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P T. 2011;36(5): 243-244, 249-254, 262

New Drugs/Drug News/New Medical Devices May 2011


Horizant Tablets And Restless Legs Syndrome

The FDA has approved gabapentin enacarbil extended-release tablets (Horizant, GlaxoSmithKline/Xenoport), a once-daily therapy for moderate-to-severe restless legs syndrome (RLS).

The gabapentin enacarbil ingredient becomes gabapentin (which is used to treat seizures) when absorbed into the body. All antiepileptic drugs carry warnings that they might cause suicidal thoughts and actions in some people. The same warning will be included in the prescribing information for Horizant.

A medication guide will also be dispensed with the product.

Possible adverse effects include drowsiness and dizziness.

Source: FDA, April 7, 2011

Sylatron for Melanoma

Merck has announced the FDA’s approval of peginterferon alfa-2b injection (Sylatron) for the adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of surgical resection, including complete lymphadenectomy. This is the first FDA-approved agent for the adjuvant treatment of melanoma in more than 15 years.

Patients may inject the once-weekly SQ dose themselves. The recommended dose is 6 mcg/kg weekly for eight doses, followed by 3 mcg/kg weekly for up to five years. Premedication with oral acetaminophen 500 to 1,000 mg should be given 30 minutes before the first dose of Sylatron and as needed for subsequent doses.

The risk of serious depression and other serious neuropsychiatric disorders is increased with alpha interferons, including this drug. Sylatron should be permanently discontinued if severe neuropsychiatric disorders or encephalopathy persists, if grade 4 nonhematological toxicity occurs, if a dose of 1 mcg/kg weekly cannot be tolerated, or if new or worsening retinopathy develops.

Source: Merck, April 12, 2011

Vandetanib (Zactima) For Advanced Thyroid Cancer

Vandetanib (AstraZeneca), an orphan drug currently known as Zactima, ZD-6474, and AZ-D6474, has been approved for patients with inoperable and metastatic medullary thyroid cancer. The use of this kinase inhibitor should be carefully considered because of the treatment-related risks.

The approval was based on the results of the Zactima Efficacy in Thyroid Cancer Assessment (ZETA), a phase 3 double-blind trial. A Risk Evaluation and Mitigation Strategy (REMS) will be included because of the potential for QT prolongation, torsades de pointes, and sudden death.

Before this approval, there were no FDA-approved drug treatments for this rare form of thyroid cancer. The orphan drug designation for medullary thyroid cancer was granted in 2005.

Sources: FDA, Los Angeles Times, April 6, 2011


Rituxan Plus Steroids For Two Rare Disorders

Rituximab (Rituxan, Genentech/Roche), in combination with glucocorticoids, has been approved for the treatment of Wegener’s granulomatosis and microscopic polyangiitis, which cause vasculitis. Both of these orphan diseases affect men and women of all ages and ethnic backgrounds. The cause is unknown.

Rituximab is an antibody that works primarily by reducing the number of B cells in the blood. A boxed warning mentions infusion and severe mucocutaneous reactions and progressive multifocal leukoencephalopathy (PML), a serious brain infection. This drug is not recommended for patients with a severe, active infection.

Rituximab was first approved in 1997. and is also indicated for non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, and rheumatoid arthritis.

Source: FDA, April 19, 2011

Actemra to Treat Rare Form Of Juvenile Arthritis

Tocilizumab (Actemra, Genentech/Roche), given alone or with methotrexate, has been approved for the treatment of active systemic juvenile idiopathic arthritis (SJIA), or Still’s disease, in children two years of age and older.

This rare, potentially life-threatening disorder causes severe systemic inflammation. SJIA is distinguished from other forms of juvenile idiopathic arthritis (JIA) by the prominence of systemic and inflammatory features (e.g., fevers; rash; inflamed lymph nodes, liver, and spleen; and high white blood cell and platelet counts). SJIA affects about 10% of all patients with JIA.

In 2010, the FDA approved tocilizumab, an interleukin-6 (IL-6) receptor blocker for adults with moderately to severely active rheumatoid arthritis who were not responding to other therapies.

A boxed warning mentions the potential for serious infections. Adverse effects have included upper respiratory tract infections, headache, sore throat, and diarrhea.

Source: FDA, April 15, 2011

Zostavax Shingles Vaccine For Younger Individuals

Merck’s live attenuated virus vaccine, Zostavax, is now approved for the prevention of shingles in people 50 to 59 years of age. Zostavax is already approved for use in individuals 60 years of age and older. Shingles, caused by the varicella-zoster virus, affects approximately 200,000 healthy people in this age group each year in the U.S.

In a study, Zostavax reduced the risk of developing shingles by approximately 70%, compared with placebo. The vaccine was originally approved in 2006.

Source: FDA, March 24, 2011

Paliperidone (Invega) For Youths With Schizophrenia

Paliperidone (Invega, Janssen) extended-release tablets have been approved for the treatment of schizophrenia in adolescents 12 to 17 years of age. This atypical antipsychotic medication was first approved in the U.S. in December 2006 for adults with schizophrenia.

The drug’s efficacy was established in a six-week study using a fixed weight-based treatment group design. Doses ranged from 1.5 to 12 mg/day. Overall tolerability of paliperidone was shown in adolescents within a dose range of 3 to 12 mg/day.

Source: Johnson & Johnson, April 11, 2011

Menactra Meningitis Vaccine For Infants and Toddlers

Menactra, made by Sanofi-Pasteur, has been approved for children as young as nine months of age to prevent invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, Y, and W-135. N. meningitidis is a leading cause of meningitis in young children.

Meningococcal disease progresses rapidly and can cause death within hours. The highest rate of meningococcal disease occurs in children younger than one year of age.

The vaccine is given as a two-dose series beginning at nine months, three months apart. Menactra was originally approved in 2005 for people 11 through 55 years of age. In 2007, the vaccine was approved for children as young as two years of age.

Source: FDA, April 22, 2011


Topamax Recalled: Musty Odor

Johnson & Johnson (J&J) has recalled topiramate (Topamax) because of an unusual odor thought to be caused by a chemical, 2,4,6-tribromoanisole (TBA). Topiramate is an anticonvulsant and a migraine preventative.

Two lots of 100-mg Topamax tablets in 60-count bottles are affected (0KG110 and 0LG222). Approximately 57,000 bottles have been recalled. The lots were distributed from October 19 to December 28, 2010, in the U.S. and Puerto Rico.

TBA is the same preservative thought to have caused the odor that prompted the recall of other J&J products, including Tylenol. Wholesalers are advised to stop distributing any affected lots, to return the product, and to notify customers about the recall.

Source: Med Page Today, April 14, 2011

Obama/FDA Plan to Reduce Abuse Of Opioids

The Obama administration is seeking to decrease widespread prescription opioid abuse in the U.S. During 2007, for instance, more than 33 million Americans 12 years of age and older misused extended-release (ER) and long-acting (LA) opioid drugs.

An education program supported by the FDA is focusing on reducing the misuse and misprescribing of opioids, commonly used for pain relief. The plan is a collaborative effort of agencies of the Departments of Justice, Health and Human Services, Veterans Affairs, and Defense, among others.

Strategies include expanding state-based prescription drug-monitoring programs; recommending responsible ways of removing unused drugs from homes; supporting education for patients and health care providers; and decreasing the number of “pill mills” and doctor shopping through law enforcement.

A REMS has been announced for all ER and LA opioids. Drugs such as oxycodone (OxyContin), morphine (Avinza), methadone (Dolophine), transdermal fentanyl (Duragesic), and eight other brands are often misused, leading to overdoses, addiction, and even death. The REMS focuses on educating doctors about pain management, selection of appropriate patients, and improving patient awareness about safe drug use.

Physicians would need training before being permitted to prescribe brand-name products known under their generic names: hydromorphone (Dilaudid), oxycodone, oxymorphone (Opana), transdermal buprenorphine (Norspan), oxymorphone, methadone, and transdermal fentanyl.

Source: FDA, April 19, 2011; The New York Times

Updated Criteria in Diagnosing Alzheimer’s Dementia

For the first time in 27 years, clinical diagnostic criteria for Alzheimer’s disease (AD) dementia have been revised. The original 1984 criteria described only later stages, when symptoms of dementia are already evident. The new guidelines cover the full spectrum of AD as it gradually changes over time and address the use of imaging and biomarkers in blood and spinal fluid that can help determine whether changes in the brain and body fluids are resulting from AD.

Earlier criteria defined AD as having a single stage (dementia). The diagnosis was based solely on clinical symptoms and was confirmed only at autopsy. It is now known that AD can cause changes in the brain a decade or more before symptoms appear and that symptoms do not always directly relate to abnormal changes in the brain caused by AD. Some older people have abnormal levels of amyloid plaques at autopsy yet never showed signs of dementia during life. Amyloid deposits may begin early in the disease process, but tangle formation and loss of neurons sometimes occur later and may accelerate just before clinical symptoms appear.

The new guidelines now cover three stages: (1) preclinical, with amyloid buildup and early nerve cell changes in the brain but without evident significant clinical symptoms; (2) mild cognitive impairment, marked by memory problems but not compromising a person’s independence; and (3) dementia.

The guidelines also expand the concept of AD dementia beyond memory loss as its most main characteristic. A decline in word-finding, vision and spatial problems, and impaired reasoning may be the first symptoms to be noticed. Biomarker testing may be used to increase or decrease the level of certainty about a diagnosis of AD dementia and to distinguish AD dementia from other dementias.

Sources: Alz Dement, The New York Times, NIH, April 19, 2011

Price of Makena to Drop

KV Pharmaceutical plans to reduce the price of hydroxyprogesterone caproate (Makena) from $1,500 per dose to $690 per dose. The drug is indicated for preventing preterm births. KV also will be providing the drug at no cost for patients with the greatest financial need.

The company took these steps because of the concerns that were raised about the original cost, which put pressure on Medicaid budgets. The action was taken after the FDA announced on March 30 that it would allow pharmacies to continue to produce less expensive versions of the drug. That move was aimed at defusing the controversy about the price of Makena. The same compound had been available for years for $10 to $20 per dose.

Because Makena must be given for about 20 weeks, the cost will be about $30,000 for each at-risk pregnancy, which could add more than $4 billion to the nation’s health care bill. KV had defended Makena’s price, saying the company had spent more than $200 million to develop the drug, which saved an estimated $50,000 for every preterm birth avoided.

Source: The Washington Post, April 1, 2011

Medicare to Cover Cost of Provenge

Men with advanced prostate cancer who have Medicare insurance will be able to receive full coverage of Dendreon’s sipuleucel-T (Provenge). The company has priced the drug at $93,000 for three infusions, which it says is in line with the cost of similar cancer drugs per month of added life. Shown to extend median survival by 4.1 months, the vaccine is also being studied in patients with earlier-stage prostate cancer.

Sources: The New York Times, March 28, 2011; Reuters, March 30, 2011

Actos May Prevent Full-Blown Diabetes

In a multicenter study, a pioglitazone tablet (Actos, Takeda) taken each morning prevented the development of type-2 (adult-onset) diabetes in more than 70% of people who were considered to be at high risk for the disease. There was also a 31% decrease in the rate of carotid artery thickening.

Sources: N Engl J Med 2011;364:1104–1115; Health Day News, March 25, 2011

Some Lung Cancers Are Resistant to Drug Therapy

A new study may help to explain why some lung cancers become resistant to targeted medications.

Researchers analyzed tumor samples from 37 patients with non–small-cell lung cancer (NSCLC). They identified two new genetic changes associated with resistance, confirming resistance-related genetic changes that had been identified in previous studies. They also discovered that genetic mutations associated with drug resistance sometimes disappeared after treatment was halted. The findings highlight the importance of monitoring the molecular status of lung cancer tumors throughout treatment.

Lead author Dr. Lecia Sequist said, “It is really remarkable how much we oncologists assume about a tumor based on a single biopsy taken at one time, usually the time of diagnosis.”

Many cancers can evolve in response to exposure to various therapies over time. It is recommended that oncogene-driven cancers be subjected to repeated biopsies, when feasible, throughout the course of the disease. This could help health care practitioners decide whether to resume targeted therapy or begin standard therapy.

The role of genetic mutations in the treatment of NSCLC is discussed in an article by Corey Langer on page 263.

Sources: Sci Translat Med, Yahoo News, March 23, 2011

Tindamax or Flagyl For Bacterial Vaginosis?

Bacterial vaginosis is a common but potentially dangerous infection, with no satisfactory cure. The infection is linked to birth complications and sexually transmitted diseases. Tinidazole (Tindamax, Mission), recently licensed in the U.S., has potential as a treatment; it has a longer half-life than the standard, metronidazole (Flagyl, Pfizer) and a good side-effect profile. However, University of Alabama researchers say that the two drugs are essentially similar.

The researchers assigned 593 women to receive oral metronidazole 500 mg, tinidazole 500 mg, or tinidazole 1 g twice daily for seven days. The team found no differences in cure rates between the drugs or between dosages. At day 14, 80% of the women receiving metronidazole, 83% receiving tinidazole 1 g, and 73% using tinidazole 500 mg were considered cured or improved.

Overall, cure rates were 77% at the 14-day follow-up and 65% at the one-month visit. Micro biologic cure was defined as a Nugent score of below 7. Using a stricter Nugent criterion of cure (a score below 4), the researchers still found no significant difference in cure rates between treatment arms; the cure rate at day 14 was 54%.

No differences were observed in overall recurrence rates (29% at the first month and 31% at the second month). Women who reported engaging in sexual activity during the study were significantly more likely to have bacterial vaginosis at follow-up visits. Of note, nearly 97% of the women in the study reported a history of an STD; 83% reported a history of bacterial vaginosis and thus might have represented a more difficult-to-cure group. Adverse effects were similar for all treatment arms. Yeast infections were reported by 15% of the women.

Source: Am J Obstet Gynecol 2011;204: 211.e1–e6

SSRI Antidepressants: No Increased Heart Risk

Depression is associated with an increased risk of coronary heart disease in healthy people. Although tricyclic anti-depressants (TCAs) are linked to an increased risk of adverse cardiovascular (CV) outcomes, selective serotonin reuptake inhibitor (SSRI) antidepressants may be a better option for many patients because they are linked to a lower CV risk. Less is known about the newer serotonin–norepinephrine reuptake inhibitors (SNRIs).

Researchers from St. Louis and Arkansas evaluated more than 93,000 veterans to see whether antidepressants raised the risk of myocardial infarction (MI) and all-cause mortality. VA guidelines mandate 12 weeks of antidepressants for patients experiencing a new episode of depression. In the study, 79% of patients received guideline-concordant care, 8% received no antidepressants, and 13% received antidepressants from one to 11 weeks. Patients were classified as having been treated with a specific anti-depressant if they took the same drug for 12 or more continuous weeks and refilled at least one prescription. They were considered not treated if they received less than 12 weeks of any drug. SSRIs were the most common antidepressants that were received for 12 weeks or longer.

Drug therapy was associated with a lower risk of MI and appeared to reduce the higher risk of MI attributable to depression. Receiving an antidepressant for 12 or more weeks was associated with significantly reduced rates of MI for all classes of antidepressants (SSRIs, SSNIs, and TCAs), compared with receiving less than 12 weeks of treatment. The risk of all-cause mortality was also less with 12 weeks of treatment with all classes of antidepressants.

It isn’t clear why treatment decreased the risks of MI and mortality rates. The alleviation of depression could have been a result of a direct effect of the drugs, or perhaps patients who used medication for 12 or more weeks were also more likely to comply with other prescriptive health behaviors.

The team also noted an average 3% reduction in risk for every additional month patients took antidepressants from all drug classes.

Source: Am J Med 2011;124(4):318–324

Propofol (Diprivan) And ICU Infections

Although generally safe, propofol (Diprivan, AstraZeneca) has been linked to postoperative and hospital-induced infections. Possible drug contamination has been identified as a cause in some cases, but this theory does not explain all instances of infection.

Researchers from Saudi Arabia conducted a post hoc nested cohort study within a randomized controlled trial to determine whether preservative-free propofol infusion might have an independent role in adverse outcomes. They compared one group of 399 patients who did not receive propofol and one group of 124 patients who did; they then calculated the cumulative and average daily dose of propofol for the first seven days in the intensive-care unit (ICU).

In adjusted analyses, the use of propofol was associated with a nearly doubled risk of ICU-acquired infection, sepsis, and septic shock. Patients who received more than the median propofol dose had more infections and a higher incidence of severe sepsis and septic shock.

The researchers suggest that propofol could have increased the risk of infection by impairing monocyte and neutrophil function and reducing bacterial clearance. The drug’s higher caloric intake could also influence outcomes; moderate caloric intake is linked to better results. Extrinsic contamination is also possible, although the risk of nosocomial infection from contamination is very low in ICU patients. Another possibility is that lipid-based agents such as propofol support rapid growth of microorganisms.

After a modified formula containing the preservative EDTA was introduced in the U.S., there were no further cluster outbreaks of postoperative nosocomial infections with propofol infusions. However, EDTA-containing formulations of propofol are not considered to be anti-microbially preserved products under U.S. Pharmacopeia standards.

If an infection is triggered by caloric intake, a new lipid-free formulation of propofol might help. Fospropofol disodium (Lusedra, Eisai) was recently approved for monitored sedation in adults. It is water-soluble and is expected to lower the risk of infection. Until more studies are conducted, it might be wise to avoid the prolonged use of propofol, especially preservative-free formulations, in patients needing continuous sedation.

Source: Am J Infect Control 2011;39: 141–147

Long-Term Steroids Relieve Rhinosinusitis

Chronic rhinosinusitis with nasal polyposis can cause nasal blockage, facial pain, and hyposmia. Patients tend to relapse, and their response to therapy is often incomplete. Researchers from the United Kingdom suggest that starting with two weeks of oral steroids, followed by 26 weeks of topical steroids, is an effective way to eradicate the infection.

In their randomized study, 60 adults with rhinosinusitis and nasal polyps received oral prednisolone 25 mg/day or placebo for two weeks. For both groups, this regimen was followed by fluticasone propionate (Flonase, GlaxoSmithKline) nasal drops 400 mcg twice daily for eight weeks, then by fluticasone propionate nasal spray 200 mcg twice daily for 18 weeks.

Primary outcomes measures were polyp grade, hyposmia score, quality of life, symptoms, nasal patency, adrenal function, and bone turnover. Patients in either treatment group who showed an improvement in more than one minimal important difference in either polyp grading or hyposmia on the Visual Analogue Scale (VAS) by the end of six months were classified as responders. Fifty-one patients completed the study.

Most of the prednisolone patients (83%) improved by more than the minimal important difference in either polyp grade or hyposmia Visual Analogue Scale by 28 weeks, compared with 57% of placebo patients. A similar number of patients in both groups reported adverse events, none of which were serious. Notably, the researchers found no residual adrenal suppression or reduction in osteoblast activity at 10 or 28 weeks.

Nasal obstruction and an impaired sense of smell affect quality of life. Although oral steroids appear to stimulate the olfactory neurons, the sustained improvement in olfaction suggests a reduction in local mucosal inflammation and edema as the mechanism. There were also reductions in markers of eosinophil activation and inflammation with systemic (but not topical) cortico steroids. This finding suggests that the reduced polyp size and improved sense of smell resulted from local anti-inflammatory effects, not from systemic steroid spillover.

Source: Ann Intern Med 2011;154:293–302

Gout Treatment: Complex and Challenging

Patients with gout tend to have multiple comorbidities and, as a result, they have several contraindications to the drugs that are approved for gout management. Despite the contraindications, more than 90% of these patients may be receiving inappropriate prescriptions.

Drugs for gout generally have prominently noted contraindications, but studies have not addressed their prevalence in patients with gout.

In their study, the researchers, from New York, classified 575 patients with gout according to International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) code (cohort I), American College of Radiology criteria (cohort II), and the presence of uric acid crystals (cohort III). They found that most patients had at least one contraindication to a gout therapy, and many had contraindications to more than one therapy. Of the 94% of patients in the first cohort who had at least one contraindication to nonsteroidal anti-inflammatory drugs (NSAIDs), for instance, 18% were prescribed those agents, including 9% of patients with a strong contraindication. Twenty percent of patients in cohort I, 25% of those in cohort II, and one-third of patients in cohort III received allopurinol (Zyloprim, Prometheus) despite the contra indications. Colchicine was contraindicated in more than 40% of the study patients.

Although FDA criteria were used to define drug contraindications, which allowed for a rigorous external standard, the teams did not address drug–drug interactions or the extent to which multiple moderate contraindications to a single drug might collectively constitute a strong contraindication. Therefore, their data not only overestimated, but also might have underestimated, the frequency of contraindications.

The researchers suggested some reasons why physicians still prescribed the drugs despite contraindications. Physicians may feel compelled to make the best drug choice from among a limited availability of agents. One physician prescribed prednisone over colchicine or NSAIDs in a patient with diabetes and renal insufficiency, apparently preferring to risk steroid-induced hyperglycemia over NSAID-induced renal failure or colchicine toxicity. Physicians sometimes also fail to recognize the presence, nature, or severity of the contraindication.

The researchers acknowledged the need for more professional and patient education as well as for alternative gout therapies with fewer contraindications. They cite the recent approvals of febuxostat (Uloric, Takeda); pegylated uricase (Peg-Uricase, Savient); and colchicine (Colcrys, URL Pharma) with its new dosing schedule as potential alternatives.

Source: Am J Med 2011;124:155–163

Stable Versus Escalating Dosing of Opioids

Comparing two different opioid approaches in 575 patients, researchers found that even in carefully selected tertiary-care patients, substance misuse was a significant problem—and 40% of the problems were not apparent within the first six months.

Upon admission to the Greater Los Angeles Veterans Affairs Medical Center, patients were assigned to either a conservative, stable-dose group or a more liberal, escalating-dose group. For the stable-dose group, dose increases were kept to a minimum, with the target of a steady dosage over the 12 months of the study. Doses were increased only when it was deemed medically necessary. Patients reporting inadequate pain relief were allowed to increase adjuvant medications or were encouraged to use coping skills such as exercise.

Patients in the escalating-dose group who reported inadequate pain relief were given non-opioid/non-drug choices plus a moderately increased dose and could switch from a short-acting to a long-acting medication. The dose was not increased when it would have been medically or ethically irresponsible, based on side effects or possible substance abuse. The three primary outcomes were improvement in usual pain levels, pain relief from drugs, and improved functioning.

Although differences in primary outcomes between the two groups were not statistically significant, the escalating-dose strategy did lead to modest improvements in self-reported acute relief without an increase in misuse. The escalating-dose patients showed an 80% increase in dosage over the 12 months; the stable-dose group showed only a 16% increase.

The results suggest that escalating-dose patients with access to higher doses experienced larger, immediate decreases in pain after taking the medication, compared with the stable-dose group. However, the acute effect of the dose tended not to last and did not translate into any differences in pain scores or general functioning.

Over the course of the study, about 27% of patients were discharged as a result of opioid misuse or noncompliance, but the researchers found no differences between groups in the rate of opioid misuse. Dropout rates were similar: 33% in the stable-dose group and 26% in the escalating-dose group. Discontinuations owing to substance misuse or noncompliance were attributed to alcohol or illicit substance abuse in 10% of patients, noncompliance with the regimen in 15%, or noncompliance with clinic procedures in 4%. Most discontinuations occurred in the first six months: 30% in the first two months, another 30% by six months, and 5% in the last two months.

The results can be interpreted in two ways:

Pro stable-dose strategy. Despite the 80% increase in the escalating-dose group’s dose, pain severity and disability did not improve. The only small positive effect seemed to be acute relief. The lack of a significant benefit, therefore, argues for a more conservative approach or even the withdrawal of opioids altogether. Even in the stable-dose group, the dose had to be increased somewhat, which suggests that tolerance is a problem even with conservative management.

Pro dose-escalation strategy. The dose-escalation protocol did not lead to more opioid misuse; it did show a small but significant pain relief. However, because this approach included significant limitations on dose escalation and because opioid side effects were not captured, the researchers caution against over-generalizing to support greater opioid dosing as a general strategy.

This is the first one-year trial to assess pain relief and substance misuse outcomes from opioid treatment of chronic, nonmalignant pain. Because it took more than six months for most of the misuse to become evident, the researchers recommend more long-term studies.

Source: J Pain 2011;12(2):288–296


NIH News

Genetic Studies in Melanoma

Researchers at the National Institutes of Health (NIH) have surveyed the landscape of the melanoma genome, the DNA code of this skin cancer. Using whole-exome sequencing, the team is decoding 1% to 2% of the genome that contains protein-coding genes.

A major cause of melanoma is sun overexposure, which can damage DNA and cause genetic changes within skin cells. The team explored the melanoma genome’s genetic alterations. In the metastatic stage, cells have the highest number of gene mutations. Melanoma is challenging because of this high rate.

Most mutations do not have a functional role in melanoma. After ruling out these mutations, the scientists focused on those most likely to cause melanoma. They identified 68 genetic changes that appeared to be somatically mutated at a high rate, then identified 16 genes judged to be melanoma driver mutations.

Mutations in one gene (TRRAP) were remarkable for occurring at the exact position in six patients with melanoma. TRRAP harbors a recurrent mutation clustered in one position along the string of DNA code in about 4% of cases. This suggests that it is a driver and probably an oncogene.

Oncogenes enable cells to survive rather than die off normally. The team had not expected to identify novel hot-spot mutations. TRRAP is found in many species, suggesting its importance in normal function and that mutations in this gene would detrimentally affect protein function. To confirm a possible cell-survival function for it, the researchers disrupted the gene in mutant cell lines. The cells had an increase in apoptosis over time. Cancer cells normally do not undergo cell death, and thus they survive. The test showed that TRRAP is a cancer-causing oncogene, because the mutant cell is dependent on it.

The researchers also used cell signaling pathway analysis, identifying glutamate signaling as a pathway involved in melanoma. In 2003, a study in Nature Genetics implicated the glutamate signaling pathway in melanoma.

Sources: Nat Genet, NIH, April 15, 2011, online

Nevirapine (Viramune) Reduces HIV Risk in Breast-Feeding Infants

Giving breast-feeding infants of HIV-infected mothers a daily dose of the anti-retroviral drug nevirapine (Viramune, Boehringer Ingelheim) for six months halved the risk of transmitting HIV infection to the infants at six months of age compared with giving them the drug daily for six weeks. The longer regimen resulted in a 75% reduction in HIV transmission risk through breast milk for infants of HIV-infected mothers with higher T-cell counts who had not yet begun HIV treatment.

These early findings, presented at the 18th Conference on Retroviruses and Opportunistic Infections, apply to mothers and infants in developing nations.

Breast milk contains protective antibodies from the mother that formula feeding does not provide. Giving the infants of HIV-infected mothers an anti-retroviral drug daily for the full duration of breast-feeding safely minimized the threat of HIV transmission through breast milk and preserved the health benefits of extended breast-feeding.

More than 1,500 mother–infant pairs in South Africa, Tanzania, Uganda, and Zimbabwe are participating in the HIV Prevention Trials Network (HPTN 046), which began in February 2007 and is scheduled to conclude in July 2011.

The infants received daily nevirapine for the first six weeks after birth. Infants who remained free of HIV then received either daily nevirapine or placebo until six months after birth or the cessation of breast-feeding, whichever came first.

The primary analysis revealed that 2.4% of the infants receiving six weeks of nevirapine had acquired HIV through breast-feeding by six months of age, but only 1.1% of the infants who received six months of nevirapine had acquired HIV through breast-feeding by that time—a 54% difference.

After the preventive nevirapine regimen was stopped at six months, though, the rate of subsequent HIV transmission via breast-feeding was the same whether or not the infants had received daily nevirapine for six weeks or six months.

The percentage of infants who experienced serious health problems was nearly the same in both groups (17% in the six-week group, 19% in the six-month group). Most of these problems were infectious diseases not associated with nevirapine. Only 5% of the infants in each group had a health problem that required temporarily stopping the regimen.

The team also analyzed the impact of the mother’s health and antiretroviral treatment on the benefit of providing daily nevirapine to breast-feeding infants for six months rather than six weeks. One group included the infants of mothers who had a T-cell count of at least 350 cells/mm3 of blood and who did not yet require antiretroviral therapy. In these infants, the six-month nevirapine regimen decreased HIV transmission through breast milk by 75%, compared with the six-week regimen. In infants born to women with T-cell counts lower than 350 cells/mm3 who received anti-retroviral therapy for their own health, viral transmission to infants via breast milk was zero, or nearly zero, regardless of the duration of the nevirapine regimen.

Source: NIH, March 3, 2011

Making Brain Cells From Skin Cells to Study Schizophrenia

Researchers at Penn State, the Salk Institute for Biological Studies, and other institutions have developed a way to recreate a schizophrenic patient’s own brain cells, which can then be studied in a Petri dish. The method brings scientists closer to understanding the biological underpinnings of this brain disease.

The team took samples of skin cells from patients and reprogrammed the original skin cells to become undifferentiated (induced pluripotent) stem cells.

After generating stem cells from skin cells, the authors cultured them to become brain cells, or neurons. They compared the neurons derived from the patients with the neurons created from the stem cells of healthy individuals. Neurons generated from patients with schizophrenia made fewer connections with each other compared with healthy cells.

Antipsychotic agents were then given to test their ability to improve how neurons communicate with neighboring cells. The model system allows the team to study how antipsychotic drugs work in live, genetically identical neurons from patients with known clinical outcomes, so that the team can correlate pharmacological effects with symptoms.

The new method represents a step toward personalized medicine. Scientists can examine patient-derived neurons that are perhaps equivalent to a particular patient’s own neural cells. They may be able to see how a particular drug will affect a patient’s brain cells, without needing the patient to try the drug, which might cause side effects. Patients can design their own treatment without having to undergo experimentation directly.

Sources: Nature online, Penn State News, April 13, 2010

Discovery: Three Groups Of Intestinal Bacteria

It appears that in terms of composition, the intestinal bacteria of people around the world, regardless of their sex, race, or age, can be grouped into three distinct clusters known as enterotypes. The bacteria in each enterotype display common features. Findings from a new study indicate that gut flora affect how we digest both food and medications.

A research group, led by Dr. Peer Bork in Germany, found no link between the enterotypes and ethnic background of their subjects and found no relationship to sex, weight, health status, or age. It is theorized that the intestines of infants are randomly colonized by different pioneering species of microbes.

Gut microbes aid in food digestion and synthesize vitamins, using enzymes that our cells cannot make. Some day, doctors might be able to tailor diets or medications to match a patient’s enterotype, or they might be able to use enterotypes to find alternatives to antibiotics. Instead of eradicating disease-causing bacteria that disrupt the ecological balance of the gut, scientists may try to reinforce the good bacteria.

More testing is needed to search for enterotypes in Africans, Chinese, and other ethnic groups. So far, all subjects have come from industrial nations and thus eat similar foods.

The Bork team analyzed the microbes in 22 people from Denmark, France, Italy, and Spain, and then combined their results with previous studies of Japanese and American subjects. They found that all the microbiomes fell into three distinct groups, with each of the three enterotypes comprising a different balance of species. People with Enterotype 1, for example, had high levels of Bacteroides species. In those with Enterotype 2, Bacteroides spp. were relatively rare, but Prevotella was unusually common. Ruminococcus was a large factor in Enterotype 3.

It is unknown why people have different gut types; this could be related to differences in how the immune system distinguishes between friendly and harmful bacteria or to different ways of releasing hydrogen waste from cells. In older people, more microbial genes are involved in breaking down carbohydrates, possibly because the gut in this age group is less efficient at processing these nutrients. The fact that bacterial genes are associated with traits such as age and weight indicates that there might also be markers for traits like obesity or diseases like colorectal cancer. This could have implications for diagnosis and prognosis.

Dr. Bork and his colleagues found confirmation of the three enterotypes when they turned to other microbiome surveys; the findings continued to hold up after they expanded their own study to 400 people.

Sources: Nature (online), The New York Times, April 20, 2011; Drug Discov Dev, April 21, 2011


Marvin M. Goldenberg, PhD, RPh, MS

Name: Pipeline Embolization Device

Manufacturer: ev3, Menlo Park, Calif.

Approval Date: April 6, 2011

Purpose: The device enables neurosurgeons to treat brain aneurysms without performing open surgery.

Description: The flexible mesh tube is made of platinum and nickel–cobalt chromium alloy. It can be used to block off large (2–2.5 cm) or giant (larger than 2.5 cm) wide-necked intracranial aneurysms in the cavernous and paraclinoid regions of the internal carotid artery. Giant aneurysms are thought to represent 5% to 8% of all intracranial aneurysms. Treatment of larger aneurysms is associated with higher morbidity and mortality than smaller lesions.

The surgeon implants the device by attaching it to the end of a catheter, which is then inserted into an artery in the leg. The catheter is threaded into the carotid artery and into position at the aneurysm, where the device is expanded against the walls of the artery and across the neck of the aneurysm, cutting off blood flow to the aneurysm. The blood remaining in the blocked-off aneurysm forms a clot, which reduces the likelihood of enlargement or rupture. Aneurysms treated successfully with the device often shrink over time.

Benefit: Approximately 30,000 people in the U.S. experience ruptured aneurysms each year, according to the American Association of Neurological Surgeons. Aneurysms are more prevalent in women and in people 50 to 60 years of age. This new product offers surgeons an alternative to open surgery or placement of materials such as coils or a liquid embolic agent to treat the aneurysm. In a study, 70% of aneurysms remained blocked off without significant narrowing of the section of the artery that had been treated with the device.

Precaution: In the same study, nine patients experienced strokes in the year after treatment, but this rate was significantly less than the 20% rate expected for this condition. Patients also experienced headache, bleeding, nausea, and vision problems. The Pipeline device should not be used if the patient has an infection or cannot take antiplatelet therapy. Patients should receive adequate antiplatelet therapy before implantation.


Name: Consulta and Syncra

Manufacturer: Medtronics, Inc., Minneapolis, Minn.

Approval Date: March 24, 2011

Purpose: Two cardiac resynchronization therapy–pacemaker (CRT–P) devices permit remote follow-up in patients with heart failure who have an implanted pacemaker. Both systems provide automatic capabilities that help to ensure CRT, even if the patient has atrial fibrillation.

Description: Consulta and Syncra include the same technology but have different features. Both contain a leadless electrocardiographic (ECG) waveform and a network data-monitoring capability that permits remote follow-up. Via the network, patient data are transmitted from the implanted device by a portable monitor through cellular signals or a standard telephone line. Within minutes, physicians and nurses can view fluid status, arrhythmias, stored ECGs, and information about device integrity on a secure Internet Web site.

Benefit: Atrial arrhythmias are a primary cause of reduced cardiac resynchronization therapy; consequently, there is a need for devices that can deliver lifesaving CRT in these patients. Physicians can monitor patients from the office or elsewhere. Programming flexibility helps to prevent phrenic nerve stimulation, thereby helping to avoid the need for more invasive surgery.

Consulta is the first CRT–P device that includes fluid status monitoring, which can identify patients at risk for worsening heart failure before symptoms develop.