text:
Share your thoughts!
Let us know what you think...
What others are saying
There are no contributions yet.
The cocking handle spring is an item that is prone to wear and tear and should be replaced every so often or when installing a new cocking handle or when the spring is removed during scheduled servicing of the firearm. This spring is a great part to have on hand and in your spare HK parts bin.
Fits all™ cocking handles standard and extended for the following firearms:
Please note: This spring does not work on the HK 21E & HK 23E models.
In stock
There are no contributions yet.


text:
Love traveling but hate tedious long transits? SKYSCANNER has good news for you – 7 amazing new destinations from Mauritius to London can now be reached direct from Singapore Changi Airport.
Though we live on a island, bustling Singapore is not exactly one's idea of tropical paradise perfection. But if Hawaii is too far away and Bali too bourgeoisie, you might want to consider a trip to Mauritius, the little island gem hidden in the Indian Ocean. With Air Mauritius now offering direct flights to Sir Seewoosagur Ramgoolam International Airport, Mauritius is but 7 hours away from Changi Airport. Make the short hop over to enjoy the bountiful attractions of this little spit of land, from beautiful sand and pebble beaches, idyllic little villages and tranquil lagoons of emerald to dramatic, jagged sea cliffs.
2. San Francisco, USA
United Airlines has suffered a bout of bad press recently, but they did do one thing right – beginning a new non-stop service from Singapore Changi Airport to the United States' City on the Bay. Gorgeous San Francisco, with its rolling hills, Victorian architecture and world-famous Fisherman's Wharf used to only be accessible via a transit through Hong Kong or Tokyo. But now, the Golden Gate Bridge and San Francisco Cable Car is that much closer to you.
3. Amritsar, India
Most famed as the birthplace of Sikhism, India's Amritsar is revered by millions as the world's most sacred city and is home to the spectacular Golden Temple, which sits amidst a reflective pool of clear water. Today Amritsar is but a mere 5 hours away, thanks to Scoot beginning a thrice-weekly direct flight to the city known as the Holy Pool of Nectar. Don't miss a visit to this pilgrimage destination even if you're not religious – a trip to Amritsar to admire stunning architecture like the Golden Temple and Jallianwala Bagh is well-worth the 5 hours of flight it takes to get there.
4. Düsseldorf, Germany
Feel like a little taste of Europe? How about some tender pork knuckles and a frosty pint of Altbier in the place where this delicious beer was born, Düsseldorf? Located in western Germany, Düsseldorf is not just one of the country's most economically successful business hubs but also a fashion and arts hub. Sitting astride the Rhine River, Düsseldorf is also home to the 'longest bar in the world' – Altstadt Düsseldorf.
5. Nadi, Fiji
If there was heaven on Earth, it would most likely take the form of the Fiji islands. An archipelago of more than 300 islets in the South Pacific Ocean, the Fiji islands are well-renowned for their unbelievable, ethereal beauty, from the clearest of blue seawaters to the most golden of sandy beaches, accented with lush greenery, palm trees and numerous luxury resorts. You can now access all this perfection is just 10 hours, with Fiji Airways' new direct flight from Singapore Changi Airport to the town of Nadi on Viti Levu island.
6. Canberra, Australia
Canberra may not get the tourist hype of sister cities Sydney, Melbourne and Brisbane, but Australia's capital city has much to offer travellers as well. It is rare for a whole city to be entirely planned, much less by winners of a design competition – but Canberra is one such place. As a result, the city is incredibly neat and organized, with buildings arranged in clean hexagons, circles and triangles.
7. London, United Kingdom
Yes, you can now take a budget flight to London. Norwegian Airlines is beginning a new non-stop service from Singapore Changi Airport to London Gatwick Airport that will hold the record for the longest long-haul budget flight ever operated, with about 13 hours of flight time at a fare of only about S$630 (return). Your dream of strolling along Westminster Abbey, shopping at the West End and sailing down the River Thames at dusk may be much closer than you imagined.

subset: commoncrawl


text:
Custom Frames Mockups set allows you quickly and easily add a frame to your artworks like prints, posters, photos, art and more. All 7 scenes have 12 frames - it's many variations! :)
Frames provides amazing mockups including:
Smart objects
7 beautiful scenes
12 frames
Video tutorial: https://youtu.be/6xqsI3mWYR4
You'll need an account to access this in our app. Please create a password to continue.
Download from the App Store or text yourself a link to the app
Good news! Since you already have a Gumroad account, it's also been added to your library.Tweet Share
Looking to create an account?
Did you mean to login?


text:
ABUJA - Nigerian authorities should investigate attacks by security forces on journalists at a recent protest in Abuja and hold those responsible to account, the Committee to Protect Journalists (CPJ) said on Saturday.
On November 12, security forces fired live rounds to disperse a group of demonstrators at the department of state services (DSS) headquarters in Abuja, the capital, and shot at journalists and beat at least one reporter, according to journalists who spoke to CPJ, news reports, and a video of the protest uploaded to YouTube by the International Centre for Investigative Reporting, the CPJ said in a statement.
Demonstrators gathered at the DSS building to call for the release of Omoyele Sowore, a political activist and founder of the Sarah Reporters news website, according to those reports. No one was shot in the incident, according to the journalists who spoke to the CPJ.
"There is absolutely no justification for security officers to shoot at or attack journalists working to cover a protest," said Angela Quintal, CPJ Africa program coordinator, in Washington DC.
"Nigerian authorities must investigate allegations that department of state services agents targeted journalists doing their job and hold those responsible to account," she said.


text:
Home » Posts tagged 'teva' (Page 2)
Tag Archives: teva
Teva: FDA Approves of Generic Tobi in US
JERUSALEM–(BUSINESS WIRE)–Oct. 14, 2013– Teva Pharmaceutical Industries Ltd. announces today that the U.S. Food and Drug Administration has granted approval of the generic equivalent to Tobi® (Tobramycin Inhalation Solution USP) in the United States. Pursuant to an agreement with Novartis on this product, Teva expects to launch this product in late November. Marketed by Novartis, Tobi had annual sales of approximately $350 million in the United States, according to IMS data as of June 30, 2013. READ ALL AT………..
Tobramycin is an aminoglycoside antibiotic derived from Streptomyces tenebrarius and used to treat various types of bacteria infections, particularly Gram-negative infections. It is especially effective against species of Pseudomonas.[1]
Tobramycin works by binding to a site on the bacterial 30S and 50S ribosome, preventing formation of the 70S complex. As a result, mRNA cannot be translated into protein and cell death ensues. Tobramycin is preferred over gentamicin for Pseudomonas aeruginosapneumonia due to better lung penetration.
Like all aminoglycosides, tobramycin does not pass the gastro-intestinal tract, so forsystemic use it can only be given intravenously or intramuscularly. Ophthalmic (tobramycin only, Tobrex, or combined with dexamethasone, sold as TobraDex) and nebulised formulations both have low systemic absorption. The formulation for injection is branded Nebcin. The nebulised formulation (brand name Tobi) is indicated in the treatment of exacerbations of chronic infection with Pseudomonas aeruginosa in patients diagnosed with cystic fibrosis. A proprietary formulation of micronized, nebulized tobramycin has been tested as a treatment for bacterial sinusitis.[2] Tobrex is a 0.3% tobramycin sterile ophthalmic solution is produced by Bausch & Lomb Pharmaceuticals. Benzalkonium chloride 0.01% is added as a preservative. It is available by prescription only in the United States and Canada. In certain countries, such as Italy, it is available over the counter. Tobrex and TobraDex are indicated in the treatment of superficial infections of the eye, such as bacterial conjunctivitis. Tobramycin (injection) is also indicated for various severe or life-threatening gram-negative infections : meningitis in neonates, brucellosis, pelvic inflammatory disease, Yersinia pestis infection (plague).
Like other aminoglycosides, tobramycin is ototoxic: it can cause hearing loss, or a loss ofequilibrioception, or both in genetically susceptible individuals. These individuals carry a normally harmless genetic mutation that allows aminoglycosides such as tobramycin to affect cochlear cells. Aminoglycoside-induced ototoxicity is generally irreversible.
As with all aminoglycosides, tobramycin is also nephrotoxic, meaning it is toxic to thekidneys. This effect can be particularly worrisome when multiple doses accumulate over the course of a treatment or when the kidney concentrates urine by increasing tubular reabsorption during sleep. Adequate hydration may help prevent excess nephrotoxicity and subsequent loss of renal function. For these reasons parenteral tobramycin needs to be carefully dosed by body weight, and its serum concentration monitored. Tobramycin is thus said to be a drug with a narrow therapeutic index.
Mass-spectrum of tobramycin
- "Tobramycin" (pdf). Toku-E. 2010-01-12. Retrieved 2012-06-11.
- "Nebulized Tobramycin in treating bacterial Sinusitis" (Press release). July 22, 2008. Retrieved 2009-12-06.
A widely accepted therapy for treating respiratory infections caused by Gram- negative bacteria involves intravenous administration of a single antibiotic or combinations of antibiotics. Gibson et al., 2003 Am. J. Respir. Crit. Care. Med.
168(8):918-951 ; Ramsey, 1996 N. Engl. J. Med. 335(3): 179-188. However, this method of treatment has several significant limitations including: (1 ) narrow spectrum of activity of existing antibiotics, (2) insufficient concentrations of antibiotic reaching the respiratory tract to ensure rapid onset and high rates of bacterial killing, and (3) development of adverse side effects due to high systemic concentrations of drug.
Aerosol administration of antibiotics (Conway, 2005 Chronic Repir. Dis. 2:35- 41 ; O'Riordan, 2000 Respir. Care 45(7):836-845) addresses several of the limitations of parenteral administration (Flume and Klepser, 2002 Pharmacotherapy 22(3 Pt 2):71 S-79S; Kuhn, 2001 Chest. 120:94S-98S). It enables topical delivery of high concentrations of drug to the endobronchial spaces and reduces side effects by lowering systemic exposure to antibiotic. However, patients having chronic respiratory conditions, such as chronic obstructive pulmonary disease, cystic fibrosis and bronchiestasis, may receive prolonged and repeated antibiotic therapies over the entire duration of their adult lives. Gibson et al., 2003 Am. J. Respir. Crit. Care. Med. 168(8):918-951 ; Ramsey, 1996 N. Engi. J. Med. 335(3): 179-188. Therefore, cumulative antibiotic toxicity and development of resistance remains a significant problem. Chronic obstructive pulmonary disease (COPD), a smoking-related condition characterized by progressive and poorly reversible airflow obstruction and airway inflammation, is the fourth most common cause of death in developed countries. COPD is projected to be the third leading cause of global deaths in 2020 and is the only one of the four most common causes of death with an increasing mortality rate. In 2008 in the United States, there were an estimated 10 million patients diagnosed with chronic obstructive pulmonary disease (COPD). SDI COPD Claims Analysis, May 2009. Murray et at., 1997 Lancer 349: 1269-76. Approximately 7 million U.S. patients receive treatment for COPD. Mannino et al; The Epidemiology and
Economics of COPD, Proc Am Tho e Soc 2007. In the US, direct COPD costs in 2002 were approximately $18.0 billion. Statistics from National Center for Health Statistics, National Health Interview Survey: Research for the 1995-2004 redesign, Hyattsville, Maryland: U.S. Department of Health and Human Services, CDC, NCHS. Vital and Health Stat 2( 26), 1999.
The clinical course of COPD is characterized by chronic disability, with intermittent, acute exacerbations which may be triggered by a variety of stimuli including exposure to pathogens, inhaled irritants (e.g., cigarette smoke), allergens, or pollutants. "Acute exacerbation" refers to worsening of a patient's COPD symptoms from his or her usual state that is beyond normal day-to-day variations, and is acute in onset. See, Rabe et al., 2007 Am J Res Crit Care Med, 176: 532- 555. Acute exacerbations of COPD greatly affect the health and quality of life of patients with COPD. Bathoorn, E, Int J Chron Obstruct Pulmon Dis. 2008 3(2):217- 229. Acute exacerbation of COPD is a key driver of the associated substantial socioeconomic costs of the disease. Approximately 73% ($13 billion) of direct COPD costs in 2002 were due to hospitalizations related to acute exacerbations of COPD. Investigators from the Burden of Obstructive Lung Disease (BOLD) Initiative have estimated the cumulative discounted cost of COPD care in the US to be $880 billion by 2020 – an average of more than $44 billion per year over two decades. Lee et al., 2006 ATS Proceedings, 3:A598. Multiple studies have also shown that prior exacerbation is an independent risk factor for future hospitalization for COPD.
Garcia-Aymerich et al., 2003, Thorax, 58:100-105. Hospitalization consumes roughly 70% of COPD healthcare expenditure in the US. McGhan et al., 2007, Chest, 132(6): 1748-1755. Accordingly, for a new drug therapy to significantly reduce the health and economic costs of COPD, it must address acute exacerbations of COPD.
It is clear that there is a continued need for an improved method of treatment for acute and chronic respiratory infections caused by Gram-negative and Gram- positive bacteria, particularly multidrug resistant bacteria, such as P. aeruginosa. This is particularly evident in patients having chronic respiratory conditions where current therapies are limited by problems with development of resistance and toxicity. Such method of treatment would preferably comprise inhalation of an aerosolized antibiotic composition that delivers a therapeutically effective amount of the active pharmaceutical ingredients directly to the endobronchial space of the airways or to the nasal passages. Such treatment would ideally be efficacious, reduce the frequency of drug resistance, and improve safety.
PCT Publication No. WO2005/1 0022 to Gilead Sciences, Inc. (formerly Corus Pharma) discloses a fosfomycin plus tobramycin combination formulation for delivery by aerosolization. The concentrated fosfomycin/tobramycin combination formulation containing an efficacious amount of fosfomycin and tobramycin is able to inhibit susceptible bacteria. Fosfomycin and tobramycin are formulated in solution such that when reconstituted, the pH is between 4.5 and 8.0 or as a dry powder. Also disclosed is a method for treatment of respiratory tract infections by a formulation delivered as an aerosol having mass medium aerodynamic diameter predominantly from 1 to 5 microns, produced by a jet or ultrasonic nebulizer (or equivalent) or dry powder inhaler.
tobramycin solution for inhalation of various formulations are described in the prior art. 例如,美国专利第5,508,269号公开了一种制剂,该制剂包括在Iml的盐水中40_100mg (毫克)的氨基糖苷被稀释成四分之一生理盐水强度,该制剂的PH值在5. 5到6. 5之间,其中该溶液以5ml浓缩形式气雾给药。 For example, U.S. Patent No. 5,508,269 discloses a preparation which is included in the brine Iml 40_100mg (mg) was diluted into a quarter normal saline aminoglycoside strength, the PH value of the preparation of 5 . 5 to 6.5 between, wherein the solution in concentrated form 5ml aerosol administration. [0011] 美国专利6987094公开了一种气雾制剂,其包括75mg/ml妥布霉素的水性溶液,该溶液包括O. 45%w/v (质量/体积百分比)的氯化钠,该制剂的pH值在4. O到5. 5之间,而渗透压在250到450m0sm/l (毫渗透克分子/毫升)。[0011] U.S. Patent 6,987,094 discloses an aerosol formulation which comprises an aqueous solution of 75mg/ml tobramycin, the solution comprises O. 45% w / v (mass / volume) of sodium chloride, the preparation the pH value of 4. O to 5.5, between the osmotic pressure of 250 to 450m0sm / l (mg penetration mol / ml). [0012] 美国专利申请2007/0116649公开了一种气雾制剂,其包括约100mg/ml到200mg/ ml的抗革兰阴性抗生素。 [0012] U.S. Patent Application 2007/0116649 discloses an aerosol formulation comprising about 100mg/ml to 200mg / ml of antibiotics against gram-negative. 提到了妥布霉素制剂,但是没有公开有妥布霉素的实验。Tobramycin formulations mentioned, but there is no disclosure tobramycin experiment. [0013] 美国专利申请2007/0071686公开了一种妥布霉素组合物,其包括约80mg/ml到120mg/ml的妥布霉素、一酸性辅助剂和低浓度的氯化钠。[0013] U.S. Patent Application 2007/0071686 discloses a tobramycin composition comprises about 80mg/ml to 120mg/ml of tobramycin, an acidic auxiliary agents and a low concentration of sodium chloride. 所述酸性辅助剂可以是硫酸钠或磷酸钠。 The acidic auxiliary agent may be sodium or sodium phosphate. 根据US2007/0071686,活性剂的浓度不超过120mg/ml,这是因为据说妥布霉素的浓度因粘度原因对雾化有负面影响。According to US2007/0071686, the concentration of the active agent is not more than 120mg/ml, this is because the concentration of tobramycin said reasons due to the viscosity of a negative impact on atomization. 而且,根据US2007/0071686的妥布霉素组合物利用喷雾器给药给患者,即活性成分通过潮式呼吸吸入。Moreover, the composition according to US2007/0071686 of tobramycin administered to patients using the spray, that the active ingredient through the tidal breathing inhalation. [0014] 欧洲专利2186508尤其公开了一种少于4ml溶液的组合物,其包括的60 – 200mg/ ml的、在生理上可接受的载体上的氨基糖苷抗生素。 [0014] In particular, in European Patent 2,186,508 discloses a composition of the solution is less than 4ml, comprising of 60 – 200mg / ml, and in a physiologically acceptable carrier aminoglycoside antibiotics. EP2186508中的实验显示,包括120mg/ ml妥布霉素的组合物使用PARI LC PLUS®牌喷雾器(德国Starnberg的Pari Boy N压缩器公司)给药需要约10分钟。EP2186508 The experiments showed that including 120mg / ml tobramycin compositions using PARI LC PLUS ® brand spray (Starnberg, Germany The Pari Boy N compressor company) to about 10 minutes of administration. 尽管这少于商业上可获得的TOBI®给药所需的时间,但从患者配合度和患者友好角度考虑,所需的时间还是太长。 Although this is less than the commercially available TOBI ® dosing time required, but with the degree of the patient, and patient-friendly point of view, the time is too long. EP2186508提到,使用呼吸致动吸入装置对于前面提到的商业上可获得的系统可以获得更快的给药时间。 EP2186508 mentioned breath actuated inhalation device used for the previously mentioned commercially available systems can be obtained faster delivery time. 但是,EP2186508 中使用呼吸致动吸入装置(AcroDose™)所获得的给药时间的实验仅限于低浓度的妥布霉素(60mg/ml)。However, EP2186508 using the breath actuated inhaler device (AcroDose ™) obtained experimental delivery time is limited to low concentrations of tobramycin (60mg/ml). 其还指出,使用AcroDose™系统的60mg/ml组合物给药,还必须给药第二可分量。 It also noted that the use AcroDose ™ system 60mg/ml composition administered may also be administered a second component. 从患者友好和配合角度来看,需要加入和给药第二可分量代表一种缺点。 Friendship and cooperation from the patient's point of view, and the administration need to add a second component represents a drawback can be. [0015] 妥布霉素溶液也以局部给药出名,例如治疗角膜炎,参见Davis等人在"Canad. J Ophtal. "(加拿大眼科杂志,1978年第13期273页)的文章,Davis等人在"Arch Opthalmol" (眼科杂志,1978年第96卷123-125页)的文章和Unter man等人在" J. Cataract Refract. Surg. "(白内障手术杂志,1988年第14卷500-504页)的文章。[0015] tobramycin solution is also famous for topical administration, such as treatment keratitis, see Davis et al in "Canad. J Ophtal." (Canadian Journal of Ophthalmology, 1978 13 273) of the article, Davis, etc. in "Arch Opthalmol" (Ophthalmology 1978 Volume 96 pages 123-125) of articles and Unter man and others in "J. Cataract Refract. Surg." (cataract surgery magazine, Volume 14, 500-504, 1988 pages) of the article. [0016] 现有给药手段和治疗方案的公知缺点是给药所需的时间,尤其影响患者的配合度和患者的生活质量。 Existing methods of administration and treatment programs known
FDA OKs Teva's Injectable Treanda
FDA OKs Teva's Injectable Treanda
FDA Approves Teva's Injectable Treanda
Sept. 17, 2013 (GLOBES)–Teva Pharmaceutical Industries Ltd. (NYSE: TEVA; TASE: TEVA) has announced that the US Food and Drug Administration (FDA) has approved a new injectable version Treanda for treatment of indolent B-cell non-Hodgkin lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen, and chronic lymphocytic leukemia. read all at
Bendamustine (INN, trade names Treakisym, Ribomustin, Levact and Treanda; also known as SDX-105) is a nitrogen mustard used in the treatment of chronic lymphocytic leukemia[1] and lymphomas. It belongs to the family of drugs called alkylating agents. It is also being studied for the treatment of sarcoma.[2]
Bendamustine was first synthesized in 1963 by Ozegowski and Krebs in East Germany(the former German Democratic Republic). Until 1990 it was available only in East Germany. East German investigators found that it was useful for treating chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myelomaand lung cancer.
Bendamustine received its first marketing approval in Germany, where it is marketed under the tradename Ribomustin, by Astellas Pharma GmbH's licensee, Mundipharma International Corporation Limited. It is indicated as a single-agent or in combination with other anti-cancer agents for indolent non-Hodgkin's lymphoma, multiple myeloma, and chronic lymphocytic leukemia. SymBio Pharmaceuticals Ltd holds exclusive rights to develop and market bendamustine HCl in Japan and selected Asia Pacific Rim countries.
In March 2008, Cephalon received approval from the United States Food and Drug Administration to market bendamustine in the US, where it is sold under the tradename Treanda, for treatment of chronic lymphocytic leukemia.[3]
In October 2008, the FDA granted further approval to market Treanda for the treatment of indolent B-cell non-Hodgkin's lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. [4]
Bendamustine, 4-{5-[Bis(2-chloroethyl)amino]-1-methyl-2-benzimidazolyl}butyric acid:
was initially synthesized in 1963 in the German Democratic Republic (GDR) and was available from 1971 to 1992 there under the tradename Cytostasan®. See, e.g., W. Ozegowski and D. Krebs, IMET 3393 γ-[1-methyl-5-bis-(β-chloroethyl)-aminobenzimidazolo-(2)]-butyryl chloride, a new cytostatic agent of the group of benzimidazole nitrogen mustards. Zbl. Pharm. 110, (1971) Heft 10, 1013-1019, describing the synthesis of bendamustine hydrochloride monohydrate. Since that time, it has been marketed in Germany under the tradename Ribomustin®. Bendamustine is an alkylating agent that has been shown to have therapeutic utility in treating diseases such as chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, and breast cancer.
While bendamustine has been demonstrated as efficacious, it is known to be unstable, especially in aqueous solutions, leading to technical difficulties in its preparation and administration. Researchers, therefore, have investigated methods of improving the preparation and stability of bendamustine and its formulations. For example, German (GDR) Patent No. 159877 discloses a method for preparing bendamustine free base by reaction of the bis-hydroxyl precursor with thionyl chloride followed by recrystallization from water.
German (GDR) Patent No. 34727 discloses a method of preparing derivatives of bendamustine. The described derivatives differ from bendamustine in the substitution at the 1-position.
German (GDR) Patent No. 80967 discloses an injectable preparation of bendamustine hydrochloride monohydrate, ascorbic acid, and water. GDR 80967 describes that lyophilization of compounds such as bendamustine is only possible if the compound is of sufficient stability that it can withstand the processing conditions. The preparation described in GDR 80967 is not lyophilized.
German (GDR) Patent No. 159289 discloses a ready-to use, injectable solution of bendamustine hydrochloride that avoids lyophilization. GDR 159289 describes an anhydrous solution of bendamustine hydrochloride in 1,2-propylene glycol or ethanol.
U.S. application Ser. No. 11/330,868, filed Jan. 12, 2006, assigned to Cephalon, Inc., Frazer, P A, discloses methods of preparing lyophilized pharmaceutical compositions comprising bendamustine hydrochloride.
Chemotherapeutic uses
Bendamustine has been used both as sole therapy and in combination with other agents including etoposide, fludarabine, mitoxantrone,methotrexate, prednisone, rituximab, vincristine and 90Y-ibritumomab tiuxetan.
One combination for stage III/IV relapsed or refractory indolent lymphomas and mantle cell lymphoma (MCL), with or without prior rituximab-containing chemoimmunotherapy treatment, is bendamustine with mitoxantrone and rituximab.[5] In Germany in 2012 it has become the first line treatment of choice for indolent lymphoma.[6] after Trial results released in June 2012 showed that it more than doubled disease progression-free survival when given along with rituximab. The combination also left patients with fewer side effects than the older R-CHOP treatment.[7]
Common adverse reactions are typical for the class of nitrogen mustards, and include nausea, fatigue, vomiting, diarrhea, fever, constipation, loss of appetite, cough, headache, unintentional weight loss, difficulty breathing, rashes, and stomatitis, as well as immunosuppression, anemia, and low platelet counts. Notably, this drug has a low incidence of hair loss (alopecia) unlike most other chemotherapy drugs.[8]
- Kath R, Blumenstengel K, Fricke HJ, Höffken K (January 2001). "Bendamustine monotherapy in advanced and refractory chronic lymphocytic leukemia". J. Cancer Res. Clin. Oncol. 127 (1): 48–54. doi:10.1007/s004320000180. PMID 11206271.
- Bagchi S (August 2007). "Bendamustine for advanced sarcoma". Lancet Oncol. 8 (8): 674. doi:10.1016/S1470-2045(07)70225-5.PMID 17726779.
- "Cephalon press release – Cephalon Receives FDA Approval for TREANDA, a Novel Chemotherapy for Chronic Lymphocytic Leukemia". Retrieved 2008-03-23.
- "Cephalon press release -Cephalon Receives FDA Approval for TREANDA to Treat Patients with Relapsed Indolent Non-Hodgkin's Lymphoma". Retrieved 2008-11-03.
- Weide R, Hess G, Köppler H, et al. (2007). "High anti–lymphoma activity of bendamustine/mitoxantrone/rituximab in rituximab pretreated relapsed or refractory indolent lymphomas and mantle cell lymphomas. A muticenter phase II study of the German Low Grade Lymphoma Study Group (GLSG)". Leuk. Lymphoma. 48 (7): 1299–1306. doi:10.1080/10428190701361828. PMID 17613757.
- New Combo Replaces CHOP for Lymphoma. Dec 2012
- "'Rediscovered' Lymphoma Drug Helps Double Survival: Study". June 3, 2012.
- Tageja, Nishant; Nagi, Jasdeepa; "Bendamustine: something old, something new"; Cancer Chemotherapy and Pharmacology, 2010 Aug;66(3):413-23. doi: 10.1007/s00280-010-1317-x.
External links
- Manufacturer's official website intended for US patients
more info
Bendamustine hydrochloride, 4-{5-[Bis(2-chloroethyl) amino]- l-methyl-2- benzimidazolyl} butyric acid hydrochloride, of the formula (VI) :
was initially synthesized in 1963 in the German Democratic Republic (GDR) and was available from 1971 to 1992 there, as the hydrochloride salt, under the trade name Cytostasan®. Since that time, it has been marketed in Germany under the trade name Ribomustin®. Bendamustine Hydrochloride as injection is available in the United States under the tradename Treanda®. Bendamustine hydrochloride is an alkylating agent that is approved for the treatment of non-Hodgkin's lymphoma, multiple myeloma and chronic lymphocytic leukemia.
Bendamustine hydrochloride is a benzimidazole analog. While bendamustine has been demonstrated as efficacious, it is known to be unstable, especially in aqueous solutions, leading to formation of non-bendamustine products (i.e. "degradation impurities") which leads to technical difficulties in its preparation and administration. In light of its instability in aqueous solution, bendamustine is supplied as a lyophilized cake of bendamustine hydrochloride salt. US2006/159713, US 2006/128777 and WO2010/036702 disclose various impurities of Bendamustine hydrochloride which are as follows:
Jena et al. were the first to disclose the synthesis of Bendamustine hydrochloride in German (GDR) Patent No. 34727. Krueger et al. in German (GDR) Patent No. 159877 recite a method as summarized in scheme-1, for the synthesis of bendamustine hydrochloride comprising the reaction of the 4-[l-methyl-5-bis-(2- hydroxyethyl)-benzimidazolyl-2]butyric acid ethyl ester (4) (or the corresponding methyl, propyl or butyl ester) with thionyl chloride in chloroform at 0-5°C to form 4-[l- methyl-5-bis-(2-chloroethyl)-benzimidazolyl-2]butyric acid ethyl ester (5). Excess of thionyl chloride is destroyed by stirring the reaction mixture in aqueous HCl. Finally chloroform is distilled off and stirred at 95°C for 3 hours. The reaction mixture is partially concentrated and the residue is diluted with water and stirred upto crystallization. Further purification is done by recrystallization from water.
Scheme-1: Method disclosed by Krueger et al. in DD159877 for the synthesis of Bendamustine hydrochloride
Bendamustine hydrochloride (6)
Ozegowski et al in Zentralblatt fuer Pharmazie, Pharmakotherapie und Laboratoriumsdiagnostik 1 10 (10), 1013-1019 (1971) discloses a process for the preparation of bendamustine hydrochloride monohydrate. The Chinese journal "Chinese journal of New Drugs ", 2007, No. 23, Vol. 16, 1960-61 and J. Prakt. Chem. 20, 178-186 (1963) disclose another method for the synthesis of Bendamustine hydrochloride monohydrate starting from 2,4-dinitrochlorobenzene as summarized in scheme-2.
The crucial conversions are reaction of l-methyl-2-(4′-ethyl butyrate)-5- amino]-lH-benzimidazole 6 with ethylene oxide in the presence of water, sodium acetate and acetic acid, by maintaining at 5°C for 5 hours and overnight at 20°C to give 4-{5-[bis-(2-hydroxy-ethyl)-amino]-l-methyl-lH-benzimidazol-2-yl}-butyric acid ethyl ester (dihydroxy ester) 7 as a jelly mass, which on chlorination using thionyl chloride in chloroform and subsequent in situ hydrolysis with concentrated HCI gave bendamustine hydrochloride. It also discloses a process for the recrystallization of bendamustine hydrochloride from water and the product obtained is a monohydrate with a melting point of 148-151°C.
IP.com Journal 2009, 9(7B), 21 discloses another process as shown below for the preparation of ethyl-4-[5-[bis(2-hydroxyethyl) amino]- l-methylbenzimidazol-2- yl]butanoate (III) wherein ethyl-4-(5 -amino- 1 -methyl- lH-benzo[d]imidazol-2-yl) butanoate (II) is reacted with 2-halo ethanol in the presence of an inorganic base selected from the group consisting potassium carbonate, potassium bicarbonate, sodium
The PCT application WO 2010/042568 assigned to Cephalon discloses the synthesis of Bendamustine hydrochloride as summarized in schem-3 starting from 2,4- dintroaniline in six steps. The crucial step is reductive alkylation of Il-a, using borane- tetrahydrofuran and chloroacetic acid at ambient temperature, producing compound of formula I-a. Acid mediated hydrolysis of I-a using concentrated hydrochloric acid at reflux produced bendamustine hydrochloride which has a purity of 99.1%. The above PCT Patent application also discloses a method of purification of Bendamustine hydrochloride by agitating the Bendamustine hydrochloride in a mixture of DMF and THF at 75°C for about 30 minutes followed by cooling to ambient temperature and isolating the solid by filtration.
Bemdamuatine hydrochloride
The PCT application WO 2011/079193 assigned to Dr. Reddy's Laboratories discloses the synthesis of Bendamustine hydrochloride as summarized in schem-4 starting from compound of formula (II). The crucial step is alkylation of compound of formula II with 2-haloethanol in the presence of an organic base to give a compound of formula (III) which on chlorination with a chlorinating agent affords a compound of formula (IV). Compound of formula (IV) on hydrolysis in acidic medium gives bendamustine hydrochloride. It further discloses purification of bendamustine hydrochloride using aqueous hydrochloric acid and acetonitrile.
Bendamustine hydrochloride (Pure)
The most of the prior art processes described above involve
• The use of ethylene oxide for the preparation of bendamustine hydrochloride, which is often not suitable for industrial scale processes due to difficulty in handling ethylene oxide, since it is shipped as a refrigerated liquid.
• Further, the known processes involve the use of strongly acidic conditions and high temperatures for the hydrolysis of ethyl ester of bendamustine and subsequent in-situ formation of bendamustine hydrochloride, thereby resulting in increased levels of various process-related impurities IMP. -A (RRT-0.46), IMP. -B (RRT-1.27) and IMP. -C (RRT-1.31) whose removal is quite difficult and make the process less economically viable.
International Application Publication No. WO 2009/120386 describes various solid forms of bendamustine hydrochloride designated as bendamustine hydrochloride Form 1, bendamustine hydrochloride Form 2, bendamustine hydrochloride Form 3, bendamustine hydrochloride Form 4, amorphous bendamustine hydrochloride or a mixture thereof, processes for their preparation and lyophilized composition comprising the solid forms. According to the disclosure, monohydrate of bendamustine hydrochloride has been prepared previously. The monohydrate has a reported melting point of 152-156°C which is similar to that of the observed melting point of bendamustine hydrochloride Form 2.
It is known that synthetic compounds can contain extraneous compounds or impurities resulting from their synthesis or degradation. The impurities can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. Generally, impurities in an active pharmaceutical ingredient (API) may arise from degradation of the API itself, or during the preparation of the API. Impurities in Bendamustine hydrochloride or any active pharmaceutical ingredient (API) are undesirable and might be harmful.
Regulatory authorities worldwide require that drug manufacturers isolate, identify and characterize the impurities in their products. Furthermore, it is required to control the levels of these impurities in the final drug compound obtained by the manufacturing process and to ensure that the impurity is present in the lowest possible levels, even if structural determination is not possible. The product mixture of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and byproducts of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product mixture. At certain stages during processing of the active pharmaceutical ingredient, the product is analyzed for purity, typically, by HPLC, TLC. or GC analysis, to determine if it is suitable for continued processing and, ultimately, for use in a pharmaceutical product. Purity standards are set with the intention of ensuring that an API is as free of impurities as possible, and, thus, are as safe as possible for clinical use. The United States Food and Drug Administration guidelines recommend that the amounts of some impurities are limited to less than 0.1 percent.
Generally, impurities are identified spectroscopically and by other physical methods, and then the impurities are associated with a peak position in a chromatogram (or a spot on a TLC plate). Thereafter, the impurity can be identified by its position in the chromatogram, which is conventionally measured in minutes between injection of the sample on the column and elution of the particular component through the detector, known as the "retention time" ("RT"). This time period varies daily based upon the condition of the instrumentation and many other factors. To mitigate the effect that such variations have upon accurate identification of an impurity, practitioners use "relative retention time" ("RRT") to identify impurities. The RRT of an impurity is its retention time divided by the retention time of a reference marker.
It is known by those skilled in the art, the management of process impurities is greatly enhanced by understanding their chemical structures and synthetic pathways, and by identifying the parameters that influence the amount of impurities in the final product.
Therefore, there remains a need for improved process for the preparation of bendamustine hydrochloride, producing high yield and purity, and well-suited for use on an industrial scale. Despite the existence of various polymorphic forms of bendamustine hydrochloride, there exists a need for a simple process for the preparation of the stable form of bendamustine hydrochloride which is amenable to scale up and results in high yield and purity.
Bendamustine, (4-{5-[bis(2-chloroethyl)amino]-1-methyl-2-benzimidazolyl}butyric
is an atypical structure with a benzimidazole ring, which structure includes an active nitrogen mustard. Bendamustine was initially synthesized in 1963 in the German Democratic Republic and was available from 1971 to 1992 in that location under the name Cytostasan®. Since that time, it has been marketed in Germany under the tradename Ribomustin®. It is currently available for use in the United States under the tradename Treanda® (Cephalon, Inc., Frazer, Pa.). It has been widely used to treat chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, and breast cancer.
Like other nitrogen mustards, bendamustine hydrolyzes in aqueous solution, with the major degradant being the primary alcohol HP1 (See U.S. application Ser. No. 11/330,868, the entirety of which is incorporated herein):
In light of its instability in aqueous solution, bendamustine is currently supplied as a lyophilized powder for injection. Just prior to its infusion, the medical practitioner reconstitutes the powder with Sterile Water for Injection. Reconstitution should yield a clear, colorless to pale yellow solution and the powder should completely dissolve in about 5 minutes. If particulate matter is observed, the reconstituted product should not be used and should be discarded. The reconstituted product is then transferred to a 0.9% Sodium Chloride Injection infusion bag within 30 minutes of reconstitution. This admixture should be a clear and colorless to slightly yellow solution. If the admixture comprises particulate matter or is discolored, it should be discarded and a fresh sample prepared.
The salt bendamustine hydrochloride is an alkylating agent, originally synthesized in 1963 at the Institute for Microbiology & Experimental Therapy in Jena, German Democratic Republic, with the intent to produce an agent with both alkylating and antimetabolite properties. Jenapharm (now Schering AG) formerly marketed it in Germany under the trade name Cytostasan from 1971 to 1992. Cytostasan was a lyophilised powder for solution for injection (vials) conatining 25 mg of Bendamustine HCI. It was widely used but never studied systematically in patients until the 1990s, then German investigators demonstrated its clinical activity in a number of malignancies. Since 1993, Ribosepharm was marketing bendamustine in Germany under the brand name Ribomustin RBO. Ribomustin is available as a lyophilized powder for injection, containing 100 mg of drug in each 50 ml_ vial, or 25 mg of drug in each 20 ml_ vial, also comprising mannitol, and indicated for the treatment of chronic lymphocytic leukemia. The lyophilized powder is reconstituted as close to the time of patient administration as possible with 40 ml_ (for a 100 mg product) or 10 mL (for a 25 mg product) of sterile water for injection. The reconstituted product then is further diluted to 500 mL with 0.9% sodium chloride for injection. The route of administration is by intravenous infusion over 30 to 60 minutes.
Another bendamustine product is sold in the United States by Cephalon, Inc. as TREANDA® for Injection, a lyophilized powder in a single-use vial indicated for the treatment of patients with chronic lymphocytic leukemia and indolent B-cell non-Hodgkin's lymphoma. A 25 mg dose vial contains 25 mg of bendamustine hydrochloride and 42.5 mg of mannitol, and a 100 mg dose vial contains 100 mg of bendamustine hydrochloride and 170 mg of mannitol.
TREANDA is intended for intravenous infusion only after reconstitution with Sterile Water for Injection USP, and then further dilution with either 0.9% Sodium
Chloride Inj.ection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Inj.ection, USP. The pH of the reconstituted solution is 2.5-3.5. TREANDA is supplied as a sterile non-pyrogenic white to off-white lyophilized powder, in a single-use vial.
Bendamustine hydrochloride is very unstable in an aqueous solution. The bis-2-chlorethylamino bond is hydrolyzed in weak acid, neutral, or alkaline solution. Monohydroxybendamustine [HP-1 ] is formed rapidly in the presence of water. Bendamustine ethyl ester [BM1 EE] is formed when bendamustine reacts with ethyl alcohol. BM1 EE can be formed during drug substance manufacturing, e.g., during recrystalization and/or purification processes. BM1 EE is a more potent cytotoxic drug than bendamustine.
Teva and Alexza Announce Teva's License to Market ADASUVE® in the U.S.
Loxapine (Loxapac, Loxitane)
is a typical antipsychotic medication, used primarily in the treatment of schizophrenia. It is a member of the dibenzoxazepine class and structurally related to clozapine (which belongs to the chemically akin class ofdibenzodiazepines). Several researchers have argued that Loxapine may behave as anatypical antipsychotic.
Loxapine may be metabolized by N-demethylation to amoxapine, a tetracyclic antidepressant.
Adasuve® (loxapine) inhalation powder is approved in the U.S. for the acute treatment of agitation associated with schizophrenia and bipolar disorder
May 8, 2013
Teva Pharmaceuticals USA, Inc., a subsidiary of Teva Pharmaceutical Industries Ltd (NYSE: TEVA), and Alexza Pharmaceuticals, Inc. (NASDAQ: ALXA) announced today that the companies have entered into an exclusive U.S. license and supply agreement for ADASUVE (loxapine) inhalation powder 10 mg for the acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults. Teva will be responsible for all U.S. commercial and clinical activities for ADASUVE, including U.S. post-approval clinical studies, and has gained rights to conduct additional clinical trials of ADASUVE for potential new indications in neurological disorders. Alexza will be responsible for manufacturing and supplying ADASUVE to Teva for commercial sales and clinical trials.
About Alexza Pharmaceuticals, Inc.
Alexza Pharmaceuticals is focused on the research, development and commercialization of novel, proprietary products for the acute treatment of central nervous system conditions, including agitation, acute repetitive seizures and insomnia. Alexza's products are based on the Staccato®system, a hand-held inhaler that is designed to deliver a drug aerosol to the deep lung, providing rapid systemic delivery and therapeutic onset, in a simple, non-invasive manner.
FDA Approves New Drug Application (NDA) for Teva's Quartette (levonorgestrel/ethinyl estradiol and ethinyl estradiol) Tablets for the Prevention of Pregnancy
ethinyl estradiol
Quartette™ Represents the Next Generation of Extended Regimen Oral Contraceptives
Teva Pharmaceutical Industries Ltd. today announced that the U.S. Food and Drug Administration (FDA) has approved Quartette™ (levonorgestrel/ethinyl estradiol and ethinyl estradiol) tablets for the prevention of pregnancy. Quartette™ represents the next generation of extended regimen oral contraceptives to be approved by the FDA, and was designed to minimize breakthrough bleeding (BTB) between scheduled periods. The approval of Quartette™ demonstrates Teva's continued commitment to the development and production of an innovative range of pharmaceutical products that support the health of women around the world.
"Breakthrough bleeding can be experienced with any birth control pill, especially during the first few months, and is one of the reasons a large number of women discontinue extended regimens," said Dr. James A. Simon, clinical professor of Obstetrics and Gynecology at the George Washington University School of Medicine. "The estrogen in Quartette™ increases at specific points and provides four short light periods a year. Breakthrough bleeding decreases over time, which might help encourage patient adherence."
The approval was based on a development program that included results from Phase I, Phase II and Phase III clinical trials designed to evaluate the safety and efficacy of Quartette™. The Phase III clinical trial, which involved more than 3,000 women, found that Quartette™ was 97 percent effective at preventing pregnancy. Data further demonstrated that the most common adverse reactions (≥2%) in the Phase III clinical trial were headaches, heavy/irregular vaginal bleeding, nausea/vomiting, acne, dysmenorrhea, weight increased, mood changes, anxiety/panic attack, breast pain and migraines. The primary clinical trial that evaluated the efficacy of Quartette™ also assessed BTB. BTB and unscheduled spotting decreased over successive 91 day cycles.1
Quartette™ features a unique 91-day oral regimen, whereby the dose of estrogen increases at three distinct points over the first 84 days and the amount of progestin remains consistent; this is followed by seven days of 10 mcg of ethinyl estradiol.
"Teva is the leader in the pharmaceutical industry in the marketing and development of extended regimen oral contraceptives, and Quartette™ represents the next generation of these contraceptives. It is a uniquely differentiated product and is based on Teva's research into when breakthrough bleeding is most likely to occur with these regimens," said Jill DeSimone, senior vice president & general manager, Global Teva Women's Health. "Quartette™ is the newest product in our global women's health franchise and is an example of our dedication to providing a variety of contraceptive and family planning options that fit women's lifestyles."
Nippon and Teva receive approval for biosimilar G-CSF (fligrastim) in Japan
As with the original drug, acts on neutrophil precursor cells, to promote the proliferation, differentiation and its biosimilar filgrastim of (recombinant) promotes the release of neutrophils from the bone marrow, enhances its function. In the field of cancer treatment, it is used for chemotherapy-induced neutropenia mainly cancer.
Filgrastim is a granulocyte colony-stimulating factor (G-CSF) analog used to stimulate the proliferation and differentiation of granulocytes.[1] It is produced by recombinant DNA technology. The gene for human granulocyte colony-stimulating factor is inserted into the genetic material of Escherichia coli. The G-CSF then produced by E. coli is different from G-CSF naturally made in humans.
It is marketed by Amgen under the brand name Neupogen, in India it is also marketed by Abbott Healthcare under the brand name Imumax, Dr. Reddy's Laboratories under the brand name Grafeel, In Pakistan CCL Pharmaceuticals (Pvt) Ltd under the brand name Grastin, Zenotech Laboratories Limited under the brand name Nugraf, Raichem lifesciences under the brand name Shilgrast, Intas Biopharmaceuticals under the brand name Neukine, Emcure biopharmaceuticals under the brand name Emgrast, Reliance Life Sciences under the brand name Religrast and Sandoz under the name Zarzio.
Apricus Biosciences is currently developing and testing a product (under the brand name Nupen) which can deliver filgrastim through the skin to improve post-chemotherapy recovery of neutrophil counts.
Phase III Study of Oral Laquinimod for Relapsing-Remitting Multiple Sclerosis
Laquinimod is an experimental immunomodulator developed by Active Biotech and Teva. It is currently being investigated as an oral treatment for multiple sclerosis (MS).
Laquinimod is the successor of Active Biotech's failed experimental immunomodulator linomide.[1]
The compound has been investigated in two Phase II trials using successive magnetic resonance scans (MRI). Laquinimod seems to be able to reduce the MS disease activity on MRI.[2][3] However, the response to a given dose was discrepant between both studies.[4]
Phase III studies for MS started in December 2007.[5] In 2011, Teva announced its clinical trials involving laquinimod had failed, being unable to significantly reduce relapses into MS among patients beyond a placebo.[6] However, the final results of above mentioned phase III trial proved oral laquinimod administered once daily slowed the progression of disability and reduced the rate of relapse in patients with relapsing–remitting multiple sclerosis [7]
Mar 6, 2013 –
CONCERTO Study Enrolling Patients Globally to Evaluate Impact of Laquinimod on Disability Progression
Teva Pharmaceutical Industries Ltd. and Active Biotech announced today enrollment of the first patient in the CONCERTO study – the third Phase III placebo-controlled study designed to evaluate the efficacy, safety and tolerability of once-daily oral laquinimod in patients with relapsing-remitting multiple sclerosis (RRMS). The primary outcome measure of CONCERTO will be confirmed disability progression as measured by the Expanded Disability Status Scale (EDSS).
"Previous Phase III studies in more than 2,400 people with RRMS suggest a unique profile of laquinimod, directly affecting the neurodegenerative processes that lead to disability progression, the main concern in the treatment of RRMS," said CONCERTO principal investigator, Dr. Timothy Vollmer, Professor of Neurology, University of Colorado Denver, Medical Director of the Rocky Mountain Multiple Sclerosis Center, and Co-Director of the RMMSC at Anschutz. "We are currently enrolling patients in this third pivotal study to further examine the clinical benefits of laquinimod on disability progression, the primary endpoint of the CONCERTO trial, and brain atrophy, at both the previously studied 0.6 mg dose, and now a higher 1.2 mg dose."
The multinational, randomized, double blind placebo-controlled study will aim to enroll approximately 1,800 patients at more than 300 sites globally (http://clinicaltrials.gov/show/NCT01707992). Along with the primary endpoint of time to confirmed disability progression, the study will also examine the impact of laquinimod on endpoints such as percent change in brain volume and other clinical and MRI markers of disease activity.
"For nearly 30 years, Teva has been focused on improving the lives of people with multiple sclerosis by delivering innovative treatment options that address this complex disease," said Dr. Michael Hayden, President of Global R&D and Chief Scientific Officer at Teva Pharmaceutical Industries Ltd. "The CONCERTO study demonstrates our commitment to collaborating with MS communities worldwide to further develop laquinimod and address unmet patient needs."
Laquinimod is an oral, once-daily CNS-active immunomodulator with a novel mechanism of action being developed for the treatment of MS. In animal models laquinimod crosses the blood brain barrier to potentially have a direct effect on resident CNS inflammation and neurodegeneration. The global Phase III clinical development program evaluating oral laquinimod in MS includes two pivotal studies, ALLEGRO and BRAVO.
In addition to the MS clinical studies, laquinimod is currently in clinical development for Crohn's disease and Lupus.
CONCERTO is a multinational, multicenter, randomized, double-blind, parallel-group, placebo-controlled study followed by an active treatment phase, to evaluate the efficacy, safety and tolerability of two doses of oral administration of laquinimod 0.6 mg/day or 1.2 mg/day in subjects with RRMS. This third Phase III laquinimod study will evaluate laquinimod in approximately 1,800 patients for up to 24 months, after which patients will continue to an active treatment period with laquinimod for an additional 24 months. The primary outcome measure will be time to confirmed disability progression as measured by the Expanded Disability Status Scale (EDSS). The study will also examine the impact of laquinimod on endpoints such as percent change in brain volume, as well as other clinical and MRI markers of disease activity.
MS is the leading cause of neurological disability in young adults. It is estimated that more than 400,000 people in the United States are affected by the disease and that two million people may be affected worldwide. Multiple sclerosis is a degenerative disease of the central nervous system in which inflammation and axonal damage and loss result in the development of progressive disability.
Teva Pharmaceutical Industries Ltd. (NYSE: TEVA) is a leading global pharmaceutical company, committed to increasing access to high-quality healthcare by developing, producing and marketing affordable generic drugs as well as innovative and specialty pharmaceuticals and active pharmaceutical ingredients. Headquartered in Israel, Teva is the world's leading generic drug maker, with a global product portfolio of more than 1,000 molecules and a direct presence in about 60 countries. Teva's branded businesses focus on CNS, oncology, pain, respiratory and women's health therapeutic areas as well as biologics. Teva currently employs approximately 46,000 people around the world and reached $20.3 billion in net revenues in 2012.
Active Biotech AB is a biotechnology company with focus on autoimmune/inflammatory diseases and cancer. Projects in or entering pivotal phase are laquinimod, an orally administered small molecule with unique immunomodulatory properties for the treatment of multiple sclerosis, TASQ for prostate cancer as well as ANYARA for use in cancer targeted therapy, primarily of renal cell cancer. In addition, laquinimod is in Phase II development for Crohn's and Lupus. Further projects in clinical development comprise the two orally administered compounds, 57-57 for SLE & Systemic Sclerosis and RhuDex(TM) for RA. Please visit http://www.activebiotech.com for more information.
- Tan IL, Lycklama à Nijeholt GJ, Polman CH et al. (April 2000). "Linomide in the treatment of multiple sclerosis: MRI results from prematurely terminated phase-III trials". Mult Scler 6 (2): 99–104. PMID 10773855.
- Comi G, Pulizzi A, Rovaris M et al. (June 2008). "Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study". Lancet 371 (9630): 2085–2092. doi:10.1016/S0140-6736(08)60918-6. PMID 18572078.
- Polman C, Barkhof F, Sandberg-Wollheim M et al. (March 2005). "Treatment with laquinimod reduces development of active MRI lesions in relapsing MS". Neurology 64 (6): 987–91. doi:10.1212/01.WNL.0000154520.48391.69. PMID 15781813.
- Keegan BM, Weinshenker BG (June 2008). "Laquinimod, a new oral drug for multiple sclerosis". Lancet 371 (9630): 2059–2060. doi:10.1016/S0140-6736(08)60894-6. PMID 18572062.
- ClinicalTrials.gov NCT00509145 Safety and Efficacy of Orally Administered Laquinimod Versus Placebo for Treatment of Relapsing Remitting Multiple Sclerosis (RRMS) (ALLEGRO)
- Kresege, Naomi (1 August 2011). "Teva's Copaxone Successor Fails in Latest Clinical Trial". Bloomberg. http://www.bloomberg.com/news/2011-08-01/teva-s-oral-multiple-sclerosis-drug-fails-to-meet-goal-of-clinical-trial.html. Retrieved 2 August 2011. "Teva Pharmaceutical Industries Ltd. (TEVA)'s experimental multiple sclerosis pill failed to reduce relapses more than placebo in a clinical trial, dealing a blow to the company's effort to find a successor to an older drug."
- (Comi et al. N Engl J Med 2012;366:1000).
5-Chloroisatoic anhydride (I) is alkylated with iodomethane and NaH to afford (II). Subsequent condensation of anhydride (II) with the malonic monoamide (III) in the presence of NaH in hot DMA furnishes the target quinoline carboxamide.
Reaction of 2-amino-6-chlorobenzoic acid (I) with phosgene and NaHCO3 in dioxane gives 5-chloroisatoic anhydride (II), which is methylated by means of iodomethane and NaH in DMF to yield 5-chloro-1-methylisatoic anhydride (III). Finally, anhydride (III) is condensed with the malonic monoamide (IV) by means of NaH in hot dimethylacetamide. Alternatively, condensation of anhydride (III) with ethoxy malonyl chloride (V) by means of NaOMe and triethylamine in dichloromethane affords 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3- carboxylic acid ethyl ester (VI), which is finally condensed with N-ethylaniline (VII) in refluxing toluene. Alternatively, ester (VI) is hydrolyzed by means of concentrated HCl in hot Ac2O to give the carboxylic acid (VIII), which is finally condensed with N-ethylaniline (VII) by means of SOCl2 and TEA in dichloromethane
Phase III Study of Teva's Milprosa (Progesterone) Vaginal Ring Published in Fertility and Sterility
Data Demonstrated Once-Weekly Milprosa™ Provides Similar Pregnancy Rates to Daily 8 Percent Progesterone Vaginal Gel
Mar 4, 2013 –
Teva Pharmaceutical Industries Ltd. today announced the publication of results of the Phase III clinical trial of Milprosa™ (progesterone) vaginal ring in Fertility and Sterility. The study compared the efficacy and safety of once-weekly Milprosa™ to daily 8 percent progesterone vaginal gel for luteal phase support in in vitro fertilization (IVF) and found that clinical pregnancy rates per retrieval at eight and 12 weeks were comparable between patient groups. Adverse event (AE) profiles were similar between the two treatment groups and consistent with known AEs associated with progesterone.
"The study results demonstrate that Milprosa™ may be an effective and safe option for progesterone supplementation during the luteal phase among women undergoing IVF," said Laurel Stadtmauer, M.D., Ph.D., professor of Obstetrics and Gynecology at Jones Institute for Reproductive Medicine at Eastern Virginia Medical School and study author. "Since normal luteal function may be compromised among women undergoing IVF, progesterone supplementation is essential and the more options patients have, the better. If approved, the once-weekly dosing of Milprosa™ may offer convenience for patients."
The Phase III randomized, single-blinded, multicenter, noninferiority study was conducted at 22 clinical sites in the U.S. and included 1,297 patients between the ages of 18 and 42. Of enrolled patients, 646 were randomized to Milprosa™ and 651 to the 8 percent progesterone vaginal gel.
"The Fertility and Sterility publication of the Milprosa™ Phase III data is a significant milestone for Teva, especially because fertility is a meaningful new area of specialization for the company and one in which significant unmet need exists," said Jill DeSimone, senior vice president & general manager, Global Teva Women's Health. "We look forward to continuing to share important updates about Milprosa™ and demonstrating our investment in and commitment to women's health."
About the Study
The Phase III study randomized patients into two treatment groups: one group received once-weekly Milprosa™ and the other received daily 8 percent progesterone vaginal gel. Milprosa™ and the vaginal gel were initiated on the day following egg retrieval and continued through 12 weeks' gestation. Efficacy was evaluated by comparing clinical pregnancy rates of patients at eight and 12 weeks gestation.
- At week eight, clinical pregnancy rates per retrieval were 48.0 percent for the Milprosa™ group and 47.2 percent for the vaginal gel group (between-group difference, 0.8%; 95% CI, -4.6%, 6.3%).
- At week 12, clinical pregnancy rates per retrieval for Milprosa™ and the vaginal gel were 46.4 percent and 45.2 percent respectively (between-group difference, 1.3%; 95% CI, -4.1%, 6.7%).
A secondary efficacy endpoint was the rate of live birth.
- The overall live birth rate per retrieval for women using Milprosa™ was 45.2 percent; among women using the vaginal gel, the rate was 43.3 percent.
- The majority of patients pregnant at week 12, when progesterone treatment ended, went on to have a live birth: 97.4 percent for the Milprosa™ group and 96.5 percent for the vaginal gel group.
The most commonly reported adverse events (those greater than or equal to 10% in the Milprosa™ treatment group) were nausea, headache, abdominal pain, post-procedural discomfort, abdominal distension, back pain, fatigue, vomiting and constipation. Serious adverse events (SAEs) occurred in approximately 12 percent of all patients, with no significant difference in the rate between treatment groups. The majority of SAEs that occurred were mild to moderate in severity and not related to treatment. Rates of discontinuation of treatment due to AEs were low and similar between both groups (approximately 6%).
About Milprosa™ (Progesterone) Vaginal Ring
Milprosa™ is an investigational, once-weekly progesterone ring inserted in the vagina. It is flexible and designed to continuously release a steady dose of micronized progesterone. Milprosa™ is in development to support embryo transplantation and early pregnancy (up to 10 weeks post-embryo transfer) by supplementation of corpus luteal function as part of an Assisted Reproductive Technology (ART) treatment program for infertile women.
About Supplementation of Corpus Luteal Function
The corpus luteum is a temporary endocrine gland that develops during the luteal phase of a woman's menstrual cycle. It is an important contributor of progesterone and is critical for the maintenance of early pregnancy. During in vitro fertilization, progesterone supplementation is needed because natural levels of the hormone may be insufficient. This supplementation improves implantation rates and thus pregnancy rates. Additionally, progesterone supplementation supports early pregnancy.
About Teva
Teva Pharmaceutical Industries Ltd. (NYSE: TEVA) is a leading global pharmaceutical company, committed to increasing access to high-quality healthcare by developing, producing and marketing affordable generic drugs as well as innovative and specialty pharmaceuticals and active pharmaceutical ingredients. Headquartered in Israel, Teva is the world's leading generic drug maker, with a global product portfolio of more than 1,000 molecules and a direct presence in about 60 countries. Teva's branded businesses focus on CNS, oncology, pain, respiratory and women's health therapeutic areas as well as biologics. Teva currently employs approximately 46,000 people around the world and reached $20.3 billion in net revenues in 2012.


text:
§ 65. Mr. Hurd
asked the Minister of Food if, in view of the prolongation of bread rationing, with consequent dislocation of the points-rationing scheme, he will limit the availability of points obtained by the exchange of bread rationing coupons to ensure that all consumers can get their due share of biscuits, syrup, dried fruits and other popular foods.108W
§ Mr. Strachey
I cannot agree that the exchange of bread units for points has dislocated the points rationing scheme. We have already made two B.Us. exchangeable for one point.
§ Major Bramall
asked the Minister of Food if he will arrange for a more adequate distribution of points goods to Bexley, Bexleyheath and Welling, where such goods are hard to obtain.
§ Mr. Strachey
My inquiries show that consumers in Bexley, Bexleyheath and Welling are able to spend the whole of their points allowance and that traders in the area obtain a fair share of supplies. The Ministry has, however, already released extra supplies to rebuild retailers' stocks and the consequent improvement in supplies should be noticeable during the next week or so, in Bexley and the neighbouring districts as well as in the rest of the country.


text:
Finally, movement!
Posted on Dec 11, 2012 by WHC Bassetti in Letters
After 8 days of shifting from one foot to the other the market finally took a step. In the right direction. Prices today crossed the resistance horizontal line. And while we only include it for reference prices have broken above the 50 day moving average. Many analysts consider this significant. We always consider it in the context of the rest of the chart. This chart says "buy me".
This is only a preview. You must be a subscriber to access the full text of this letter.


text:
Pending Price Increase - Feb, 2020
In February, there will be a price increase on Sauna Material Kits and Steam Generators. Steam prices will be held as long as we have inventory at old prices. Material kits at old prices must be picked up or shipped prior to Feb 29.MORE INFO
You frame & insulate. We supply all the interior parts. We provide all tongue & groove boards, bench material, door, trim and heater. Choose from dozens of features and options.MORE INFO
Not looking to build a sauna yourself from scratch. Saunafin offers a wide range of prefab saunas designed to assemble in a few hours. Prefab available for both indoor and outdoor saunas.MORE INFO


text:
Total Swimming News Archive
How to RELAX at the pool this summer
We're officially in the middle of a scorching hot summer, and as many of you will be cooling off in the pool either on holiday or at the loca...Read More
Swim Safe offer free swimming lessons in Salford Quays
Free outdoor swimming and water safety sessions for 7 to 14-year-olds are returning to Salford Quays this summer. Swim Safe is the national pro...Read More
Join the Summer Swim at ESMS in Edinburgh
Total Swimming Academies is excited to announce that we will be holding Summer Swim Lessons for ages 3+ at ESMS ...Read More
Total Swimming Academies are in the press!
Total Swimming Academies has been featured in The Bury Times and Leigh Journal, all thanks to our fabulous and free water safety pack, which y...Read More
Steve Parry on BBC Radio Merseyside!
Our director Steve Parry was on BBC Radio Merseyside talking all things swimming. In light of International Learn to Swim Week, he spoke t...Read More
International Learn to Swim Week
For International Learn to Swim Week this year, the theme was #LoveWaterSafely Enjoying water responsibly is our core message at Tot...Read More
5 things to know about GDPR...
You've probably heard a lot about GDPR by now – whether it's from the countless emails from companies you weren't...Read More
Why is swimming so good for you?
It's well known that swimming is a great activity for children to take part in as it has so many health benefits, but just what exactly ...Read More
World Asthma Day
Starting in 1998, World Asthma Day is an annual event organized by the Global Initiative for Asthma (GINA) to improve asthma awareness and ...Read More
8 things to remember when on holiday
With holiday season just around the corner, we thought we'd share some tips about staying safe on the beach while you're having fu...Read More


text:
Promotional codes and coupons at 5pointz
Everyone who loves to save money using promotional codes. Using free combinations of symbols, which, as a rule, consist of 16 digits, you can lose up to 80 percent of the price. In addition promotional codes — the best opportunity to receive gifts. Don't forget to check for a promotional code to buy 5 pointz and save. To buy profitable, check the updates section "Discounts" on the 5pointz site.co.uk.
Goods store 5pointz
At 5pointz.co.uk you will always find mens (jackets, coats, jackets, shirts, jackets, shorts, jeans, pants, vests, sweaters, jackets, sweatshirts, sweaters, sweatshirts, sweaters, hoodies, sports suits) and women's fashionable clothing (shirts, dresses, tunics, skirts, sweatshirts, sweaters, shorts, hoodies, coats, jackets). Also always in stock a variety of quality accessories: underwear, backpacks, socks, hats, cases for IPhone, baseball caps and shoes. Goods can be paid with electronic money and wire transfer to the account of 5pointz. Possible delivery in the UK and Europe.


text:
Wilbert September 30, My Saved Articles Sign in Sign up. Desi jawan bete ke sath maa ki bistar garam. Perhaps, that could put his winnings from the bet to good use? This will alert our moderators to take action Name Reason for reporting: Foul language Slanderous Inciting hatred against a certain community Others.
Watch free Zara Akbar Nude Sexi Pakistani Actress indian hindi porn
This is the second set of pictures of Pakistani big tits beauty Sazhida which we had published few days ago, check here. View author archive Get author RSS feed. Show those corrupt Police official faces too! Desi paki girl nude 6 months ago PornHub. Paki hot girl undressing in front of her friend 6 months ago PornHub.
Does a Pakistani actor posing nude mean things are changing? - The Economic Times
This story has been shared 34, times. Offbase January 5, Story continued below Imran Khan has to take drastic steps like cleaning the Police,Courts and FBR within a week's time,otherwise,everything will collapse. Desi Desi Pics Pakistani. Seems like Pakistan is fast getting filled with sexy sluts. Sexy Pakistani Shemale. Even as she claimed the photos had been morphed — which the magazine denied — and even as it seemed this was all part of a choreographed publicity stunt, word filtered through that the reaction in Pakistan seems to have been, well, rather muted.
Protect your children from adult content and block access to this site by using parental controls. Post was not sent - check your email addresses! Sexy Pakistani bhabhi watching TV when devar fucks. Show those corrupt Police official faces too! Whatever the case, there were no fatwas, no cash prizes for killing, not even street protests. Seems like Pakistan is fast getting filled with sexy sluts. This story has been shared 34, times.
5 days ago
wer findet das erotisch? ich nicht
8 days ago
I had this on tape
20 days ago
Wish I was 30 years younger...., she would (maybe) make my dream come through... Beautyful, she was, and... Waow! :)
6 days ago
Cheap and cheerful.Great!!
24 days ago
Love em both, but I'll take the blonde first if she would just go heterosexual for a bit!
14 days ago
Great scene. Could someone PM me the short haired girls name.
13 days ago
fun and enjoy
4 days ago
She looks like one of my ex coworker. I should've fucked her while I had a chance.
13 days ago
Time to edge and blow a load. Thanks for the upload.
3 months ago


text:
- All colors are not always available in all fabrics – we work with what is available and do our best to meet your needs, but certain prints or colors simply may not be offered in all fabrics.
- Generally, stretch knit fabrics do not match non-stretch woven fabrics - These fabrics are made differently and therefore the colors are going to look different. Don't count on being able to find an exact match for a stretch fabric with a non-stretch fabric.
- Costume fabrics today are not generally expec
Our Blog
Dance costumes ARE NOT street clothes, and should not be laundered after every performance. Many stage costumes are NEVER laundered, but they are simply aired out and perfumed! Here are some tips:
Tags: Costume Care Tips, Costume Fabric Tips, Minnesota Dancer Magazine
Spring cleaning this year has unearthed some old saved 'clippings' (obviously from before the advent of social media). The article below includes some really great advice for anyone who sweats! I have not personally tried these 'fixes' and worry that using these solutions may not be the best for specialty performance fabrics, but these tips may work very well with 'regular' clothing.Read More
As the saying goes…"Once a fashion designer, always a fashion designer." But this can sometimes be a hazard: I am always dissecting people's outfits and costumes! My "designer eye" is always critiquing what I see, both the good and the bad.
Tags: Costume Fabric Tips, Costume Design Tips, Costume Fit & Size Tips, Minnesota Dancer Magazine
I attended and really enjoyed a fashion show last week, put on by some very talented designers, featured by The Fashion Group International, Inc. of Minneapolis & St. Paul. This fabulous 'Minnesota Designer's Showcase' was sponsored by the Bloomington Sofitel Hotel and MANY volunteer professionals that made it all possible.
Tags: Custom Dance Team Costumes, Costume Fabric Tips, Quality in Costumes
If your dance costume is manufactured out of hologram, surface-printed Spandex/Lycra fabrics, you should have been told that the fabric is stunningly beautiful, but also that it is nearly impossible to clean. Were you told this?
Tags: Costume Fabric Tips
© Deborah J. Nelson/Satin Stitches Ltd.
I am thrilled that one of my favorite blogs is still being read on this blog site, titled-Should Awards Shows Provide Inspiration for Dance Costume Designs?
Of course! Did you enjoy watching the Emmy Awards this past Sunday evening? With two full hours of Red Carpet shows, the actual broadcast, and then at least two full hours of recapping what was worn, it has been thrilling.Read More
Tags: Costume Fabric Tips
© Deborah J. Nelson/Satin Stitches Ltd.
Is the NUDE bodysuit or catsuit making a comeback? Maybe? Maybe not!
Now that I've seen Pink perform at the Grammy's on Sunday evening, doing her aerial act while singing, I was reminded of Jennifer Lopez and her unfortunate nude catsuit that she wore on New Year's Eve. One was good and one was bad. Can you guess which was which, and why? Hmmmm.
Think about this question. Both had large expanses of nude-toned spandex, giving the appearance of nothingness, or of nudity. One had scattered rhinestones as decoration. One had clusters of rhinestones that gave the impression of coverage of various female body parts.Read More
Tags: Costume Fabric Tips
I still hear it all the time, and even from sewers: What exactly is Lycra or spandex, and how do I work with it successfully? In my June blog titled FABRIC 101, I discussed all types of information about all types of fabrics. I tried to cover most of the different types of fabrics that dance professionals would consider using in their dance performance costumes.
I barely touched on the most obvious fabric, which is spandex. Spandex is a godsend for the performance world!
Tags: Costume Fabric Tips


text:
All orders shipped with UPS Express.
Always free shipping for orders over US $250.
All orders are shipped with a UPS tracking number.
Items returned within 14 days of their original shipment date in same as new condition will be eligible for a full refund or store credit.
Refunds will be charged back to the original form of payment used for purchase.
Customer is responsible for shipping charges when making returns and shipping/handling fees of original purchase is non-refundable.
All sale items are final purchases.
Give us a shout if you have any other questions and/or concerns.
Email: [email protected]
Phone: +1 (23) 456 789
aere's CHANGE Collection as previewed at Kuala Lumpur Fashion Week 2017 marks an evolution of growth for the brand. Featuring fresh design ideas and fabric intertwined with aere's signature sophistication and versatility, the collection is a reflection of growth; embracing change but staying true to yourself. The runway pieces from this collection is truly exclusive and limited!
Inspired by aere's signature waterfall cut top, ELLIA is updated with a gorgeous and soft textured fabric in rich blue. Featuring a double layer front waterfall cut and aere's signature gold zipper and charm.
Measurements for product (in INCHES):


text:
Error code -21 is only a username or password error.
**If you have gotten this error more than 5 times you will need to wait 15 minutes and the lockout to be removed automatically**or you can have your admin delete the lockout or reset your password.
To delete lockout:
The admin will have to log into Point central. Go to users>Locked out users. If there is a locked out user simply press the delete option. Then the user can test point access again. If the user still gets the error move onto the next step.
To reset password:
In Point central go to 1. Users 2. list users 3.Find the user getting the error. Press edit on their username.
Down about half way you will see a password box.
Enter the new password twice and make sure to click update


text: I use songs to help dealing with having advanced cancer. There are songs for every mood that I have. One of the songs I listen to when I want to make fun at having cancer and poke it in the eye is called "Cancer Sucks". I hope it brings a smile to others.


text:
3 - 7 years. Every morning, Handa, a young girl from the Luo tribe, feeds breakfast to Mondi, her grandma?s black hen. This morning, however, Mondi is nowhere to be seen. So Handa and her friend Akeyo set off on a hunt, coming upon two fluttery butterflies, three stripy mice, four little lizards, five beautiful sunbirds, and many more intriguing creatures. But where could Mondi be? Is that a faint cheeping they hear under the bush? Might Mondi have a surprise in store (or maybe even ten of them)? 32 pages. Paperback.
Get Special Savings, Event Announcements and the Latest Information.


text:
Why Treatment for Vesicoureteral Reflux Is Important
The good news is that VUR doesn't present immediate problems and may improve or resolve as your child gets older. But without treatment, it could allow a bladder infection to progress into a kidney infection. Our pediatric urology providers often recommend a treatment plan that starts with monitoring the bladder and kidneys and may include prescribing antibiotics to prevent urinary tract infections (UTIs). In severe cases, your child's provider may recommend surgery to cure the VUR and avoid permanent damage to the kidneys.


text:
- Home
- Kilts and Highland Wear
- Kilt Jackets and Waistcoats
- Men's Tartan Waistcoat
Product Description
The Mens Reiver Tartan Waistcoat is made from our Reiver 10 oz light weight tartan fabric and is fully tailored in the UK. They come with the following features:
- 100% 10 oz Reiver Wool
- 5 Button Closure
- Plain Satin Type Lining & Plain Buttons
- Sizes 38-52 (Short, Regular and Long fittings)
- Dry Clean Only
The make-up time for waistcoats is currently 6 weeks. Please take this into consideration if required for a specific date.
Please note: custom made/bespoke items are excluded from the returns policy except for when a genuine defect has been identified.
The tartan waistcoat featured in the photograph is in the MacRae Red Modern tartan (MCR/M).
Product Reviews
Write Review


text:
At level up aesthetics, we don't just try and look like we lift. We actually develop the strength that goes in accordance with the look. In this post, I am going to break down why strength is equally important in 3 simple thoughts.
1. Numbers don't lie
When you're challenging yourself week after week, the challenge will literally cause you to feel like you're becoming a better you. There is absolutely no way to dispute the fact that you're improving. When your strength goes up it shows up in the weight you're lifting.
2. Strength correlates to how you look
There is a strong correlation between your strength and aesthetics. When you're lifting heavier your body becomes better. This, of course, comes in addition to proper proportions and diet.
3. Primal confidence
We don't live in a world where strength is essential for survival. However, I believe we still have primal instincts embedded within us. So by having the strength, you feel much more confident in your ability to protect.
The common thought is that by purely having aesthetics you will attract women. I have found women are primarily attracted to a man's behavior (aesthetics are important for the initial 30 seconds, but behavior takes you the distance).
So the strength you develop actually helps you tap into the dominant side which can unlock a lot of attractive behaviors.


text:
Exceptional Chiropractor Wanted- Memphis, TN
We are looking for a great doctor to be a part of a successful family/wellness-based practice here in the Midsouth. Learn how to communicate the need for corrective chiropractic and the benefits of wellness care. Learn how to get new patients in the door and get them started under your care. Build your confidence and proficiency as a doctor in a family friendly environment where people go to get well. Learn the system that Dr. Wootton (a millennial) used to pay back his student loans in under 6 years after graduating. If you are positive, outgoing, energetic and teachable doctor then we are looking for you! This position includes: salary, percentage bonus, vacation, retirement and priceless information on how to run and own your own successful practice.
Check out our website at: www.woottonfamilychiro.com


text:
Trending News
Must Reads
Most Popular
Most Popular
Great Finds
More sections
By date
Log into your Newser account
Forgot your password
Logging in
Joined Newser on:
Email Subscriptions
Find what you're looking for
More about Newser:
About Us
Contact Us
Terms of Use
Privacy Policy
Site Map
Want to contribute?
Suggest a Story
Our apps:
iPhone iPad
Stories 1 - 20 |
Next >>
100 Dead Rabbits and a 'Village Gripped by Fear'
Who's killing the bunnies in Minihy-Treguier?
- A French town is being terrorized by a serial killer—but humans aren't the target. The
reports that someone in the village of Minihy-Treguier has so far slaughtered more than 100 rabbits, slipping into residents' yards, yanking rabbits out of their hutches, and either stomping them to death...
More »
27 Rabbits Abandoned at Train Station
Officials in Long Island are eager to know who did this
- Officials in Long Island, New York are offering a reward for information leading to the person or people responsible for dumping 27 rabbits by a Suffolk County train station, per the AP. The Suffolk County Society for the Prevention of Cruelty to Animals says it was notified on Sunday that...
More »
You Can Buy Mike Pence's Bunny Book. Or You Can Buy John Oliver's
'Last Week Tonight' is trolling the VP, for a couple of good causes
- John Oliver did a segment on Mike Pence during Sunday's episode of
Last Week Tonight
, focusing mostly on all the positions the vice president holds that Oliver finds distasteful—among them his opposition to women in the military, abortion rights, and LGBT rights. But Oliver promised Pence supporters he'...
More »
SPCA Needs Help After Cops Find 286 Rabbits at One Home
That's 284 over the city limit in Sacramento
- A Sacramento animal shelter is seeking supplies and cash donations to care for nearly 300 rabbits taken from a single property. FOX40 reports the bunnies are of varying ages and not available for adoption, at least not yet, because they're part of an investigation. Folsom Police Department Det. Donald...
More »
Who Poisoned the Bunnies of Las Vegas?
Dozens are dead, and volunteers are angry at the state
- Volunteers who showed up at a state mental health facility in Las Vegas over the weekend to help care for wild rabbits that roam the grounds came across a disturbing sight: about 50 dead rabbits, reports the A P. The volunteers also found vegetables they suspect were coated in antifreeze,...
More »
Against an Inferno, Man Rescues the Smallest Creature
Wild rabbit saved
- Whether you consider it brave or foolish, it's tough not to consider it incredible. NBC News has video of a driver who pulled over on California's Highway 1 near La Conchita to save a wild rabbit from the blazing wildfire that's painting the backdrop orange. As the...
More »
Wild Rabbits Surf on Sheep to Flee New Zealand Flood
'The rabbits had a jolly good try at staying on'
- It was a woolly ride, but three wild rabbits managed to escape rising floodwaters in New Zealand by clambering aboard sheep and surfing to safety on their backs, the AP reports. Ferg Horne, 64, says he's been farming since he left school at age 15 and has never seen...
More »
Your Pet Is Fleecing You
Survey finds that we grossly underestimate the tens of thousands our pets cost us
- You might want to drop man's best friend a bill: It turns out that not only is your dog chewing holes in your socks, he's eating a hole in your wallet—a much bigger one than you think, reports CNBC . According to a survey of pet owners by...
More »
Suspiciously Playful Bunny Is Pot Grower's Undoing
Pinpon unwittingly led authorities straight to the marijuana plants
- One girl's pet bunny in Huaura, Peru, apparently had a hard time playing it cool when he stumbled onto a secret marijuana stash in a neighboring home; he seemed suspiciously frisky every time he returned from his recurring escape. So she took it upon herself to follow her little...
More »
'Traumatizing' Rabbit Classic Getting a Remake
Ben Kingsley, John Boyega to star in 'Watership Down'
- Ben Kingsley has played Gandhi, Sweeney Todd, and now … a rabbit? The esteemed English actor will team up with John Boyega (Finn in
Star Wars: The Force Awakens
) to star in an animated remake of what Indiewire calls "everyone's favorite traumatizing book for children": Richard Adams' 1972...
More »
US Cases of Dangerous 'Rabbit Fever' Are Spiking
It's spread to people through contact with infected animals, ticks
- A disease thought to have the potential for use in biological warfare is on the rise in the US. The CDC warns that the rare bacterial disease "rabbit fever," or tularemia—spread by ticks and rabbits—has turned up in 100 people across four states as of Sept....
More »
Washington Town's Woe: Bunnies and Their Feces
Hundreds of rabbits are wreaking havoc on this island hamlet
- Apparently the rabbits on Washington state's Whidbey Island are going at it like, well, rabbits. The population in the town of Langley, home to barely more than 1,000 humans, is now numbering into the hundreds, reports NBC News , with residents saying "we've never seen it like...
More »
News Anchor Loses It During Kardashian Segment
"This family, I'm sick of this family!": Florida's John Brown
- It can be mentally and emotionally draining being a news anchor. It surely must take a toll on your soul to report day in and day out on the complexities of ISIS, the Iran nuclear deal—and, for one Florida newscaster, the Kardashians. Viewers witnessed John Brown's distress over...
More »
Radio DJ Kills Bunny With Bicycle Pump Live on Air
To provoke debate about 'hypocrisy' of animal welfare debate
- A Danish radio DJ chose a controversial way of drawing attention to what he sees as the flawed debate over animal welfare: He hit a 9-week-old rabbit named Allan three times with an iron bicycle pump while on the air Monday, then wrung its neck. Later, Asger Juhl of Radio24syv...
More »
DEA Agent Warns Utah of Pot-Crazed Rabbits
He argues against legalization of medical pot
- People who advocate legalizing medical marijuana in Utah clearly haven't given much thought to the risk of pot-crazed rabbits running wild, a DEA agent testified last week. Special Agent Matt Fairbanks told a state Senate hearing about how in the course of his marijuana eradication work, he had encountered...
More »
High School Teacher Kills, Skins Rabbit in Class
Idaho district apologizes after parents complain
- A high school science lesson got a little too graphic for some students and parents in Idaho: A 10th-grade biology teacher has apologized after bringing a rabbit into class, breaking its neck, and then skinning it in front of the class, reports KTVB . The teacher didn't clear the lesson...
More »
Feds Demand Magician Submit Rabbit 'Disaster Plan'
USDA backtracks on rule after case publicized
- Marty the Magician is no stranger to red tape—the Department of Agriculture has long required him to have a license for the rabbit he uses in his act—but even he was surprised when the government ordered him to pull a rabbit disaster plan out of his hat. Under...
More »
Celeb Bunny Meets Untimely Demise
Earless German rabbit stepped on by cameraman
- An earless baby bunny that was a rising star on Germany's celebrity animal scene had his 15 minutes of fame brought to an abrupt end when he was accidentally stepped on by a television cameraman. The fate of 17-day-old Til, a bunny with a genetic defect, was plastered across...
More »
Giant Bunny Fossils Discovered Off Spain
'King of rabbits' was 6 times the size of modern bunnies
- On the Spanish island of Minorca up to 5 million years ago, the rabbit was king. Researchers there have discovered fossils belonging to the biggest-ever member of the bunny family, LiveScience reports.
Nuralagus rex,
weighing in at
some 26 pounds—about six times the size of modern rabbits—had largely...
More »
In China, Bunny Frenzy Breeds Trouble
Buyers scramble for lucky but troublesome pets for Year of the Rabbit
- The Year of the Rabbit begins tomorrow, and China is facing something that wasn't an issue for the Year of the Tiger: a surplus of New Year pets. Rabbits represent beauty and wealth in Chinese tradition, and the country has seen a frenzy of rabbit-buying in recent weeks. But many...
More »
Stories 1 - 20 |
Next >>
Popular on Newser
Shelter: We Have the 'World's Worst Cat'
Border Patrol Bulldozes Iconic Garden
Kobe Bryant, Daughter Dead in Helicopter Crash
Cops Find Missing Teenager as Psychics Had Predicted
Philanthropist Makes $1B Promise
On This Day:
January 26
10 Years of Headlines


text:
*** POTENTIAL TO EXTEND (STPP) This three bedroom DETACHED home has been maintained to a very high standard by the current owners. The property is situated on a CORNER PLOT in a popular residential area, close to well-regarded SCHOOLS and local amenities. The accommodation comprises of a spacious living/dining room, kitchen, downstairs cloakroom and a family bathroom. Outside there are well tended gardens and a driveway leading to garage. Offered for sale with NO ONWARD CHAIN
Please call us on 01344 860 121 orRequest a Viewing


text:
Down Syndrome – Genetic ConditionDown syndrome is a genetically inherited disorder which affects 1 in 800 live births in America every year. Down syndrome is the most common genetic condition present right at birth. The exact causes of the disorder are unknown but it is clear that the affected individuals inherit additional genetic material at conception. Instead of inheriting 23 chromosomes from the mother and 23 from the father, one whole additional chromosome 21 is passed down to the embryo. In some milder forms of the syndrome only parts of the additional chromosome 21 are inherited. The extra genetic material is responsible for physical and mental developmental delays. It is, however, very difficult to estimate the extent of the condition right at birth. Some Down syndrome patients live relatively healthy lives while others require long term medical care. In addition, children with the condition learn at different pace and reach developmental milestones later than the general population. With proper care and early intervention programs which include physical, occupational, and speech therapy the child will reach his or her full potential and live as fulfilling a life as possible. Mild to moderate cognitive impairment is observed as well but many learn to take care of themselves and lead relatively independent lives. When it comes to the physical symptoms of Down syndrome, individuals are characterized by short torsos and limbs, flat facial profiles, small ears, long tongues and small mouth. The disorder is usually accompanied by an array of medical problems. In many cases persons are affected by respiratory, gastrointestinal, and heart defects. Heart problems have to be diagnosed right at birth and surgery may be required to remove the anomalies. Long term medication is often necessary to maintain proper functioning of the heart. Many Down syndrome patients are also susceptible to infections and more often than not have low muscle tone. Hearing and vision problems are also commonly detected.
Birth Complications with Down SyndromeAlthough the exact causes are unknown risk factors for Down syndrome have been identified. There is a strong correlation between the age of the mother and the presence of Down syndrome. Women over the age of 35 have a much greater chance of having a developmentally challenged child than their younger counterparts. The risk keeps on increasing with age. As the condition is so common, regular screening for Down syndrome is available for couples. The screening is primarily performed to give the prospective parents the opportunity to decide whether to keep or terminate the pregnancy or to prepare for raising a child with special needs. The screening is therefore administered during the first trimester of the pregnancy. Blood tests are often enough to point to the presence of certain hormones and proteins that reveal the condition. The initial screening has been proven 87 percent effective. Those who follow up in the second trimester receive results that are 95 percent accurate. It should be noted that screening is not done for diagnostic purposes but to assess the chance that the child has for having inherited additional genetic material.
Medical Conditions Associated with Down SyndromeThe most prevalent medical problems that follow Down syndrome are heart anomalies. Almost half of the diagnosed individuals have congenital heart problems. The most widespread heart condition is the septal defect, which is present in 9 out 10 cases. The septal defect is characterized by a hole in the wall that separates the chambers of the heart. The condition results in blood build up in one of the chambers, which puts a strain on the organ. Those with only minor problems require minor procedures, while the more severe cases go through open heart surgery to fix the anomaly. Another very common health concern is the loss of hearing. Almost 50 percent of Down syndrome individuals have issues with the middle ear. Excess fluid builds up and distorts the ability to hear. As a result the child will have difficulties learning to speak as the sounds are muffled and deformed. Surgery or hearing aids are the primary form of treatment coupled with regular sessions with a speech therapist. In addition, Down syndrome individuals often suffer from vision problems. They are short sighted, long sighted, or have a condition called lazy eye where one of the eyes does not develop properly and does not possess strong focusing ability. Other common eye problems are cataracts and proneness to eye infections. Many patients also suffer from tooth decay and poor oral health. The teeth are progressively broken down by bacteria or the gums are severely infected. Down syndrome individuals often have weak motor skills preventing them from being able to brush their teeth properly. Also, their levels of saliva are lower, making the gums and teeth more prone to bacterial infections. High fluoride toothpaste is often recommended for prevention. Electric tooth brushes might be easier than the manual ones, and some persons need help with brushing their teeth.


text:
Love this item?
Subscribe to unlock this item and 1,900,000 web, design & stock assetsEnjoy Unlimited Downloads
Already an Envato member?
Sign in here.
Sign in here.
This graphic resource allows you to apply a retro / vintage style in your text, shape or logo vector. You just need to replace them into the Smart Object of your favorite style! Each Retro Text Effect have been created with care with the finest details. All elements are clearly labeled and in organized folders.
- 12 PSD Files
- 2000×1500 px
- Smart Object Replacement
- 100% Editable
- Color is easily changed
- Elements labeled in organized folders
- Help File
Please Note:
- These are a Photoshop® Files. Adobe Photoshop® CS4 or + is required to open these files and edit them.
- Links to download these fonts are available in the Help File.
Applications SupportedAdobe Photoshop
File TypesPSD
Color SpaceRGB
Dimensions2000(w) × 1500(h) px
- Documentation Included
- Layered
Commercial LicenseFurther Information
Similar Graphic TemplatesSee more
More from Easybrandz2See more
Stay up to date with design trends. New items added daily