Like Burrs On Your Clothes, Molecule-size Capsules Can Deliver Drugs By Sticking To Targeted Cells

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Cornell University (2009, August 11). Like Burrs On Your Clothes, Molecule-size Capsules Can Deliver Drugs By Sticking To Targeted Cells, ScienceDaily. – It is now possible to engineer tiny containers the size of a virus to deliver drugs and other materials with almost 100 percent efficiency to targeted cells in the bloodstream.

 

According to a new Cornell study, the technique could one day be used to deliver vaccines, drugs or genetic material to treat cancer and blood and immunological disorders. The research is published in the journal Gene Therapy.

“This study greatly extends the range of therapies,” said Michael King, Cornell associate professor of biomedical engineering, who co-authored the study with lead author Zhong Huang, a former Cornell research associate who is now an assistant professor at the Shenzhen University School of Medicine in China. “We can introduce just about any drug or genetic material that can be encapsulated, and it is delivered to any circulating cells that are specifically targeted,” King added.

 

The technique involves filling the tiny lipid containers, or nanoscale capsules, with a molecular cargo and coating the capsules with adhesive proteins called selectins that specifically bind to target cells. A shunt coated with the capsules is then inserted between a vein and an artery. Much as burrs attach to clothing in a field, the selectin-coated capsules adhere to targeted cells in the bloodstream.

 

After rolling along the shunt wall, the cells break free from the wall with the capsules still attached and ingest their contents.

 

The technique mimics a natural immune response that occurs during inflammation, which stimulates cells on blood vessel walls to express selectins, which quickly form adhesive bonds with passing white blood cells. The white blood cells then stick to the selectins and roll along the vessel wall before leaving the bloodstream to fight disease or infection.

 

Selectin proteins may be used to specifically target nucleated (cells with a nucleus) cells in the bloodstream.

 

The study shows that since only the targeted cells ingest the contents of the nanocapsules, the technique could greatly reduce the adverse side effects caused by some drugs.

 

In a previous paper, King showed how metastasizing cancer cells circulating in the blood stream can stick to selectin-coated devices containing a second protein that programs cancer cells to self-destruct.

 

Said King, “We’ve found a way to disable the function of cancer cells without compromising the immune system,” which is a problem with many other therapies directed against metastasis.

 

The current study demonstrates that genetic material can be delivered to targeted cells to turn off specific genes and interfere with processes that lead to disease. The researchers filled nanocapsules with a small-interfering RNA (siRNA) and targeted them to specific circulating cells. When the targeted cells ingested the capsules, the siRNA turned off a gene that produces an enzyme that contributes to the degradation of cartilage in arthritis.

 

In a similar manner, the method could be used to target the delivery of chemotherapy drugs, vaccine antigens to white blood cells, specific molecules that mitigate auto-immune disorders and more, King said.


 

Journal reference:

•1.                  Huang et al. An immobilized nanoparticle-based platform for efficient gene knockdown of targeted cells in the circulation. Gene Therapy, Online June 25, 2009; DOI: 10.1038/gt.2009.76

Adapted from materials provided by Cornell University. 

Study Shows High Total Cholesterol in Midlife Could Raise Risk for Alzheimer’s Disease

Reviewed by Elizabeth Klodas, MD, FACC 

WebMD.com, Aug. 12, 2009, by Salynn Boyles — Adults with even moderately elevated cholesterol in their early to mid-40s appear to have an increased risk for Alzheimer’s disease and related dementias decades later, a new study shows.

Researchers followed more than 9,800 people for four decades in one of the largest and longest age-related dementia trials ever conducted.

They found that those with high or even borderline high total cholesterol in their 40s had a significantly increased risk for developing Alzheimer’s disease years later.

“People tend to think of the brain and the heart as totally separate, but they are not,” study co-author Rachel A. Whitmer, PhD of Kaiser Permanente Division of Research in Oakland, Calif., tells WebMD. “We are learning that what is good for the heart is also good for the brain — and that midlife is not too soon to be thinking about risk factors for dementia.”

Cholesterol and Alzheimer’s Disease

The study included 9,844 northern California residents enrolled in the same health insurance plan throughout the study.

Close to 600 had developed either Alzheimer’s disease or a related condition known as vascular dementia by the end of the study, when they were in their 60s, 70s, and 80s.

Total cholesterol in the high range at study entry was associated with a 66% increase in Alzheimer’s risk, while having borderline high cholesterol raised the risk for vascular dementia by 52%.

According to current guidelines, total cholesterol of 240 or higher is considered high, and a cholesterol of 200 to 239 is considered borderline high.

The researchers did not have information on HDL “good” and LDL “bad” cholesterol because the significance of these different types of lipids was not widely understood four decades ago.

But it is safe to assume that most people whose total cholesterol was high had high levels of bad cholesterol because about two-thirds of total cholesterol reflects LDL, Whitmer says.

Good for Heart, Good for Brain

The study, conducted by researchers with Kaiser and Finland’s University of Kuopio, is one of the first to examine risk for vascular dementia, a group of dementia syndromes associated with reduced blood supply to the brain.

Lead author Alina Solomon, MD, of the University of Kuopio tells WebMD that the study adds to the growing evidence that controlling heart disease risk factors like cholesterol, blood pressure, diabetes, and weight in midlife can protect the brain in old age.

“Keeping your weight down, eating right, and getting regular exercise can keep your heart healthy as you age, and it may also keep your brain sharp,” she says.

Alzheimer’s Association Chief Medical and Scientific Officer William H. Thies, PhD, agrees that it is increasingly clear that lifestyle influences risk, even among people who have a genetic predisposition for developing late-life dementias.

“We can’t really say how much of risk is lifestyle and how much is genetic,” he says. “We know that most patients with Alzheimer’s also have vascular disease and that the risk factors for vascular disease are modifiable with lifestyle.”

Making Changes to Lower Risk

Computer specialist James Pitman, 44, has gotten the message and is making lifestyle changes to bring his high cholesterol down in hopes of reducing his risk for heart disease, diabetes, and dementia later in life.

The Oakland, Calif., resident, who has a family history of diabetes and Alzheimer’s disease, has lowered his total cholesterol from 280 to 260 by eating better and revamping his exercise routine. He tells WebMD that he hopes to lower his numbers more by making additional changes.

“I didn’t exactly win the genetic lottery, so I will probably have to go on drugs eventually to lower my cholesterol,” he says. “But I am going to do all I can with diet and exercise.”

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FOR IMMEDIATE RELEASE
Wednesday, Aug. 12, 2009                                  

NIAID Scientists View Past Flu Pandemics for Clues to Future Course of 2009 H1N1 Virus

Flu Viruses Notoriously Unpredictable; Robust Pandemic Preparedness Efforts Crucial

 

A commonly held belief that severe influenza pandemics are preceded by a milder wave of illness arose because some accounts of the devastating flu pandemic of 1918-19 suggested that it may have followed such a pattern. But two scientists from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, say the existing data are insufficient to conclude decisively that the 1918-19 pandemic was presaged by a mild, so-called spring wave, or that the responsible virus had increased in lethality between the beginning and end of 1918. Moreover, their analysis of 14 global or regional influenza epidemics during the past 500 years reveals no consistent pattern of wave-like surges of disease prior to the major outbreaks, but does point to a great diversity of severity among those pandemics.

In their commentary in the Aug. 12 issue of the Journal of the American Medical Association, David M. Morens, M.D., and Jeffery K. Taubenberger, M.D., Ph.D., note that the two other flu pandemics of the 20th century, those of 1957 and 1968, generally showed no more than a single seasonal recurrence; and in each case, the causative virus did not become significantly more pathogenic over the early years of its circulation.

The variable track record of past flu pandemics makes predicting the future course of 2009 H1N1 virus, which first emerged in the Northern Hemisphere in the spring of 2009, difficult. The authors contend that characteristics of the novel H1N1 virus, such as its modest transmission efficiency, and the possibility that some people have a degree of pre-existing immunity give cause to hope for a more indolent pandemic course and fewer deaths than in many past pandemics.

Still, the authors urge that the 2009 H1N1 virus continue to be closely tracked and studied as the usual influenza season in the Northern Hemisphere draws near. Like life, the authors conclude, paraphrasing Danish philosopher Soren Kierkegaard, “influenza epidemics are lived forward and understood backward.” Thus, the robust, ongoing efforts to meet the return of 2009 H1N1 virus with vaccines and other measures are essential responses to a notoriously unpredictable virus.

ARTICLE:   DM Morens and JK Taubenberger. Understanding influenza backward. Journal of the American Medical Association 302: 679-80. DOI: 10.1001/jama.302.6.679 (2009).

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China has become a huge supplier of drug and device components and finished products – and associated quality problems have made headlines worldwide. If you are considering or already using a Chinese supplier, what can you do to research the company — and not end up a headline yourself?

Here’s a terrific resource you may not have considered: Let FDA help you do your research!

 

Any Chinese firm exporting medical products to the US is subject to FDA inspection, and the resulting Establishment Inspection Reports (EIRs) and 483s give an insider’s look at a plant: the history of the firm, the names of the top executives, a description of their operations, and, of course, the FDA Investigator’s assessment of their conformance to quality regulations. Finally, the EIR includes a “Discussion with Management” that, when read carefully, can give you real insight into the personality of the firm and management’s attitude to and comprehension of FDA regulations. FDA doesn’t put these EIRs and 483s on their own website. But by using the Freedom of Information Act, FOI Services has built up a good collection of these revealing documents for you to download on the spot.

 

Have a look right now! We’ve put together a sampling of document descriptions for our bestselling Chinese EIRs and 483s – just go to our home page at www.foiservices.com and click on the Chinese flag in the left hand column. Be sure to look over each entry – we’ve included a typical EIR for you to download at no charge!

 

Researching Chinese firms is notoriously difficult: save yourself time, frustration, and potentially devastating quality problems – take advantage of the documents your competitors have found extremely valuable in their own due diligence.

 

As always, if you’d like help finding or ordering a document, you are welcome to call at +1-301-975-9400; our information specialists are here to assist you.

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Search & download unpublished FDA documents acquired under the Freedom of Information Act,
browse hot topics, and learn from teleconferences by leading regulatory experts

The FOI Online library consists of over 118,000 drug, device, and other FDA related documents. Click on a document type below for a detailed description and sample document pages. 

For Examples of Chinese Inspection Reports Available, Take a Look Below

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  • Changzhou Pharmaceutical Factory

Jiangsu, China
October 28-31, 2002
FDA Investigators: Horan, Robert; Szestypalow, Kathy
Size of 483: 3 pages
Products: Unspecified pharmaceutical products

Pre-approval cGMP inspection of API manufacturing facility. Observations include an employee cleaning equipment in a controlled area while wearing a band-aid and no other hand covering. Document contains the firm’s well-written, point-by-point response to the 483.

Order No. 5221674A – $89.95 per copy

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  • Shanghai Medicinal Factory #15

Shanghai, China
October 27-31, 2003
FDA Investigators: Horan, Robert; Ting, Susan
Size of 483: 3 pages
Products: Unspecified pharmaceutical and veterinary products

For cause inspection initiated as a cGMP inspection covering all products made at this facility. The firm’s compliance status was OAI (Official Action Indicated) following an inspection the previous year. This 2003 follow-up inspection found significant data integrity problems, as well as several cGMP deficiencies. A separate section of the EIR was dedicated to the data integrity concerns, which left the investigators with the feeling that they “did not have confidence in the integrity of any of the data” they were examining. It is noted that evidence of deliberate data misrepresentation was found. The EIR also noted that a plant manager apologized for management “not having been truthful”. A copy of the company’s response to the 483 (which denies any deliberate wrongdoing) is included, along with the Warning Letter and subsequent correspondence.

Order No. 5214261F – $89.95 per copy

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  • Delta Synthetic

Taiwan, China
October 27-29, 2003
FDA Investigators: Flynn, George;
Needham, Richard
Size of 483: 3 pages
Products: Unspecified Drug Master File (DMF)

Pre-approval inspection was prompted by an unspecified NDA and an unspecified ANDA. The 483 lists 21 deficiencies, including an observation that none of the manufacturing equipment had been qualified. Also included in the file are the firm’s response to the 483 and a Warning Letter issued after receipt of the 483 response to the FDA.

Order No. 5218629B – $89.95 per copy

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  • Suzhou No.4 Pharmaceutical Factory

Suzhou, China
March 29 –
April 1, 2004
FDA Investigators: Flynn, George;
Needham, Richard
Size of 483: 3 pages
Products: Unspecified ANDA & DMF

Inspection of Active Pharmaceutical Ingredient (API) manufacturer assigned under Compliance Programs 7352.832 and 7356.002F. This inspection resulted in a recommendation for an unacceptable classification for the facility. Twelve deficiencies were noted regarding validation, instrument calibration, and impurity profile data as well as other areas. The firm’s response is included.

Order No. 5203873A – $89.95 per copy

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  • Syntec Scientific

Chang Hua, Taiwan, China
May 2-5, 2005
FDA Investigator: Masley-Joseph, Karen
Size of 483: 3 pages
Products: Non-sterile orthopedic screws and plates

Inspection of medical device manufacturer which covered the firm’s MDR practices, Management Controls, Design Controls, CAPA, and Production and Process Controls. Observations included a lack of documentation for disposition of nonconforming or returned product and a lack of written procedures for reporting MDRs to FDA.

Order No. 5237276B – $69.95 per copy


 

  • Huadong Medicine

Hangzhou, China
October 17-20, 2005
FDA Investigator: Leonin, Paraluman
Size of 483: 2 pages
Products: Unspecified ANDA

Initial inspection of Active Pharmaceutical Ingredient (API) manufacturer, which served as a pre-approval inspection for an unspecified ANDA product. The firm was deemed acceptable to manufacture, but notable deficiencies regarding documentation and SOPs were cited. In particular, the SOP for an unidentified system is said to have given no guidance as to “what should be done when any of the parameters used to monitor the system is out of specification”.

Order No. 5237223A – no charge per copy


 

  • Leshan Saniju- Long March Pharmaceuticals

Sichaun, China
October 21-25, 2002
FDA Investigators: Faul, Kent; Horan, Robert; McReavey, James; Szestypalow, Katherine
Size of 483: 1 page
Products: Gentamicin Sulfate, Oxytetracycline

This was a follow-up inspection due to the firm being under an import alert for human and veterinary products. The import alert had been prompted after a 1999 inspection raised concerns involving data integrity and significant cGMP deficiencies. Following the 1999 inspection, the firm underwent ownership and management changes and improved the manufacturing system. Based on the previous inspection, much of this 2002 inspection focused on the impurity profile for gentamicin sulfate. Though only relatively minor observations were noted on the 483, and none regarding gentamicin sulfate, the investigators remained concerned “regarding the ability of the firm’s method to achieve adequate resolution and quantitation of certain impurities”. As noted in subsequent correspondence, the firm was recommended as acceptable for manufacture of APIs with the exception of gentamicin sulfate. Leshan Saniju-Long March’s response to the 483 is included.

Order No. 5210835A – $89.95 per copy


 

  • Chongqing Daxin Pharmaceutical

Chongqing, China
September 24-25, 2001
FDA Investigators: Edwards, Charles; Henry, Yvette
Size of 483: 1 page
Products: Unspecified Active Pharmaceutical Ingredient (API) products

Here’s an example of an inspection that went well. This was a GMP Qualifying Inspection done in accordance with CP 7356.002F. Though four observations were noted, the firm’s corrections were already noted on the 483 when it was prepared.

Order No. 5217242B – $69.95 per copy



 

  • Huzhou Zhanwang Chemical Pharmaceutical

Huzhou, Zhejiang, China
October 31 –
November 3, 2005
FDA Investigator: Paraluman, Leonin
Size of 483: 1 page
Products: Unspecified ANDAs

Pre-approval and cGMP inspection of Active Pharmaceutical Ingredient (API) manufacturer. Two significant observations regarding documentation and incomplete laboratory records were noted, and two non-483 findings were also discussed with management. Following the inspection and the firm’s response to the 483, FDA emphasized that the firms’ corrective actions would be further evaluated at the next inspection.

Order No. 5238172C – $89.95 per copy


 

  • Tianjin Xin Xin Pharmaceutical

Tianjin, China
September 4-7, 2000
FDA Investigators: Campbell, Karyn; Laska, Susan; Ting, Susan
Size of 483: 4 pages
Products: Unspecified Active Pharmaceutical Ingredients (APIs)

Follow-up compliance inspection following February 2000 Warning Letter and Import Alert that resulted from a prior inspection. This current inspection resulted in recommendations for a continued Import Alert and an Untitled Letter. Significant findings involving incomplete process validation were noted and previous objectionable conditions were found not to have been corrected sufficiently. One example is the firm’s investigation into previously returned lots, which were returned due to metallic particles. Investigators found that no attempt had been made to ensure prevention of future occurrences. File includes Tianjin Xin Xin’s response to the 483, a subsequent, seven-page December 2000 Warning Letter, firm’s response to the Warning Letter, and, finally, FDA’s response which reflects a still-incomplete satisfaction with the firm’s processes.

Order No. 5217486B – $89.95 per copy


 

  • Jiangsu Heingrui Pharmaceutical

Lianyungang, Jiangsu, China
September 11-13, 2000
FDA Investigators: Campbell, Karyn; Laska, Susan; Ting, Susan
Size of 483: 4 pages
Products: Unspecified Active Pharmaceutical Ingredients (APIs)

Compliance follow-up inspection following a June 2000 Warning Letter. Jiangsu Heingrui’s response to the previous 483 and Warning Letter were deemed “deficient”. At the conclusion of this September 2000 inspection, the firm was still listed as unacceptable for manufacturing APIs. The 21 observations on the 483 include inconsistent impurity analysis, no annual review of records or quality investigations, inadequate process validation and inadequate analytical methods validation. During discussion between management and the investigators, the QC Director admits that “there is no mechanism for quality to be notified or a controlled system for investigations”. A November 2000 Warning Letter was issued after receipt of the firm’s 483 response, requesting an Import Alert. This file includes the 483 response, the November Warning Letter, and the firm’s response to the Warning Letter.

Order No. 5217664B – $89.95 per copy


 

  • Fujian Fukang Pharmaceutical

Fuzhou, China
March 24-27, 2003
FDA Investigators: Cantellops, Dennis; Flynn, George
Size of 483: 1 page
Products: Gentamicin Sulfate, Chlortetracycline HCl, Chlortetracycline Feed Grade

Inspection of API manufacturer for pharmaceutical and veterinary products conducted in accordance with CP 68001 and CP56002F. The investigators compliment the firm’s preparation for the inspection, but do note 9 deficiencies regarding degradation studies, product annual review, and integrity testing, among other areas.

Order No. 5217325B – $69.95 per copy


 

  • Xinjiang Pharmaceuticals

Xinjiang, China
September 18-19, 2000
FDA Investigator: Laska, Susan
Size of 483: 1 page
Products: Unspecified Active Pharmaceutical Ingredient (API)

Surveillance GMP inspection. This was the initial inspection of this API manufacturer and revealed that the firm was operating with no process validation, no documentation of investigations into out-of-specification results, no impurity profile, and deficient analytical methods, among other issues. The 483 lists 11 observations. Upon finding the firm’s 483 response inadequate, FDA issued a Warning Letter in December 2000. Both follow-up documents are included in this file.

Order No. 5217485B – $89.95 per copy


 

  • Tianjin Zhong Xin Pharmaceutical

Tianjin, China
November 17-20, 2003
FDA Investigators: Dickinson, Gwyn; Faul, Kent
Size of 483: 3 pages
Products: Unspecified Active Pharmaceutical Ingredients (APIs)

Pre-approval and cGMP inspection of a firm with a history of significant deficiencies and warning letters. This inspection was a follow-up to a 2000 inspection and Warning Letter. The EIR details the current inspection and findings, as well as a good deal of the previous observations and corrections. Investigators found that most of the 2000 deficiencies had been corrected, and noted the firm’s positive attitude toward compliance, but cited continuing problems with inadequate test methods. No Warning Letter was issued and the firm was declared acceptable for manufacture of the relevant APIs.

Order No. 5214261G – $89.95 per copy