traditional family and religious values. ButRead MoreHousing Coordinator3909 Words   |  16 PagesHOUSING REGULATIONS The following policies are very important to the college and we want to place special emphasis on them. Read over the policies carefully so that you will be fully aware of our policies and your responsibilities. Connors State College reserves the right to change these policies or any portion thereof at any time without prior notice. 1. Air Vent Blockage The air vents located above and/or in the room door in the air conditioned buildings are designed for airflow fromRead MoreIgbo Dictionary129408 Words   |  518 PagesonaryDictionary of Ònà ¬Ã¯â‚¬ ¬chà   Igbo 2nd edition of the Igbo dictionary, Kay Williamson, Ethiope Press, 1972. Kay Williamson († ) This version prepared and edited by Roger Blench Roger Blench Mallam Dendo 8, Guest Road Cambridge CB1 2AL United Kingdom Voice/ Fax. 0044-(0)1223-560687 Mobile worldwide (00-44)-(0)7967-696804 E-mail R.Blench@odi.org.uk http://www.rogerblench.info/RBOP.htm To whom all correspondence should be addressed. This printout: November 16, 2006 TABLE OF CONTENTS Abbreviations:Read MoreAnnotated Bibliography: Plagiarism39529 Words   |  158 PagesJ. A., Wright, T., Mogoanta, L. and Alman, B. (2012), Plagiarism: An assault on the integrity of scientific research. J. Orthop. Res., 30:  1867 1868. Granitz, N. and Loewy, D. (2007). Applying Ethical Theories: Interpreting and Responding to Student Plagiarism. Journal of Business Ethics, 72(3), 293-306. Luke, B. and Kearins, K. (2012), Attribution of words versus attribution of responsibilities: Academic plagiarism and university practice. Vaccine, 30(50): 7131-7133. Rushby, N. (2013), PlagiarismRead MoreThe Effects of Advertising on Children33281 Words   |  134 PagesAustralia 2007 This work is copyright. Apart from any use as permitted under the Copyright Act 1968, no part may be reproduced by any process without prior written permission from the Commonwealth. Requests and inquiries concerning reproduction and rights should be addressed to the Manager, Communications/Media, Australian Communications and Media Authority, PO Box 13112 Law Courts, Melbourne Vic 8010. Published by the Australian Communications and Media Authority Canberra Central Office Purple Building