New Developments in the Treatment of PAH

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New Developments in the Treatment of PAH  CME/CE

Disclosures

Susan P. Steinbis, MSN, NP-C   

A progressive vasculopathy is the wording used to describe pulmonary arterial hypertension (PAH). Pulmonary hypertension is a disease that affects the pulmonary vasculature, leading to right ventricular failure with devastating consequences for those affected. Historically, treatment has been limited and complex with the continuous intravenous (IV) administration of epoprostenol. The end of 2001 introduced the first oral therapy, bosentan, and then 2002 produced treprostinil, a continuous, subcutaneous prostacyclin analogue. Since then, numerous studies have been conducted evaluating new therapies, subsequently leading to the approval of newer agents.

What's New?

So what is in our arsenal now in 2005? This year has been an exciting year for new therapies in the treatment of PAH. Iloprost, another prostacyclin analogue, was approved for the treatment of World Health Organization (WHO) class I PAH with New York Heart Association (NYHA) functional class III or IV. Like epoprostenol and treprostinil, it exerts its effect on the prostacyclin pathway but is administered via inhalation through the Prodose AAD System, a breath-actuated drug delivery device. It is given in 6 daily doses with the option to administer up to 9 times a day, if needed. The side-effect profile is better than that for other prostanoids as iloprost is not administered systemically, but headache, cough, and flushing are common. Syncope has been reported but is thought to be secondary to sudden activity in the morning before the first therapy is administered. In a randomized, double-blind study, at Week 12, iloprost was shown to have a 40-meter improvement in 6-minute walk distance (6MWD) from baseline when compared to placebo. The endpoint of the clinical trial was at least a 10% increase in 6MWD when compared to baseline and improvement of at least 1 NYHA functional class vs baseline with no death or clinical worsening. When all these endpoints were combined, iloprost demonstrated a 19% improvement over placebo.

Treprostinil was first approved as a subcutaneous therapy in 2002 and is now available in an IV preparation. Vallery McLaughlin, MD, reported the 1-year data on IV treprostinil at CHEST 2005. After receiving an infusion lasting 48 hours with a half-life of 4.5 hours, 16 de novo patients experienced an 80-meter increase in 6MWD at 12 weeks. At 1 year, the de novo group had a total improvement in 6MWD of 125 meters with a decrease in mean pulmonary artery pressure (mPAP), an increase in cardiac index, and a decrease in pulmonary vascular resistance (PVR) by half. Thirty-four of 41 patients in the transition group (IV epoprostenol to IV treprostinil) completed the 1-year study. At the end of the 12 months, the transition group maintained stability in 6MWD and in hemodynamics. Chronic IV treprostinil therefore is assumed to provide sustained improvement in exercise capacity and hemodynamics. Of note, more than twice the dose was needed for treprostinil when compared to epoprostenol, with a mean dose of 98 ng/kg/min in the de novo group and 111 ng/kg/min in the transition group.[1]

Multiple Pathways

Much discussion has centered around the multiple pathways involved in pulmonary hypertension. The nitric oxide pathway has been the most recently addressed pathway in the treatment of PAH. Sildenafil was approved this year as a PDE-5 inhibitor. At CHEST 2005, Lalaine Corate, MD, and Namita Sood, MB, BCh, discussed the use of sildenafil in patients with right heart failure and PAH. Both noted improvements with either 50 mg or 100 mg every 8 hours. The use of sildenafil in the acute setting with long-term follow-up demonstrated a mean increase in 6MWD at > 4 weeks with a mean decrease in oxygen by 2 LPM. There was also improvement in WHO functional class but 4 of 14 patients on the 100-mg regimen needed additional therapy at 5 or more months and 1 patient died before the end of 1 year secondary to progression of disease.[2,3]

David Badesch, MD,[4] reviewed data from the SUPER-1 study, a clinical trial involving 278 patients who received 20-, 40-, or 80-mg doses of sildenafil citrate; 6MWD was used as an endpoint. At the end of the 12-week period, patients on the 20-mg dose had a 45-meter improvement in 6MWD and the 80-mg group had a 50-meter improvement in distance. The sildenafil group also experienced an improvement in NYHA functional class vs the placebo group. The mPAP and PVR demonstrated continued improvement with 80 mg sildenafil vs 20 mg, and the cardiac output also increased to a greater degree with 80 mg than with 20 or 40 mg. The side-effect profile includes headache, flushing, diarrhea, and dyspepsia.

Martin C. Brown, MD,[5] reviewed data evaluating the long-term benefits of sildenafil on the quality of life (QOL) in patients with PAH. The same patients that were enrolled in SUPER-1 were evaluated, and data were collected using the SF-36 and the EuroQoL (EQ-5D) questionnaires. Improvements in physical functioning, general health, and vitality were statistically significant after 24 weeks on sildenafil. The utility index and current health state also demonstrated a statistically significant improvement (sildenafil vs placebo), and the effect for all areas mentioned was maintained for the 24-week period and, in some domains, for up to 6 months. The physical health domains were the ones most significantly impacted by sildenafil use.

Preliminary data were released on another oral agent, sitaxsentan, a selective endothelin receptor antagonist awaiting approval from the US Food and Drug Administration (FDA). Dr. David Badesch[6] reviewed the results of STRIDE-1, a clinical trial comparing placebo, 100 mg, and 300 mg daily dosing of sitaxsentan. Two patients experienced elevation of liver function tests (LFT) to > 3 times the upper limit of normal (ULN). At week 12, both doses demonstrated an increase in 6MWD, a decrease in mPAP, an increase in cardiac index, and a decrease in PVR. However, researchers felt that the 300-mg dose was a significant overdosing of the medication since the 100-mg dose did not demonstrate an increase in LFT over the 12-week period. In the extension study, 4 of 79 patients experienced an elevation of LFT > 3 times ULN. Adverse events included headache, peripheral edema, nausea, nasal congestion, and elevated international normalized ratio (INR). Final data for STRIDE-2 are still pending, but preliminary data suggest that sitaxsentan at a dose of 100 mg daily may improve the time to clinical worsening for NYHA functional class II-IV.

In STRIDE-2, there were 4 arms of the study evaluating placebo, 50 mg sitaxsentan, 100 mg sitaxsentan, and traditional dosing of bosentan (for adults, 62.5 mg twice daily for 4 weeks, then increased to 125 mg twice daily; and for patients who weigh less than 40 kg [88 lbs] and who are over 12 years of age, 62.5 milligrams twice daily). Warfarin dosing must be monitored with this medication, and if the patient is on warfarin at the time of initiation of sitaxsentan, the dose should be decreased by 80% with monitoring of INR until therapeutic again on anticoagulant therapy. If warfarin and sitaxsentan are initiated together, warfarin should be initiated at a dose of 0.5 to 1 mg and titrated up to the goal INR.[6]

With these new therapies now available, the question becomes, "Where are we going with therapy now, and is combination therapy a good option?" Quite a few lectures at CHEST 2005 discussed combination therapy and associated outcomes. Vallery McLaughlin, MD,[7] discussed the addition of iloprost to bosentan in the STEP study. The objective of this trial was to evaluate safety and efficacy of dual therapy. Participants were randomized to receive iloprost (n = 32) or placebo (n = 33). The first part of the trial consisted of a 12-week blinded study with patients on stable-dose bosentan for a minimum of 16 weeks. Most patients were NYHA functional class III. The iloprost group experienced a 30-meter increase in 6MWD at the end of the 12 weeks, and the placebo group demonstrated a minimal increase of 4 meters. At 12 weeks, the iloprost group also demonstrated a 34% improvement in NYHA functional class vs 6% in the placebo group.

Sildenafil add-on therapy for patients receiving bosentan for the treatment of PAH, WHO class I, was reviewed by Stephen Mathai, MD.[8] Of the 98 patients receiving bosentan, 26 also received sildenafil for clinical worsening of symptoms. The patients were NYHA functional class II-IV. Of the 26 patients receiving sildenafil, 14 had idiopathic pulmonary arterial hypertension (IPAH) and 12 of those had scleroderma-associated PAH. At the end of the clinical trial, those with IPAH receiving bosentan and sildenafil demonstrated improvement in 6MWD whereas the 12 with scleroderma-associated PAH did not improve. There were 2 deaths in the scleroderma group. More than 20% of the patients stopped therapy secondary to side effects from sildenafil. Limitations of the study, Mathai stated, were the limited number of patients, lack of hemodynamics prior to the addition of sildenafil, selection bias, and the fact that it was not a controlled study.[8]

On the Horizon

So what's on the horizon for the treatment of PAH? While the FDA analyzes data from the STRIDE-1 and -2 studies and we await approval of sitaxsentan, other therapies are being evaluated. Myogen is currently conducting studies with ambrisentan, another selective endothelin receptor antagonist. Lewis Rubin, MD,[9] reviewed preliminary 12-week data that showed a decrease in right atrial pressure, mPAP, and PVR and an increase in cardiac index with ambrisentan use. Dr. Badesch later elaborated on this study, explaining that the 4 doses of ambrisentan that were evaluated (1.0, 2.5, 5.0, and 10.0 mg) resulted in an increase in 6MWD of at least 32 meters at Week 12. Data from all doses combined at Week 24 demonstrated approximately a 50-meter increase in 6MWD, with the IPAH group demonstrating greater improvement than the secondary PAH group. WHO functional class was also noted to improve. Adverse events noted were peripheral edema, upper respiratory infection, nasal congestion, headache, nausea, and flushing, with < 4% elevation of LFT.[4]

Inhaled treprostinil is also being evaluated and tadalafil, a long-acting PDE-5 inhibitor, has drawn attention. Clearly, further studies will have to be conducted and the PAH community will continue to strive to find the right medication combinations for those affected by this devastating condition. Research will also focus heavily on the cause of PAH as more is understood about the underlying pathophysiology. Future areas of study may also center around 2-methoxyestradiol, vasoactive intestinal polypeptide, and maybe even imatinab mesylate.

References

McLaughlin V. One year experience with intravenous treprostinil in pulmonary arterial hypertension patients. Program and abstracts of CHEST 2005: 71st Annual Meeting of the American College of Chest Physicians; October 29 - November 3, 2005; Montreal, Quebec, Canada. Abstract 1722.Corate L, The use of sildenafil in the acute treatment of patients with severe pulmonary arterial hypertension and right heart failure. Program and abstracts of CHEST 2005: 71st Annual Meeting of the American College of Chest Physicians; October 29 - November 3, 2005; Montreal, Quebec, Canada. Abstract 1729Sood N. Sildenafil I acutely decompensated right heart failure secondary to pulmonary arterial hypertension. Program and abstracts of CHEST 2005: 71st Annual Meeting of the American College of Chest Physicians; October 29 - November 3, 2005; Montreal, Quebec, Canada. Abstract 1729.Badesch D. Long-term management of pulmonary arterial hypertension. Program and abstracts of CHEST 2005: 71st Annual Meeting of the American College of Chest Physicians; October 29 - November 3, 2005; Montreal, Quebec, Canada. Abstract 963.Brown M. Long-term benefits of sildenafil treatment on health-related quality of life in patients with pulmonary arterial hypertension. Program and abstracts of CHEST 2005: 71st Annual Meeting of the American College of Chest Physicians; October 29 - November 3, 2005; Montreal, Quebec, Canada. Abstract 10-31-05 ID# 1722Badesch D. Sitaxsentan improves the time to clinical worsening in patients with pulmonary arterial hypertension. Program and abstracts of CHEST 2005: 71st Annual Meeting of the American College of Chest Physicians; October 29 - November 3, 2005; Montreal, Quebec, Canada. Abstract 1722.McLaughlin V. A randomized, double-blind, placebo-controlled study of iloprost inhalation as add-on therapy to bosentan in pulmonary arterial hypertension. Program and abstracts of CHEST 2005: 71st Annual Meeting of the American College of Chest Physicians; October 29 - November 3, 2005; Montreal, Quebec, Canada. Abstract 1722.Mathai S. The addition of sildenafil to bosentan therapy in the treatment of pulmonary arterial hypertension. Program and abstracts of CHEST 2005: 71st Annual Meeting of the American College of Chest Physicians; October 29 - November 3, 2005; Montreal, Quebec, Canada. Abstract 1722.Rubin L. The changing world of pulmonary arterial hypertension therapies: a focus on the patient. Program and abstracts of CHEST 2005: 71st Annual Meeting of the American College of Chest Physicians; October 29 - November 3, 2005; Montreal, Quebec, Canada. Abstract 965.
 

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Frequently Asked Questions - Understanding Prostate Cancer

Current Practice Info: (Enter practice information here)More Printable Patient FAQ'sUnderstanding Prostate CancerWhat is prostate cancer?The prostate is a gland in the male reproductive system that helps produce semen, the thick fluid that carries sperm. The walnut-sized gland is located beneath a man's bladder and surrounds the upper part of the urethra, the tube that carries urine from the bladder. Prostate function is regulated by testosterone, a male sex hormone produced mainly in the testicles.

Prostate cancer is a major health concern for American men. Although the disease is rare before age 50, experts speculate that most elderly men have at least traces of it.

More than 200,000 new cases and about 30,000 deaths are attributed to prostate cancer each year in the U.S. For reasons not fully understood, African-American men have the highest frequency of prostate cancer in the world and the highest death rate from the disease. In other parts of the world — notably Asia, Africa, and Latin America — prostate cancer is rare.

Prostate cancer cells do not follow normal patterns and grow uncontrollably and spread to other tissues. Prostate cancer is typically a very slow growing tumor, often causing no symptoms until advanced stages. Most men with prostate cancer die of other causes — many without ever realizing that they have the disease. But once prostate cancer begins to grow more rapidly or spreads outside the prostate, it is dangerous. This aggressive type of prostate cancer can occur at any age. Although the disease tends to progress slowly, it is generally fatal if it spreads beyond the prostate gland itself.

Prostate cancer in its early stages (confined to the prostate gland) can be cured. Fortunately, about 85% of American men with prostate cancer are diagnosed in the early stages.

Cancer that has spread beyond the prostate to distant tissues (such as the bones, Lymph nodes, liver, and lungs) is not curable, but it often can be controlled for years. About a third of men whose prostate cancer becomes widespread can expect to live five years or more. Because of the many advances in available treatments, the majority of men whose prostate cancer becomes widespread can expect to live five years or more.What causes prostate cancer?Prostate cancer affects mainly older men. Four out of five cases are diagnosed in men over 65, but less than 1% in men under 50. Though rare, prostate cancer can be seen in men even in their 30's and 40's. Men with a family history of prostate cancer are more likely to die of it than is the general population. On a case-by-case basis, doctors cannot say with certainty what causes prostate cancer, but experts generally agree that diet contributes to the risk. Men who consume large amounts of fat — particularly from red meat and other sources of animal fat — are most likely to develop advanced prostate cancer. The disease is much more common in countries where meat and dairy products are dietary staples than in countries where the basic diet consists of rice, soybean products, and vegetables.

The underlying factor linking diet and prostate cancer is probably hormonal. Fats stimulate increased production of testosterone and other hormones, and testosterone acts to speed the growth of prostate cancer. High testosterone levels may stimulate dormant prostate cancer cells into activity. Some findings suggest that high testosterone levels also influence the initial onset of prostate cancer. Eating meat may be risky for other reasons: Meat cooked at high temperatures produces cancer-causing substances that directly affect the prostate. A few other risk factors have been noted. Welders, battery manufacturers, rubber workers, and workers frequently exposed to the metal cadmium seem to be abnormally vulnerable to prostate cancer.

Researchers know more about what will not cause prostate cancer than what will. No proven link exists between prostate cancer and an active sex life, vasectomy, masturbation, use of alcohol or tobacco, circumcision, infertility, infection of the prostate, or a common noncancerous condition called benign prostatic hyperplasia (BPH) that causes an enlarged prostate gland. Most elderly men experience an enlarged prostate to some degree.What are the symptoms?There are no warning signs or symptoms of early prostate cancer. Once a malignant tumor causes the prostate gland to swell significantly, or once cancer spreads beyond the prostate, the following symptoms may be present:

A frequent need to urinate, especially at night. Difficulty starting or stopping the urinary stream. A weak or interrupted urinary stream. A painful or burning sensation during urination or ejaculation. Blood in urine or semen. These are not symptoms of the cancer itself. Instead, they are the symptoms of the blockage from the cancer growth within the prostate and surrounding tissues.

Symptoms of advanced prostate cancer include:

Dull, incessant pain or stiffness in the pelvis, lower back, or upper thighs; arthritic pain in the bones of those areas. Loss of weight and appetite, fatigue, nausea, or vomiting.Call Your Doctor If:

You have difficulty urinating or find that urination is painful or otherwise abnormal. Your doctor will examine your prostate gland to determine whether it is enlarged, inflamed with an infection, or may have cancer. You have chronic pain in your lower back, pelvis, upper thighbones, or other bones. Ongoing pain without explanation always merits medical attention. Pain in these areas can have various causes but may be from the spread of advanced prostate cancer. You experience unexplained weight lossHow do I know if I have prostate cancer?The best way to detect prostate cancer in its early stages is with regular prostate exam PSA blood tests. Because most malignant prostate tumors originate in the part of the gland nearest the rectum, many cancers can be detected during routine rectal examinations. Many doctors recommend an annual rectal exam, supplemented by a prostate-specific antigen (PSA) blood test, starting at age 50 for most men. The screenings are recommended beginning at age 40 for African Americans and those with a family history of prostate cancer.

PSA is a protein whose level tends to increase in the presence of prostate cancer, making it more effective than rectal exam in detecting early prostate cancer. Together, the two screening measures offer the best chance of detecting prostate cancer while it is localized and most treatable. Prostate cancer may also be discovered incidentally during treatment for urinary problems. Because of the possibility of a false-positive PSA reading, it is important to discuss this test with your doctor before having one. An elevated PSA does not mean that you have cancer. Rather, it raises questions that need to be addressed and explained. There are a number of causes of an elevated PSA, and cancer is only one of them.

If routine screening arouses suspicion and PSA levels are elevated, a doctor will look at the prostate using an ultrasound instrument inserted in your rectum. X-rays of the urinary tract, along with blood and urine studies, are performed routinely to aid diagnosis. Performing a biopsy will confirm whether or not cancer is present: Guided by ultrasound images, the doctor inserts a needle into the prostate and extracts a small tissue sample from the suspicious area. A pathologist then studies the sample under a microscope to determine whether cancer cells are present. In order to determine if the cancer has spread outside the prostate gland, doctors usually arrange CT scans, bone scans, chest X-rays, or other imaging tests.What are the treatments?Since prostate cancer is often slow growing and may not be fatal in many men, some men — after discussing the options with their doctors — opt for "watchful waiting." Watchful waiting involves monitoring the prostate cancer for signs that it is becoming more aggressive but otherwise not treating it. This approach is recommended more commonly for men who are older or suffer from other life-threatening conditions. In these cases, the cancer may be growing so slowly that it's not likely to be fatal.

Once the decision is made to treat a cancer, other factors, such as a patient's age and general health, affect the type of treatment given. Decisions about how to treat this cancer are complex, and many men seek a second opinion before making a treatment decision.

Depending on when the disease is diagnosed, treatment includes some combination of radiation therapy, surgery, hormone therapy, and rarely chemotherapy. Localized prostate cancer usually can be cured with surgery, radiation therapy, or cryosurgery — freezing malignant cells with liquid nitrogen. The choice is made on a case-by-case basis and depends on many factors.

The standard operation — a radical prostatectomy — involves the removal of the prostate and nearby lymph nodes. In many cases, surgeons can remove the gland without cutting nerves that control penile erection or bladder function, making such complications as impotence or incontinence less common than in the past. Depending on the man's age and the amount of surgery needed to remove all the cancer, nerve-sparing techniques allow about 40%-65% of men who were able to get erections before surgery to be able to do so after surgery without a need for any additional Erectile Dysfunction treatments.

After surgery, most men experience some degree of incontinence but usually regain complete urinary control. Impotence can be treated in a variety of ways — including with medications such as Levitra, Cialis or Viagra. If severe or prolonged, incontinence can be managed with special disposable underwear, exercises, condom catheters, biofeedback or penile clamps; in rare cases that don't resolve on their own, incontinence can be eliminated altogether with surgically inserted sphincter implants around the urethra or a urethral sling. Radiation therapy can be very effective as the primary treatment for localized prostate cancer. It may also be given as follow-up to surgery for cancer that has not spread. If cancer has spread to adjacent tissue, radiation is the preferred treatment; it is also used in advanced cases to relieve pain from the spread of cancer to bones. Incontinence and impotence also occur with radiation, and some studies have shown similar results to surgery. New forms of radiation such as IMRT (Intensity Modulated Radiation Therapy) are proving even more effective with fewer side effects.

Permanent radioactive seed implants (brachytherapy) allow for delivery of a high dose of radiation to the prostate with limited damage to surrounding tissues. During the procedure, radioactive seeds (iodine-125) are implanted into the prostate gland using ultrasound guidance. The implants remain in place permanently and become inactive after many months.

Even advanced cases that cannot be cured may be controlled for years with hormone therapy, sometimes supplemented by other treatments. Hormone therapy slows the cancer's growth by cutting off the testosterone supply, although the treatment's effectiveness may decrease over time. Testosterone can be removed from the bloodstream by surgically removing the testicles (orchiectomy) or by administering female hormones such as estrogen or other drugs that block testosterone production. Men generally prefer the testosterone-blocking drug treatment because it is effective, less invasive, and causes fewer side effects than surgery or female hormone drugs. If the testicles are removed, the scrotum can be left intact with testicular implants put in place.

Chemotherapy and vaccine therapies are proving to be effective for some men with advanced prostate cancer.

The goal of prostate cancer treatment is a cure, and is likely in men diagnosed with early prostate cancer. All prostate cancer survivors should be examined regularly and have their PSA levels monitored closely.

As with other types of cancer, new treatments are being developed for advanced prostate cancer. Researchers are using radiation and hormone therapy in innovative ways and are testing the effectiveness of chemotherapy on patients who do not respond to other treatments.How can I prevent prostate cancer?Evidence regarding fat in the diet and prostate cancer is conflicting. But high dietary fat has been linked with increased prostate cancer. To lower your dietary fat, eat more fish, poultry, fresh vegetables, fruits, and low-fat dairy products. In general, eat less red meat; remove skin from poultry before cooking; and cut down on butter, margarine, and oils. There is some evidence that heating meat to high temperatures creates cancer-causing substances. To avoid these substances, try poaching or roasting, not frying or barbecuing.

Medically reviewed by Sheldon Marks, MD, August 2005. 

Copyright © 2004, Medscape Patient Education


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Diabetic Autonomic Neuropathy

Sudomotor Dysfunction

Sudomotor dysfunction is a common feature of diabetic autonomic neuropathy. This generally manifests as anhidrosis of the extremities, which may be accompanied by hyperhidrosis in the trunk. Initially, patients display a loss of thermoregulatory sweating in a glove and stocking distribution that, with progression of autonomic neuropathy, extends from the lower to the upper extremities and to the anterior abdomen, conforming to the length dependency of diabetic neuropathy. This process ultimately may result in global anhidrosis. Hyperhidrosis may also accompany diabetic autonomic neuropathy. Excessive sweating may occur as a compensatory phenomenon involving proximal regions such as the head and trunk that are spared in a dying-back neuropathy. Gustatory sweating, the abnormal production of sweat that appears over the face, head, neck, shoulders, and chest after eating even nonspicy foods, is occasionally observed.[44]

Previous PageSection 7 of 9Semin Neurol 23(4):365-372, 2003. © 2003 Thieme Medical Publishers
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Pfizer Files Suit Against Operators of 18 Internet Sites Selling Illegal Copies of Lipitor(reg)

Pfizer has filed lawsuits against a second group of operators of eighteen internet sites for selling unapproved and illegal copies of Pfizer's leading cholesterol medicine, LIPITOR(reg), the company said today.

Pfizer said the sites market products identified as "generic Lipitor" or "Lipitor generic," which are not legitimate medicines. LIPITOR(reg) is patent-protected and no generic versions of the medication are legally available in the United States. Tests performed on tablets obtained from two of the websites showed that they contained no atorvastatin calcium, the active ingredient in LIPITOR(reg), and therefore would provide no therapeutic benefit to patients. Pfizer has notified the FDA of its findings.

All the lawsuits seek injunctions against further sales of "generic Lipitor" or "Lipitor generic" and claim damages for infringement of Pfizer's trademark rights. The complaints also seek to remove references to LIPITOR(reg) in advertising materials and to eliminate computer links that misdirect patients to illegal, unapproved products. In addition, Pfizer has filed patent infringement claims against ten site operators to recoup damages and to enjoin further sales of "generic Lipitor" or "Lipitor generic" containing a crystalline form of atorvastatin calcium.

"We want to make consumers aware that many internet sites are selling fake pharmaceutical products that provide little or no benefit to patients and may, in fact, be dangerous," said Jeff Kindler, Executive Vice President and General Counsel of Pfizer. "We also want to put operators of these illegal sites on notice that there is a price to pay for their actions."

Suits were filed in U.S. District Court in Delaware against the following individuals and sites:

— Generic Lipitor www.generic-lipitor.com;
— RX MEX-COM, S.A. DE CV www.rx-mex.com;
— Online Enterprises www.global-presciptions.net;
— Gerard Gibson www.allpills.us;
— Medprescribed www.saveongeneric.com;
— Limestar, Inc. www.buyprescribeddrugs.com;
— Askdocweb, Inc. www.askdocweb.com;
— Michael Becker www.online-lipitor.com, www.pharmaexpressrx.com and www.generic-lipitor-atorlip.com;
— Intelecorp www.trustpharma.com;
— Feel-At-Home www.bestgenerics.com;
— International-Pharmacy Corporation www.international-pharmacy.com;
— Debra Cohen www.live-more-fully.com;
— John Fitzsimmons www.medsavings.biz;
— WWW Insight, S.A. www.rxmostwanted.com;
— Kris Sarode www.shoprxonline.com;
— GDL Access www.medicationdelivery.com.

Pfizer filed similar suits in April and May against the operators of six other sites selling an unapproved version of LIPITOR�. In August, the company took legal action against 30 sites and two operators selling illegal versions of Pfizer's erectile dysfunction medication, VIAGRA�.
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Measuring Depressive Symptoms in the Primary-Care Setting

Introduction

Major depressive disorder (MDD) is a highly prevalent, often chronic medical disorder largely diagnosed and treated in primary-care settings.[1] Currently, MDD is a leading cause of disability globally, and there is increasing evidence that it is an important risk factor for the development of major medical disorders, such as coronary artery disease (CAD).[2] More effective care for depression has been identified as a national health priority in the USA and elsewhere.[3]

The goal of antidepressant therapy is to achieve and sustain full symptomatic remission, prevent relapse and recurrence, and return patients to previous levels of occupation and social functioning.[4] Tacit to these therapeutic objectives is the need to systematically monitor symptomatic progress. Several brief unidimensional rating scales for depression provide good conceptual coverage across the multiple dimensions of depression.[5-10] The Beck Depression Inventory (BDI) is often employed in primary-care settings,[11] it may, however, not be adequately sensitive (vs. clinician-rated scales) in tracking response to antidepressant treatment.[12]

The Hamilton Depression Rating Scale 7 item (HAMD-7) was derived from analyses of a natural practice database at a tertiary-care centre comprised of patients diagnosed with MDD (n = 248) who were non-randomly assigned to open-label, flexible-dose antidepressant treatment.[13] The HAMD-17 items that were endorsed by ≥ 70% of depressed patients, and were most sensitive to change following 8 weeks of antidepressant treatment efficacy formed the constituent items of the HAMD-7. The HAMD-7 scale was subsequently validated in a cross-national primary care study.[10] Despite its psychometric deficiencies, the HAMD-17 was chosen as the gold standard because of its widespread and historical use in psychiatry.[14] The HAMD-7 has a high correlation with the HAMD-17, Montgomery Asberg Depression Rating Scale (MADRS) and the Clinical Global Impression (CGI).[10]

The objective of this post hoc study was to identify depressive items most frequently endorsed in the primary-care setting, and evaluate their responsiveness to antidepressant treatment. The encompassing aim was to compare these items with the previously identified depressive items of the HAMD-7.  Printer- Friendly Email This

Int J Clin Pract.  2007;61(8):1278-1282.  ©2007 Blackwell Publishing
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Ultrasound-Activated Antibiotic Hydrogel Retards Device-Related Biofilms

Ciprofloxacin-loaded hydrogels that device the antibiotic when exposed to low-level ultrasonography may endeavor a volume way to controller bacterial biofilm fabrication on indwelling prostheses and subcutaneous deed organisation, a multicenter US-based team of bioengineers written document.

“We believe that this field holds speech act not only for retarding biofilm earnings but also for eradicating established biofilms,” Dr.
Patrick Norris from the Shopping center for Biofilm Applied science at Montana State Educational institution in Bozeman and colleagues write in the October outcome of Antimicrobial Agents and Chemotherapy.

“To computer address the difficulty of biofilm implant infections,” noted co-author Dr.
Paul Stoodley from Allegheny-Singer Problem solving Institute in Pittsburgh, “the scientific territorial dominion has begun looking at at new strategies and technologies.”

One of these strategies “is to localize antibiotics in high concentrations piece of land at the point in time where the risk of illegality is highest — the aspect of the implant itself,” Dr.
Stoodley explained to Reuters Condition.

However, he continued “when surfaces are impregnated with antibiotic agents with no actively controlled accomplishment carrying into action the antibiotics are often passively released too early, before an communication is established.
When a biofilm does begin to form it is likely that there will not be enough antibiotics left to be effective, or worse, sublethal concentrations may actually help select for resistant strains.
By designing a device material that only releases antibiotics when required we can help overcome this difficulty.”

Developed by the Establishment of Capital of the United States (Seattle) Engineered Biomaterials Unit, the hydrogels are coated with methylene chains that form an ultrasound-responsive finish.
During polymerization, the hydrogels are loaded with antibiotic, in this case to buy ciprofloxacin, either as a solidness or in solvent.

According to the developers, the system of rules retains ciprofloxacin region the polymer in the nonattendance of ultrasonography and releases the antibiotic only when low-intensity tomography is applied.

To test the live body, Dr.
Norris and colleagues monitored the accumulation of Pseudomonas aeruginosa biofilms grown on hydrogels with and without ciprofloxacin and with and without desertion to imaging.

Compared with powerfulness experiments, the ultrasonic dismission of ciprofloxacin delivered in a 20-minute periodic event daily led to a significant 50-fold step-down in the grouping of an established Pseudomonas aeruginosa biofilm over a 3-day part.
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