Bausch + Lomb and ISTA Pharmaceuticals announced that they have signed a definitive agreement under which Bausch + Lomb will acquire ISTA for $500 million. The transaction, which has been unanimously approved by the boards of directors of both companies, is expected to close in the second quarter of 2012.

B + L says the acquisition of ISTA accelerates its strategy to strengthen its pipeline and marketed products and capabilities. The combination adds ISTA’s portfolio of non-steroidal, anti-inflammatory, allergy, glaucoma and spreading agents to B + L’s complementary portfolio of existing Rx ophthalmology and OTC eye health products. The companies also have complementary development pipelines. ISTA’s pipeline includes candidates in various stages of development to treat various ocular conditions including inflammation and pain, while B + L’s pipeline of pharmaceutical innovations includes the first of a new class of ocular anti-inflammatory agents to come along in decades, and a promising approach to reducing intraocular pressure in patients with open-angle glaucoma or ocular hypertension.

“ISTA is an excellent strategic fit with Bausch + Lomb’s rapidly growing pharmaceutical business, and this combination represents an important step in Bausch + Lomb’s commitment to becoming the best global eye health company,” said Brent Saunders, president and chief executive officer, B + L. “Because Bausch + Lomb already manufactures nearly all of ISTA’s current U.S. products, our companies have known each other well for many years. With this combination, we will significantly enhance our pharmaceutical pipeline, nearly doubling the number of mid- to late-stage innovations. We look forward to delivering the benefits of this combination to customers, patients, employees and partners of both companies.”

The transaction is subject to regulatory approval and other customary closing conditions, including the approval of ISTA’s shareholders. The companies will continue to operate independently until completion of the transaction.

Fluoroquinolone Use Tied to Small Increase in RD
In an analysis of a cohort that included nearly one million patients who had visited an ophthalmologist, patients who were taking oral fluoroquinolones had a higher risk of developing a retinal detachment, compared with nonusers, although the absolute risk was small, according to a study in the April 4 issue of the Journal of the American Medical Association

Although fluoroquinolones are generally well-tolerated, they have been associated with a wide array of adverse events and linked to several forms of ocular toxicity, such as corneal perforations, optic neuropathy and retinal hemorrhages. “Despite numerous case reports of ocular toxicity, a pharmacoepidemiological study of their ocular safety, particularly retinal detachment, has not been performed,” the authors write. “Retinal detachment is a serious medical emergency that may lead to irreversible vision loss.”

Mahyar Etminan, PharmD, MSc, of the Child and Family Research Institute of British Columbia, Vancouver, Canada, and colleagues conducted a study to examine the association between oral fluoroquinolone use and the risk of retinal detachment. The study consisted of a group of patients in British Columbia who had visited an ophthalmologist over a seven-year period. Retinal detachment cases were defined as a procedure code for retinal repair surgery within 14 days of a physician service code. The overall cohort included 989,591 patients; within this group, 4,384 cases of retinal detachment and 43,840 corresponding controls were identified for analysis. Cases were more likely to be male and were more likely to have myopia, diabetes or have undergone cataract surgery. The researchers found that retinal detachment was associated with a higher likelihood of current use of fluoroquinolones (3.3 percent of cases vs. 0.6 percent of controls). For current users, the average number of days from the first fluoroquinolone prescription to the first event of a retinal detachment was 4.8 days. No risk was observed among recent users (0.3 percent of cases vs. 0.2 percent of controls) or past users (6.6 percent of cases vs. 6.1 percent of controls). The authors note that the absolute increase in the risk for this condition was small (number needed to harm=2,500 for any use of fluoroquinolones). No risk was observed in current users of β-lactam antibiotics or short-acting β-agonists. 

“This is the first study, to our knowledge, demonstrating that oral fluoroquinolones are associated with an increase in the risk of a retinal detachment. Current users of oral fluoroquinolones were nearly five times more likely to be diagnosed with retinal detachment than nonusers,” the researchers write, although because retinal detachment is rare among unexposed patients, the absolute risk increase is low. 

The authors add that the risk of RD in their study was only elevated among current users but not among recent or past users, indicating an acute adverse event. They note that the exact mechanism of retinal detachment with fluoroquinolones is unknown. “Future pharmaco-epidemiological studies should be conducted to confirm or refute these findings,” they conclude. 

‘Positive Stress’ Helps Protect ON From Glaucoma
Working in mice, scientists at Washington University School of Medicine in St. Louis have devised a treatment that prevents the optic nerve injury that occurs in glaucoma.

Researchers increased the resistance of optic nerve cells to damage by repeatedly exposing the mice to low levels of oxygen similar to those found at high altitudes. The stress of the intermittent low-oxygen environment induces a protective response called tolerance that makes nerve cells—including those in the eye—less vulnerable to harm. 

The study, published online in Molecular Medicine, is the first to show that tolerance induced by preconditioning can protect against a neurodegenerative disease.

Stress is typically thought of as a negative phenomenon, but senior author Jeffrey M. Gidday, PhD, associate professor of neurological surgery and ophthalmology, and others have previously shown that the right kinds of stress, such as exercise and low-oxygen environments, can precondition cells and induce changes that make them more resistant to injury and disease. 

Scientists previously thought tolerance in the central nervous system only lasted for a few days. But last year Dr. Gidday developed a preconditioning protocol that extended the effects of tolerance from days to months. Exposing mice to hypoxia several times over a two-week period triggered an extended period of tolerance. After preconditioning ended, the brain was protected from stroke damage for at least eight weeks. 

“Once we discovered tolerance could be extended, we wondered whether this protracted period of injury resistance could also protect against the slow, progressive loss of neurons that characterizes neurodegenerative diseases,” Dr. Gidday says.

Scientists classify glaucoma as a neurodegenerative disease based on how slowly and progressively it kills retinal ganglion cells. They don’t know if damage begins in the bodies or axons of the cells, but as more and more retinal ganglion cells die, patients experience peripheral vision loss and eventually become blind.

For the new study, Yanli Zhu, MD, research instructor in neurosurgery, induced glaucoma in mice by tying off vessels that normally allow fluid to drain from the eye. This causes pressure in the eye to increase. Dr. Zhu then assessed how many cell bodies and axons of retinal ganglion cells were intact after three or 10 weeks. 

The investigators found that normal mice lost an average of 30 percent of their retinal ganglion cell bodies after 10 weeks of glaucoma. But mice that received the preconditioning before glaucoma-inducing surgery lost only 3 percent of retinal ganglion cell bodies. 

“We also showed that preconditioned mice lost significantly fewer retinal ganglion cell axons,” Dr. Zhu says.

Dr. Gidday is currently investigating which genes are activated or repressed by preconditioning. He hopes to identify the changes in gene activity that make cells resistant to damage.

“Previous research has shown that there are literally hundreds of survival genes built into our DNA that are normally inactive,” Dr. Gidday says. “When these genes are activated, the proteins they encode can make cells much less vulnerable” to injuries.

Identifying specific survival genes should help scientists develop drugs that can activate them, according to Dr. Gidday.

Neurologists are currently conducting clinical trials to see if stress-induced tolerance can reduce brain damage after acute injuries like stroke, subarachnoid hemorrhage or trauma. 

Dr. Gidday hopes his new finding will promote studies of tolerance’s potential usefulness in animal models of Parkinson’s, Alzheimer’s and other neurodegenerative conditions.

“Neurons in the central nervous system appear to be hard-wired for survival,” he says. “This is one of the first steps in establishing a framework for how we can take advantage of that metaphorical wiring and use positive stress to help treat a variety of neurological diseases.”

Osteo Drugs May Raise Uveitis and Scleritis Risk
Drugs commonly used to prevent osteoporosis may increase the risk of uveitis or scleritis in first-time users, says an article in the Canadian Medical Association Journal.

Oral bisphosphonates have been linked to adverse events such as unusual fractures, irregular heartbeat and esophageal and colon cancer. Some case reports have shown an association between these drugs and anterior uveitis and scleritis.

Researchers in Vancouver, BC, undertook a study to examine and quantify the risk associated with uveitis or scleritis and oral bisphosphonates because the literature is limited. They included 934,147 people in British Columbia who had visited an ophthalmologist between 2000 and 2007. Of the total, 10,827 were first-time users of bisphosphonates and 923,320 were nonusers.

The incidence rate for uveitis in first-time users was 29/10,000 person-years compared with 20/10,000 in nonusers, and 63/10,000 person-years for scleritis compared with 36/10,000 for scleritis in nonusers.

“We found that first-time users of bisphosphonates are at an increased risk of scleritis and uveitis,” writes Mahyar Etminan, PharmD, MSc, of the Child and Family Research Institute and the Department of Medicine, University of British Columbia, with coauthors.

“The risk of inflammatory ocular adverse events, including scleritis and uveitis, is not highlighted in most package inserts included with oral bisphosphonates,” the authors conclude. “Our study highlights the need for clinicians to inform their patients about the signs and symptoms of scleritis and uveitis, so that prompt treatment may be sought and further complications averted.”

The authors note that patients taking oral bisphosphonates must be aware of symptoms for these eye conditions so they can seek treatment.  REVIEW