Objective: To synthesize the published literature on the efficacy, effectiveness, and toxicity of hydroxyurea (HU) when used for treatment of sickle cell disease (SCD); and to review the evidence regarding barriers to its use.

Data Sources: Articles cited in MEDLlNE®, EMBASE, TOXLine, and CINAHL through June 30, 2007.

Review Methods: Paired reviewers reviewed each title, abstract, and article to assess eligibility. They abstracted data sequentially and then independently graded the evidence.

Results: In one small, randomized trial of HU in children with SCD; the yearly hospitalization rate was lower with HU than placebo (1.1 versus 2.8, p=0.002). The absolute increase in fetal hemoglobin (Hb F%) was 10.7 percent. Twenty observational studies of HU in children reported similar increases in Hb F%, while hemoglobin concentration increased by roughly 1 g/dl.

One large randomized trial tested the efficacy of HU in adults with SCD and found that after 2 years of treatment, Hb F% increased by 3.2 percent and hemoglobin increased by 0.6 g/dl, The median number of painful crises was 44 percent (p<0.001) lower among patients treated with HU. The 12 observational studies of HU enrolling adults with SCD supported these findings.

Panelists from the Center for the Evaluation of Risks to Human Reproduction reviewed the literature for potential toxicities of HU. They concluded that HU does not cause a growth delay in children 5-15 years old. There were no data on the effects on subsequent generations following exposure of developing germ cells to HU in utero.

Some evidence supported impaired spermatogenesis with use of HU. Although we identified six patients taking HU who developed leukemia, the evidence did not support causality. Similarly, the evidence suggested no association between HU and leg ulcers in patients with SCD, although there was in patients with other illnesses. The literature supported neutropenia, skin rashes and nail changes associated with use of HU, but was sparse regarding skin neoplasms or other secondary malignancies in SCD.

Only two studies investigated barriers to use of HU. Perceived efficacy and perceived safety of HU had the largest influence on patients’ (or parents’) choice to use HU. Providers reported barriers to be patient concerns about side effects; and their own concerns about HU in older patients, patient compliance, lack of contraception, side effects and carcinogenic potential, doubts about effectiveness, and concern about costs.

Conclusions: HU is efficacious in children and adults with SCD; with an increase in Hb F%, and reduction in hospitalizations and pain crises. However, few studies have measured the effectiveness of HU for SCD in usual practice. The paucity of long-term studies limits conclusions about toxicities and about mortality. Future studies of interventions to overcome the barriers to use of HU in patients with SCD are necessary.

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Postings:  568, 573, 579, 580, 581, 582.

Spring is in the air and according to a study in STROKE that’s when the incidence of CVAs rises.  It could be related to all those cuties beginning to walk around in those skimpy “hoo-hah” garments.
http://omniphysicians.com/2008/03/07/spring-and-cva/

A MedScape case report on a 57-year-old who just came back from a cruise.  One hint:  a 30-pound weight loss in 2-3 months.  A discussion at the end summarizes the principal points of this disease entity.  A CT scan is also there for you to interpret.
http://omniphysicians.com/2008/03/06/medscape-case-report-belly-pain-in-a-57-year-old-why/

Broccoli, peppers and spinach.  Eat enough of these and your chances of prostatic CA goes down.  That’s why Popeye is 110 years old!
http://omniphysicians.com/2008/03/07/vitamin-c-versus-prostate-cancer/

This BBC article reports on a team that is developing a vaccine against angiotensin.  Theoretically, this might be THE way to fight hypertension in the future.  So, your head won’t go pounding when you see the same patient the third time in 1 ER shift complaining of the same headache.
http://omniphysicians.com/2008/03/07/vaccine-for-hypertension/

This could be huge.  They’re reporting that Germany is having problems with its heparin.  And…this heparin is not being made by Baxter.  The goose-stepping Deutschlanders state that they have had fewer than 100 cases of allergic reactions from their heparin but no deaths so far.
http://omniphysicians.com/2008/03/07/global-heparin-crisis/

Aromatherapy isn’t all it’s cracked up to be.  That’s the conclusion of a study published in Psychoneuroendocrinology (I’m not kidding!), April of this year.  Lavendar and lemon oil did not have any impact on the biochemical markers for stress, pain, and wound healing.  Pulse and blood pressures were the same as with controls.  I wonder what Dr. DiCecco has to say about this?
http://omniphysicians.com/2008/03/06/aromatherapy-stinks/

Reuters, 3/7/08:  Strokes occur more often in the spring than any other season, and the heightened risk is seen in men, women, young and old alike, new research suggests.In a study of Japanese adults who had suffered a stroke between 1988 and 2001, researchers found that the risk of having a stroke in the spring was roughly one-quarter higher than it was in the summer.

Men and women, and adults older or young than 65, all saw their stroke rise in the spring compared with all other seasons.

The findings, reported in the journal Stroke, are in line with some past studies showing that stroke rates tend to be higher in the colder months of winter and spring.

In this study, stroke risk was highest in March, April and May, regardless of known risk factors like high blood pressure, smoking and diabetes.

“The mechanisms underlying seasonal variation of strokes are not fully understood,” write Dr. Tanvir Chowdhury Turin of Shiga University of Medical Science, Japan, and colleagues.

However, they note that blood pressure is known to have a similar seasonal variation. If blood pressure is consistently elevated during colder months, that could contribute to the excess strokes seen in the spring.

Similarly, there is evidence that blood may be more prone to clotting during the colder seasons; blood cholesterol levels tend to be higher at that time of year, as do levels of certain blood proteins and blood cells involved in inflammation and clotting.

Influenza, or other respiratory infections, could also play a role, Turin’s team points out. The flu, which peaks in the winter to early spring, can worsen chronic medical conditions, including atherosclerosis — the build-up of artery-clogging plaques that can lead to heart attack or stroke.

Finding out why stroke rates vary by season will be important, according to Turin’s team, as that could point to ways to lower the risk.

SOURCE: Stroke, March 2008.

MedWire News, 3/7/08:  People with a high intake of vitamin C-rich vegetables have a decreased risk of prostate cancer, although other vegetables and fruit do not greatly affect the risk of the disease, Australian study findings suggest.It is believed that diet plays an important role in the incidence of prostate cancer, although studies so far have produced inconclusive results. However, specific bioactive compounds from plant foods have been shown to reduce prostate cancer risk.

To investigate further, Gina Ambrosini, from the University of Western Australia in Perth, and colleagues studied 1985 men who were previously exposed to asbestos and randomly assigned to receive 30 mg beta-carotene (or 0.75-30.0 mg if they had abnormal liver function tests) or 7.5 mg retinol supplements daily as part of a cancer prevention program.

In addition, the men completed a semi-quantitative food frequency questionnaire to assess average daily intakes of 43 foods during the previous year, the team reports in the journal Prostate Cancer and Prostatic Diseases.

During a median follow-up period of 12.7 years, 441 men died, there were 97 incident cases of prostate cancer, and 35 participants were lost to follow-up. Prostate cancer cases were significantly older than non-cases at baseline, at 62.6 years versus 54.7 years.

There were no overall differences in fruit and vegetable intake, although cases had significantly lower median intakes of cooked tomato, broccoli, and bell peppers. Multivariate analysis taking into account age and source of asbestos exposure revealed that vitamin A supplementation, total fruit, and vegetable intakes were not associated with prostate cancer.

However, increasing intakes of vitamin C-rich foods, such as peppers, broccoli, and spinach, were associated with a lower risk of prostate cancer, with men in the highest tertile of intake having a relative risk of prostate cancer of 0.53 versus the lowest intake.

The team concludes: “Prostate cancer risk in this study does not appear to be strongly associated with the intake of beta-carotene, retinol, fruits or vegetables, except possibly with vitamin C-rich vegetables such as peppers and broccoli.

“Although the association with cooked tomatoes was not significant, it was consistent with earlier reports.”

BBC, 3/7/08:  A four-monthly jab may one day replace the need to regularly take pills to control blood pressure, scientists say. A team from the Swiss biotechnology firm Cytos found the vaccine against a hormone in the blood significantly cut blood pressure, the Lancet reported.

The jab was tested on 72 patients with high blood pressure and it was found to work without serious side-effects.

The researchers and independent experts said the findings were promising but large-scale trials were now needed.

High blood pressure, which affects a quarter of all adults, doubles the risk of dying from heart disease or stroke and is blamed for 60,000 deaths a year in UK.

Immunisation may be of particular benefit to people who find it difficult to stick to high blood pressure medication Professor Jeremy Pearson, of the British Heart Foundation

Those who are being treated for it often have to take a daily course of pills to keep it under control.

But many people do not keep to their treatment regimes as people with high blood pressure do not display symptoms.

The researchers believe the vaccine, which works against the hormone angiotensin, which causes blood vessels to constrict and increase blood pressure, may offer a simple alternative.

They tested two different doses of the vaccine - 300 microgrammes and 100 microgrammes - as well as a dummy vaccine during the 14-week trial.

Resistance

The jabs were given at the start, and after four weeks and 12 weeks - enough to give a patient four-month resistance.

Neither dose significantly lowered blood pressure at night.

But during the day the larger dose significantly lowered blood pressure, especially during the late morning peak when blood pressure is known to increase.

And, importantly, the vaccine did not have any serious side-effects with the worst being mild flu-like symptoms.

Lead researcher Dr Martin Bachmann said the vaccine could offer a much more simple way of controlling blood pressure and could be administered during regular visits to the doctor.

“Such a regimen is likely to promote adherence to treatment, but will need to be supported by clinical data.”

Professor Jeremy Pearson, of the British Heart Foundation, agreed more research was needed, but described the results as promising.

“Immunisation may be of particular benefit to people who find it difficult to stick to high blood pressure medication, but there is still a long way to go before this approach replaces the highly-effective current treatments.

“Looking after your heart through regular exercise, cutting down on salt, and only drinking in moderation remain the best ways in which we can prevent high blood pressure.”

Professor Graham MacGregor, chairman of the Blood Pressure Association, added: “This study demonstrates an interesting new way to lower blood pressure.”

Other firms are also known to be testing blood pressure vaccines.

NY Times, 3/7/08:  Concerns about the safety of the blood thinner heparin spread to Germany on Thursday after drug authorities there received reports of patients being sickened after taking the drug.Meanwhile, Food and Drug Administration officials announced that they were asking all companies in the United States that produce heparin to test it with two new procedures.

The complex tests, nuclear magnetic resonance spectroscopy and capillary electrophoresis, are the only ones that can uncover whether the drug contains a possibly counterfeit ingredient.

Dr. Janet Woodcock, deputy F.D.A. commissioner, said that the agency would post instructions online for the tests.

Food and Drug officials said Wednesday that a possibly counterfeit ingredient had been found in certain batches of heparin linked to at least 19 deaths in the United States and more than 700 severe allergic reactions.

Federal officials said they could not yet say that the contaminant, which mimics real heparin, caused the reactions.

Until Thursday, federal investigators had been focusing on heparin manufactured by Baxter International. But Dr. Woodcock said that German health authorities told the F.D.A. that Baxter did not make the heparin linked to two separate outbreaks of allergic reactions in that country. Germany has reported fewer than 100 cases of patients suffering severe allergic reactions and shock, and no deaths.

F.D.A. officials declined to say whether the raw ingredients for the suspect German heparin came from China, the source of the starting materials used to make the contaminated heparin in the United States.

Most of the world’s heparin supply is from China. In the last six months, more than 30 Chinese companies could be found selling heparin products on major business-to-business Web sites.

“We are working as quickly as possible to analyze any potential impact on the U.S. market and worldwide,” said Deborah Autor, the director of compliance for the agency’s Center for Drug Evaluation and Research.

In the first half of last year, China exported heparin products to 42 countries and regions, according to a September 2007 report by the China Chamber of Commerce for Import and Export of Medicines and Health Products. China exported the most heparin products, about 13 tons, to Germany. It also sent 11 tons to France and about 10 tons to the United States, the report said.

Erin Gardiner, a spokeswoman for Baxter, said reports that her company was not responsible for making the suspect heparin in Germany would most likely point to a problem with the suppliers of crude heparin. “The news today indicates that the issue could be further back in the supply chain,” Ms. Gardiner said.

Last week, Baxter withdrew from the market nearly all of its heparin products.

Baxter bought the active pharmaceutical ingredient for its heparin products from Scientific Protein Laboratories, based in Waunakee, Wis., which has plants in Wisconsin and Changzhou, China. All of the suspect heparin was made from raw heparin produced in China. In some cases, those supplies were produced in small, unregulated family workshops, according to heparin traders and producers in China.

On Wednesday, Scientific Protein Laboratories announced a recall of some of its product, the active ingredient in heparin.

Most supplies of heparin in the United States are now from APP Pharmaceuticals, of Schaumburg, Ill. APP’s supplies have undergone the new tests.

German authorities have identified Rotexmedica as a manufacturer of at least some of the suspect heparin there, F.D.A. officials said.

German drug authorities could not be reached. F.D.A. officials said they were told that the German authorities had recalled an unspecified amount of heparin.

In a statement released Thursday, Scientific Protein Laboratories said, “We believe this demonstrates that the heparin problem is not within Changzhou SPL’s or Baxter’s manufacturing facilities but our investigation into the root cause of the problem will continue.”

Representative John D. Dingell, the Michigan Democrat who is the chairman of the House Energy and Commerce Committee, charged in a statement released Thursday that the F.D.A. “is drowning in drug imports that it is not able to properly regulate.”

In Europe, such foreign inspections may be even rarer. A 2006 report by a European chemical association said that even when European inspectors found serious safety issues, European regulators did not suspend the producers from supplying the European market because of a lack of government coordination.

FDA advised healthcare professionals and consumers that the Agency issued Warning Letters to six U.S. companies and one foreign individual for marketing unapproved and misbranded drugs over the internet to U.S. consumers for the prevention and treatment of sexually transmitted diseases (STDs).

http://www.fda.gov/medwatch/safety/2008/safety08.htm#STDs

Distributed via Health Alert Network
Friday, February 29, 2008, 14:10 EST (02:10 PM EST)
CDCHAN-00271-2008-02-29-ADV-N

Influenza Antiviral Use for Persons at High Risk for Influenza Complications or Who Have Severe Influenza Illness

CDC is alerting clinicians to be fully aware of the potential benefits of influenza antiviral medications during this influenza season.

Summary:

Recent surveillance data indicate that many communities are reporting substantially increased influenza activity. This CDC Health Advisory is intended to re-emphasize the importance of considering antiviral medications for use in the treatment or prevention of influenza.  The two prescription antiviral medications recommended for treatment or prevention of influenza include oseltamivir (Tamiflu®, Roche Laboratories, Nutley, NJ) or zanamivir (Relenza®, GlaxoSmithKline, Research Triangle Park, NC). These antiviral medications are also known as neuraminidase inhibitors. Recent studies suggest a considerable protective effect against complications associated with influenza when neuraminidase inhibitors are used for treatment. These benefits include reducing the risk of death among older adults hospitalized with laboratory-confirmed influenza. Because high levels of resistance to adamantane antiviral medications (rimantadine and amantadine) continue to be observed among circulating influenza A viruses, adamantanes are not recommended for treatment or prevention of influenza.

Background:

During this influenza season, a small increase in the number of influenza viruses resistant to oseltamivir has been observed in the United States. Among the 471 influenza A and B viruses tested during the 2007–08 influenza season to date, 27 (5.7%) have been found to be resistant to oseltamivir, compared with 0.7% during the 2006-07 season. All of the oseltamivir-resistant viruses have been influenza A viruses of the H1N1 subtype; 8.7% of the 310 H1N1 viruses tested are resistant to oseltamivir. No resistance to oseltamivir has been observed among the 161 influenza A (H3N2) and influenza B viruses tested to date, and no antiviral resistance to zanamivir has been detected in any subtype. 

Recommendations:

Given the low level of overall resistance to oseltamivir among circulating influenza viruses, the finding of resistance only in influenza A (H1N1) viruses, and no resistance to zanamivir, neuraminidase inhibitor medications continue to be recommended for the treatment and chemoprophylaxis of influenza. Antiviral treatment should begin within 48 hours of symptom onset if possible, but treatment should still be considered for persons who present more than 48 hours after illness onset if they have severe influenza illness or are at higher risk for severe complications from influenza. Oseltamivir is approved for treatment and prevention of influenza for persons 1 year and older, while zanamivir is approved for treatment of persons 7 years and older and prevention of influenza in persons 5 years and older. Enhanced surveillance for detection of oseltamivir-resistant influenza viruses is ongoing, and antiviral usage recommendations will be revised to account for changes in antiviral resistance trends as needed. Influenza A viral isolates from affected persons in institutional outbreaks should be subtyped. Health care providers should contact their local or state public health department for assistance when an outbreak of influenza in an institutional setting (e.g., a long-term care facility) occurs. State health departments should consult with CDC about the need for antiviral resistance testing when influenza A (H1N1) viral isolates are obtained from outbreaks in institutional settings.

In some communities, circulating influenza virus strains during this influenza season are antigenically different from those contained in current influenza vaccines.  Preliminary results from a rapid assessment of vaccine effectiveness suggest that currently available influenza vaccines provide some protection against influenza virus infection requiring medical care. However, the level of protection is likely to be lower than what is observed in seasons in which the vaccine strains are closely matched to circulating influenza virus strains.  When influenza vaccine effectiveness is reduced, clinicians should be aware of the potential for appropriately vaccinated persons to develop influenza despite vaccination.

Because approximately 2 weeks is required to develop an optimal immune response to influenza vaccination, use of neuraminidase inhibitors for prevention of influenza during a confirmed influenza institutional outbreak should be considered for persons at higher risk for influenza complications and who were vaccinated within the previous 2 weeks. Persons who were vaccinated more than two weeks before a suspected influenza virus exposure, but who are less likely to develop protective immunity after vaccination (e.g., persons in long-term care facilities or persons with immunosuppression), can be considered for antiviral chemoprophylaxis when local influenza surveillance data indicate that influenza activity is high.

Clinicians should consider whether to recommend influenza antiviral treatment based on the severity of the patient’s illness, the time since illness onset, local influenza surveillance data and influenza test results. Rapid diagnostic tests for influenza have good specificity, but are only moderately sensitive. Positive rapid tests are generally reliable when influenza activity is high in a community and are useful in deciding whether to initiate antiviral treatment. Negative rapid test results are less helpful in making treatment decisions. When local influenza activity is high, persons with severe respiratory symptoms or persons with acute respiratory illness who are at higher risk for influenza complications should still be considered for influenza antiviral treatment despite a negative rapid influenza test unless illness can be attributed to another cause.  As reported in a previous HAN, persons with severe influenza illness should also be assessed for invasive bacterial co-infection, and appropriate antimicrobial therapy directed at potential bacterial pathogens, such as methicillin-resistant Staphylococcus aureus, might be necessary.

To reduce the substantial burden of influenza in the U.S., CDC continues to recommend a three-pronged approach: influenza vaccination, use of neuraminidase inhibitor antiviral medications when indicated for treatment or prevention, and use of other measures to decrease the spread of influenza, including promotion of hand hygiene, respiratory hygiene, cough etiquette, and staying home from work and school when ill. Clinicians in communities experiencing increased influenza activity should consider prescribing the neuraminidase inhibitor antiviral medications oseltamivir and zanamivir for the treatment of influenza patients or for prevention of influenza when indicated for institutional influenza outbreaks or for persons at high risk for complications from influenza who have contraindications to influenza vaccination.

For more information, please see the CDC website: http://www.cdc.gov/flu/professionals/antivirals/

If you have any questions about this Health Advisory, please call the Influenza Division, Epidemiology and Prevention Branch at 404-639-3747.

• Public Health Update: Recall of Heparin Sodium for Injection (2/28/2008)
• FDA-483 on Heparin (2/28/08)
• Public Health Advisory (2/11/2008)
• Question and Answers (2/11/2008)
• FDA News (2/11/2008)
• Baxter to Proceed with Recall of Remaining Heparin Sodium Vial Products (2/28/08)
• Baxter Issues Urgent Nationwide Voluntary Recall of Heparin 1,000 Units/ml 10 and 30ml Multi-Dose Vials (1/25/2008)
• Transcripts of FDA Press Conferences on Adverse Events Associated with Baxter Healthcare Corporation’s Multiple-Dose Vials of Injectable Heparin

Screening Methods (3/6/2008)

• Impurity Evaluation of Heparin Sodium by Capillary Electrophoresis
• Impurity Evaluation of Heparin Sulfate by ¹H-NMR Spectroscopy

In early February, after learning about a spike in adverse events involving this product, FDA launched a far ranging investigation in both the United States and abroad. This included inspecting Baxter’s domestic facilities, examining Heparin product in the United States and sending a team of experts to China to conduct a comprehensive inspection of the Changzhou SPL facility that makes the active ingredient for this drug.

While the FDA has yet to determine the root cause of these adverse events, we have found a Heparin-like compound that is not Heparin present in some of the Heparin Active Pharmaceutical Ingredient (API) produced by Scientific Protein Labs, which maintains a facility in Wisconsin in addition to the Changzhou plant.

This contaminant is present in significant quantities, accounting for 5 to 20 percent of the total mass of each sample tested. It reacts like Heparin in many tests, which is why the traditional release tests did not detect it.

At this point, we don’t know how the Heparin-like compound got into the Heparin Active Pharmaceutical Ingredient, but we are continuing to aggressively investigate the situation.

We don’t yet have proof that this contaminant is causing the adverse events. There is an association, but not a direct causal link at this time.

To ensure that all is being done to provide a safe supply of this life-saving drug, we are releasing information on two tests that manufacturers and regulators can use to screen for this contaminant.

The two methods include proton nuclear magnetic resonance (H-1 NMR) and capillary electrophoresis (CE). The tests are to be used for ALL Heparin Sodium API prior to batch release. The API material is considered contaminated if there is a doublet peak at 2.1 ppm in H-1 NMR and a shoulder peak in CE, as illustrated in the two attachments. Heparin sodium API must contain only a single peak (singlet) at 2.1 ppm in NMR and a single peak in CE. It is recommended that both screening methods (H-1 NMR and CE) be used in addition to the regulatory and/or compendial specification requirements.

If you test Heparin and detect a contaminant, please contact FDA at: cderrecalls@cder.fda.gov or call 301-796-3358.