Cognitive behavioural therapy (CBT) for anxiety in people with dementia: study protocol for a randomised controlled trial

Background

Many people with dementia experience anxiety, which can lead to decreased independence, relationship difficulties and increased admittance to care homes. Anxiety is often treated with antipsychotic medication, which has limited efficacy and serious side effects. Cognitive behavioural therapy (CBT) is widely used to treat anxiety in a range of populations, yet no RCTs on CBT for anxiety in dementia exist. This study aims to develop a CBT for anxiety in dementia manual and to determine its feasibility in a pilot RCT.

Methods

Phase I involves the development of a CBT for anxiety in dementia manual, through a process of (1) focus groups, (2) comprehensive literature reviews, (3) expert consultation, (4) a consensus conference and (5) field testing. Phase II involves the evaluation of the manual with 50 participants with mild to moderate dementia and anxiety (and their carers) in a pilot, two-armed RCT. Participants will receive either ten sessions of CBT or treatment as usual. Primary outcome measures are anxiety and costs. Secondary outcome measures are participant quality of life, behavioural disturbance, cognition, depression, mood and perceived relationship with the carer, and carer mood and perceived relationship with the person with dementia. Measures will be administered at baseline, 15 weeks and 6 months. Approximately 12 qualitative interviews will be used to gather service-users' perspectives on the intervention.

Discussion

This study aims to determine the feasibility of CBT for people with anxiety and dementia and provide data on the effect size of the intervention in order to conduct a power analysis for a definitive RCT. The manual will be revised according to qualitative and quantitative findings. Its publication will enable its availability throughout the NHS and beyond.

Off-label Drug Use

What is off-label drug use?

In the United States new drugs are tested in clinical trials (research studies) before they are approved for use in the general public. The clinical trials are done to prove that the drug:

• Works to treat a certain medical condition
• Works the way it is expected to
• Is safe when used as directed

When the US Food and Drug Administration (FDA) is satisfied that the drug works and is safe, it and the maker of the drug create the drug label. This is not an actual label that sticks onto a bottle, but a report of very specific information about the drug. The FDA must approve this report, which is made available to all health professionals who prescribe or sell the drug.

The drug label gives information about the drug, including the approved doses and how it's to be given to treat the medical condition for which it was approved. When a drug is used in a way that is different from that described in the FDA-approved drug label, it is said to be an "off-label" use. This can mean that the drug is:

• Used for a different disease or medical condition
• Given in a different way (such as by a different route)
• Given in a different dose than in the approved label

For example, when a chemotherapy drug is approved for treating one type of cancer, but is used to treat a different cancer, it is off-label use.

Off-label is also called "non-approved" or "unapproved" use of a drug.

Is off-label drug use legal?

The off-label use of FDA-approved drugs is not regulated, but it is legal in the United States and many other countries. An exception to this is the use of some controlled substances, such as opioids (pain medicines like morphine and fentanyl). These drugs cannot legally be prescribed in the United States except for approved purposes.

While it is legal for doctors to use drugs off label, it is not legal for drug companies to market their drugs for off-label uses. This has been a hot news topic recently, as drug companies have been fined because they promoted drugs for uses not approved by the FDA. Off-label marketing is very different from off-label use.

Why are drugs used off-label?

Older, generic medicines are the ones most often used off label. New uses for these drugs may have been found and there is often medical evidence to support the new use. But the makers of the drugs have not put them through the formal, lengthy, and often costly studies required by the FDA to officially approve the drug for new uses.

Off-label drug use is common in cancer treatment. There are many reasons for this:

• Some cancer drugs are found to work against many different kinds of tumors.
• Chemotherapy treatments often use combinations of drugs. These combinations might include one or more drugs not approved for that disease. Also, drug combinations change over time as doctors study different ones to find out which work best.
• Cancer treatment is always changing and improving.
• Oncologists and their patients are often faced with problems that have few approved treatment options.
• Oncologists and their patients may be more willing to try off-label drugs than other medical specialties.

What problems are caused by off-label drug use?

Reimbursement

The biggest problem is getting insurance plans to pay for off-label drug use (reimbursement). Many insurance companies will not pay for an expensive drug that is used in a way that is not listed in the approved drug label. They do this on the grounds that its use is "experimental" or "investigational."

In cancer treatment, these issues have been largely addressed through 1993 federal legislation that requires insurance to cover medically appropriate cancer therapies. This law includes off-label uses if the treatment has been tested in careful research studies and written up in well-respected drug reference books or medical journals. In 2008, Medicare rules were changed to cover more off-label uses of cancer treatment drugs.

Still, the health insurance coverage laws and regulations are complex. If your doctor is thinking about off-label drug use, you and your doctor should carefully check your health plan's coverage. If coverage is denied the first time, it may help for the doctor to send the insurer copies of peer-reviewed journal articles or other respected sources that support the off-label use.

Legal risk

Another problem is that off-label drug use often does not reflect "standard of care" treatment. This leads to possible concern about the legal risk of prescribing off-label should a patient have an unwanted or bad outcome from the treatment.

Lack of regulation and information

The FDA does not regulate the practice of medicine. In general, once the FDA approves a drug, licensed doctors can use it for any purpose they consider medically appropriate. Off-label use can vary greatly from one doctor to another. It depends on the doctor's preferences, knowledge, and past patient experiences.

One of the biggest problems related to widespread off-label use is the lack of information about how to best use the drug beyond what was approved. One of the most reliable and easy-to-find sources of information available to health professionals, caregivers, and patients is the drug label. But the label can only contain the information that has been approved by the FDA, and it does not mention off-label uses.

The medical literature reports clinical trials, including those that are not part of the FDA approval process. This is the main source of off-label use information, although treatment guidelines may also offer options that include off-label use. Treatment guidelines are based on information from medical literature, including clinical trials, and recommend standard ways to treat certain diseases.

Lack of information on off-label drug use and outcomes may also put patients at a higher risk for medication errors, side effects, and unwanted drug reactions. It is important that the patient and doctor talk about the possible risks of using the drug and weigh them against the possible benefits.

How common is off-label drug use?

Little information is available on off-label prescribing in oncology in the US. Yet, a study done in 2008 found that 8 out of 10 cancer doctors surveyed had used drugs off-label. Off-label drug use is well-documented and very common in certain settings, such as pediatrics and HIV/AIDS care.

Studies have reported that about half of the chemotherapy used is given for conditions not listed on the FDA-approved drug label. In fact, the National Cancer Institute (NCI) has stated, "Frequently the standard of care for a particular type or stage of cancer involves the off-label use of one or more drugs." Actual off-label use is likely much higher because chemotherapy is only one aspect of cancer treatment. Studies have yet to look at all the drugs used in cancer treatment, such as anti-nausea drugs and pain medicines.

What other ways are drugs used off label in cancer treatment?

One example of off-label drug use is tricyclic antidepressants to treat certain types of pain. This old class of antidepressant drugs is approved and labeled to be used for clinical depression. Today these drugs are seldom used for depression because safer drugs are now available to treat it. But doctors have found that the tricyclics often work very well in treating certain types of pain.

Another example is lorazepam (Ativan®), an anti-anxiety drug often used as an anti-nausea drug in cancer treatment. In oncology, Ativan is most commonly given under the tongue (the sublingual route), which is also not listed on the drug label. In this case, it is being given for an off-label use and by an off-label route.

RECENT EMERGING HUB FOR GLOBAL CLINICAL RESEARCH IN INDIA

The economic environment of a country has a very strong impact on the economic system in which its industries and business firms operate. As far as economic environment of India is concerned, India's is a mixed economy. A simple mixed economic system is characterized by existence of both private and public sectors. In present the clinical trial market in India looks very lucrative. The country promises to be one of the hottest destinations for conducting global clinical trials, owing to a huge patient pool representing both chronic and infectious diseases, easy recruitment of patients, and high cost savings. Moreover, the market is getting boost from improved IPR protection with changed rules and also from reduced taxes and duties. According to our new research study on the sector called "Booming Clinical Trials Market in India", the clinical trial outsourced market in India is forecasted to grow at a compound annual growth rate( CAGR) of around 31% during 2010-2012. Presently, the market is characterized by the dominance of phase III and phase II trials, which currently hold more than 80% of the market. India has the largest pool of patients in many diseases, including cancer and diabetes. The study also points out that India's biggest advantage is its low cost. For instance, trials for a standard drug in the US can cost up to $150 million. A similar drug could be tested in India for less than half that amount. Center Watch has predicted that by 2010, the industry will spend around $250-300 million on clinical trials in India. Mc Kinsey estimates a much higher figure of $1-1.5 billion. This scenario is expected to remain intact in future as well. With detailed description of the regulatory environment and cost factors promoting the market. It also highlights several emerging market trends like clinical data management, pathology and diagnostic market, etc. The research study offers detailed statistical and analytical review on demographics, macroeconomic indicators, disease profile, clinical service market, key drivers and restraints. It contains all the requisite information that will help clients to draw up market strategies and assess opportunity areas in India's clinical trial market.Clinical trials in India is 44% less expensive than US trials.

Strategy For Reversing Type 1 Diabetes Supported By Ongoing Clinical Trial

A phase I clinical trial has confirmed that use of a generic vaccine to raise levels of an immune system modulator can cause the death of autoimmune cells targeting the insulin-secreting cells of the pancreas and temporarily restore insulin secretion in human patients with type 1 diabetes. Results of the study - led by Denise Faustman, MD, PhD, director of the Massachusetts General Hospital (MGH) Immunobiology Laboratory - are being published in the open-access journal PLOS ONE, and a larger Phase II trial is currently underway. 

Faustman's team first reported  that inducing expression of tumor necrosis factor (TNF), previously shown to destroy insulin-autoreactive T cells, cured type 1 diabetes in mice by permitting pancreatic islets to regenerate. Since high doses of TNF are toxic to humans, the clinical trials use the bacillus Calmette-Guérin (BCG) vaccine, which safely elevates TNF levels. The Iacocca Family Foundation has been the primary supporter of this work. 

"We believe we have validated in humans the treatment pathway we originally reported in mice and are seeing early evidence of effectiveness," says Faustman. "Our findings show that this simple, inexpensive vaccine modifies the autoimmunity underlying type 1 diabetes, boosting TNF production and killing the disease-causing T cells, which appears to briefly restore pancreatic beta-cell function. This is not a prevention trial. We are trying to create a regimen that will actually reverse type 1 diabetes in people who are living with the disease. We anticipate that the Phase II trial will give us more direction for turning BCG into a more sustained treatment, including the right dose and the frequency of vaccination needed to sustain a therapeutic response." 

A generic drug with over 90 years of clinical use, BCG is currently approved by the Food and Drug Administration for vaccination against tuberculosis and for the treatment of bladdercancer. The double-blind Phase I trial enrolled six long-term type 1 diabetes patients - diagnosed for an average of 15 years - who were randomly assigned to receive two doses of either BCG or a placebo spaced four weeks apart. Blood samples from the participants with diabetes were also compared with samples from six nondiabetic control participants and with samples from 75 additional individuals with diabetes and 15 without. Frequent blood tests measured participants' blood levels of insulin-autoreactive T cells, of an autoantibody, of regulatory T cells that help control the immune response, and of C-peptide, a marker of pancreatic insulin secretion. 

During the 20-week study period, two of the three participants treated with BCG showed increases in the death of insulin-autoreactive T cells and in levels of protective regulatory T cells. A temporary but statistically significant elevation in C-peptide levels, suggesting a restoration of insulin production, was also observed in the BCG-treated patients. Unexpectedly, the same responses were seen in one of the placebo-treated patients who, after enrolling in the study, coincidently developed infection with the Epstein-Barr virus, which is known to induce expression of TNF. There were no significant adverse events. The researchers expect that more frequent or higher BCG dosing than was used in this trial will be needed for long-term elimination of insulin-autoreactive T cells and a sustained restoration of C-peptide secretion and insulin production. 

"This is an exciting time for type 1 diabetes research," says Paul Burn, PhD, chair and director emeritus of the Sanford Project and professor of Pediatrics at the Sanford School of Medicine at the University of South Dakota. "Dr. Faustman and her team's clinical research data indicate that modifying the autoimmunity underlying type 1 diabetes allows for a safe and temporary restoration of insulin-secreting beta-cell function in patients with established type 1 diabetes. Restoring beta-cell function is a promising first step towards a cure. During my tenure in industry, at Sanford Health and at the Juvenile Diabetes Research Foundation, I have seen how hard it is to get a project from mice into humans, and these are very impressive results." 

These findings are consistent with recent trials in Italy that showed BCG vaccination could decrease disease activity and prevent progression of brain lesions in advanced multiple sclerosis, an autoimmune disease also caused by autoreactive T cells vulnerable to TNF-triggered cell death. A recent Turkish study suggested that repeat BCG administration, but not single a BCG vaccination, could prevent diabetes onset in children and that childhood BCG vaccinations prevent the formation of autoantibodies. The PLoS One paper reflects a 20-year journey for the Faustman lab from understanding the role of TNF to developing a way to measure death of the disease-causing T cells in type 1 diabetes and redefining how the pancreas functions in individuals who have had diabetes for decades. 

In addition to providing major funding for the now-completed Phase I trial, the Iacocca Family Foundation has committed to a leadership role in the Phase II clinical trial. Currently, $11 million has been raised out of a total of $25 million needed to conduct the Phase II study over the next three years. "The Iacocca Family Foundation is so pleased that our ongoing support for Dr. Faustman's research has generated such meaningful results. This research has been an important part of our family's commitment to find a cure for type 1 diabetes," said Kathryn Iacocca Hentz, president of the Iacocca Family Foundation. 

Current trends in the pharmacotherapy of diabetic retinopathy

INTRODUCTION

Method- Literature search was done on online database, Pubmed, Google Scholar, clinitrials.gov and browsing through individual ophthalmology journals and leading pharmaceutical company websites.

Diabetic retinopathy (DR) is characterized by the progressive development of well-defined morphological abnormalities in the retinal microvasculature that can remain relatively stable, that is non-proliferative diabetic retinopathy (NPDR) or progress to diabetic macular edema (DME) and/or proliferative DR (PDR). ^[1],[2] One of the major hallmarks of DR is increased vascular permeability, which leads to the development of retinal hemorrhages and fluid accumulation in the macula, which is referred as DME. ^[3],[4],[5] 

Since the last two decades there have been significant developments in the emerging field of pharmacotherapy of DR. The advent of laser photocoagulation three decades back, was really useful in limiting vision loss in most of the cases and is still considered gold standard therapy for the treatment of DR. However, corticosteroids and anti-VEGF agents have shown promising results with regard to prevention of neovascularisation, but remained limited in use due to their short-duration effects. More importantly none of these agents have been able to substitute the remarkable durability and effectiveness of panretinal photocoagulation in preventing vision loss in the late stages of DR. Therefore, pharmacotherapy of DR is still an adjunct to panretinal photocoagulation .

Various inflammatory mediators are up-regulated during DR including Tumour Necrosis Factor - α (TNF-α), Interleukin-1β (IL-1β) and Vacular Endothelial Growth Factor (VEGF) are investigated to play significant role in the pathogenesis of DR. These inflammatory mediators are very well modulated with corticosteroids. In the past, corticosteroids have been incorporated as a treatment option for DME and DR, because of their anti-inflammatory and anti-angiogenic effects. However, they remained limited in use as an adjunct to panretinal photocoagulation due to their short duration of effectiveness. The primary mode of delivery of corticosteroids is through the intravitreal route, so as to avoid the blood-retinal barrier limitations to reach the drug to the target site. However, these direct intravitreal injections are often associated with steroid-related adverse effects including cataract and elevation of IOP, and less common injection-related side-effects such as retinal detachment, vitreous hemorrhage, and endopthalmitis.  Despite this fact, corticosteroid therapy has been effective for DME and DR as an adjunct to laser photocoagulation, and has also shown improvements in best corrected visual acuity (BCVA). 

Intravitreal triamcinolone acetonide (IVTA) has been studied for its potent anti-inflammatory effects and has shown improvement in DME and age-related macular degeneration (AMD).  With its anti-angiogenic effects, IVTA is a valuable option in the treatment of proliferative DR.  The US FDA has approved a couple of IVTA preservative-free injections, Triesence (40 mg/ml, Alcon) and Trivaris (80 mg/ml, Allergan), so as to lessen the incidence of non-infectious endophthalmitis and other complications.

The diabetic retinopathy clinical research (DRCR) network investigated the retinal thickness (by Optical Coherence Tomography) and visual acuity outcomes of two doses (1 mg and 4 mg) of travaris in comparision to macular photocoagulation for the treatment of macular edema in a large, multicenter randomized clinical trial. After three years of follow-up, treatment with macular photocoagulation was associated with improved BCVA and fewer complications. On the other hand, two major complications of IVTA were cataract formation and ocular hypertension. However, the rate of endophthalmitis in patients enrolled in the DRDRnet and SCORE (Standard care versus Corticosteroid for Retinal vein occlusion study) trials was 0.05%.  

Moreover, various randomized clinical trials have shown that treatment with IVTA in the improvement of BCVA at three months but treatment was no longer effective at six months. ^[16] So this lack in the efficacy for chronic use and associated adverse effects at higher doses has resulted in the focus on the development of novel intravitreal steroid delivery devices that release a small quantity over a prolonged period of time.

SUSTAINED DRUG DELIVERY SYSTEM OF CORTICOSTEROIDS

For chronic inflammatory disorders like DR, there is urgent need for sustained-release corticosteroid therapy, which can help in reducing associated adverse effects. One such steroid drug delivery system in development for use in DME is the triamcinolone acetonide (TA) implant (I-vation^® ), which has already completed a Phase I trial in the long-term treatment of DME, and a Phase II clinical triamcinolone acetonide trial is being planned. ^[17],[18] It is composed of biodegradable polymers which slowly degrade over time, thereby bypassing the risk of secondary surgical complications upon removal as compared to non-biodegradable devices. ^[18] Another potential new steroid delivery system is the sustained release fluocinolone acetonide non-biodegradable intravitreal insert (Iluvien^® , Alimera Sciences). Iluvien is designed to release the drug fluocinolone acetonide up to three years. Importantly, the device is very small, which can be injected into the back of the eye with a 25-gauge needle creating a self-sealing hole. The insertion procedure is almost similar to an intravitreal injection. The two ongoing pivotal multicenter trials known collectively as FAME study have shown improvement in BCVA at low-dose insert (0.19 mg total, approx. 0.23 μg/day) out of the two doses studied.  However, in response to new drug application (NDA) seeking approval to market ILUVIEN (fluocinolone acetonide intravitreal insert) for the treatment of DME., FDA has recently issued the complete response letter to communicate its decision that the NDA cannot be approved in its present form.

Another fluocinolone acetonide intravitreal implant, Retisert^® (Bausch and Lomb) is FDA-approved for the treatment of chronic, non-infectious uveitis. A Phase III clinical trial conducted in patients with DME reported large cases of cataract and glaucoma. 

Ozurdex^® (allergen) is an extended-release biodegradable dexamethasone intravitreal implant that has been recently approved by the FDA for the treatment of macular edema secondary to retinal vein occlusions (RVO). A 2007 study found that dexamethasone (at 700 μg) was well tolerated and produced statistically significant improvements in BCVA and central retinal thickness at Day 90, but at Day 180 no significant difference in visual acuity was found and both treatments groups (350 μg and 700 μg) had an increased incidence of elevated IOP. 

The Cortiject implant (NOVA63035; Novagali Pharma) is a preservative- and solvent-free emulsion that contains a tissue-activated proprietary corticosteroid prodrug. Once released, the prodrug is converted into an active drug at the level of the retina. A single intravitreal injection of the emulsion provides sustained release of the corticosteroid over a six to nine-month period. An open-label, Phase I, dose-escalation clinical study to assess the safety and tolerability of NOVA63035 in patients with DME is currently under way.  

The Verisome delivery system (Icon Biosciences, Inc.) is also a sustained-release drug delivery system. When injected into the vitreous as a liquid via a standard 30-gauge needle, the liquid coalesces into a single spherule. The biodegradable vehicle provides controlled, extended drug release over a titratable period of up to one year. The drug delivery system degrades as the active agent is released over the intended duration. For its first clinical trial, the Verisome technology was formulated for the injectable intraocular sustained-release delivery of TA (IBI-20089).  The Phase I and II trial of IBI-20089 in patients with cystoids macular edema associated with RVO conducted using two dosing levels, (1) 25-μL dose designed to last six months, and (2) 50-μL dose designed to last one year. The patients were treated with a single intravitreal injection of Verisome containing TA through a 30-gauge needle in two sequential cohorts of five patients each. The first cohort received a lower dose containing 6.9 mg triamcinolone in 25 μL with sustained delivery calculated to last for six months. The second cohort received a higher dose containing 13.8 mg triamcinolone in 50 μL calculated to last for 12 months. Based on the results of clinical trials, it was concluded that Verisome was well tolerated by patients without any drug-related adverse events and demonstrated evidence of controlled release efficacy for a low dose of triamcinolone. The larger dose showed more evidence of efficacy than the smaller dose. 

MISCELLANEOUS ANTI INFLAMMATORY AGENTS

Nepafenac (Nevanac^® , Alcon) is an FDA-approved topical non-steroidal anti-inflammatory drug that has demonstrated efficacy against DME in one case report.  However, clinical trials are warranted.

Etanercept (Enbrel^® , Amgen, Inc. and Wyeth) is a recombinant fusion protein having anti-TNF-α property and is FDA-approved for the treatment of psoriasis. A small series of patients with refractory DME were treated with intravitreal etanercept, but no statistically significant improvement was found. 

Infliximab (Remicade^® , Centocor) is another TNF-α antagonist that is FDA-approved to treat Crohn's disease. An investigation of systemic treatment of DME with infliximab has led to a study of administration through intravitreal injection.  

Angiogenesis Inhibitor

In addition to corticosteroids, anti-angiogenic agents are found to be effective for the treatment of proliferative DR and DME. Presently, novel and more specific anti-angiogenic agents are being explored in order to address the vascular leakage and, perhaps, neovascularisation associated with DME. The most popular target of these agents is the subfamily of proteins known as VEGF, whose over-expression is believed to play a role in numerous diseases including DR and AMD. After all, laser photocoagulation remains the gold standard therapy for the treatment of proliferative DR. Whereas, newly developed anti-VEGF agents are used as an adjunct to laser photocoagulation.

Bevacizumab (Avastin^® , Genentech Inc.) is a complete full-length humanized antibody that binds to all subtypes of VEGF and is successfully used in tumor therapy as a systemic drug. ^[31] Recent studies have demonstrated the usefulness of an intravitreal injection of bevacizumab in the reduction of vascular permeability and fibrovascular proliferation in macular edema secondary to central vein occlusion, retinal neovascularization secondary to PDR, and choroidal neovascularization secondary to AMD. 

Ranibizumab (Lucentis^® , Genentech, Inc.) is a recombinant humanized antibody fragment against VEGF-A, and was approved by the FDA for the treatment of exudative AMD in the year 2006.  Recently, Roche announced (January, 2011) that one of the two Phase III (RISE Study) studies evaluating monthly Lucentis in patients with DME met its primary endpoint.

Moreover, in 2010, Lucentis has been approved by FDA for macular edema following RVO. The BRAVO study assessed the safety and efficacy profile of Lucentis for macular edema following branch-RVO. The CRUISE study assessed the safety and efficacy profile of Lucentis for macular edema following central-RVO. The primary endpoint of both studies was mean change from baseline in BCVA at six months compared with patients receiving sham injections.

In the BRAVO study, the percentage of patients in the Lucentis study group who gained 15 or more letters in BCVA from baseline at month six was 61% (compared with 29% in the sham injection study group). In the CRUISE study, the percentage of patients in the Lucentis study group who gained 15 or more letters in BCVA from baseline at month six was 48% (compared with 17% in the sham injection study group). At six months, patients in the BRAVO study who received Lucentis had a mean gain of 18.3 letters (compared to 7.3 letters in patients receiving sham injections). In the CRUISE study, at month six, patients who received Lucentis had a mean gain of 14.9 letters (compared to 0.8 letters for patients receiving sham injections).  

VEGF Trap Eye (Aflibercept, EYLEA^® , Regeneron Pharmaceuticals, Inc. and Bayer HealthCare Pharmaceuticals) is a recombinant fusion protein consisting of portions of human VEGF receptors 1 and 2 extracellular domains fused to the Fc portion of human IgG1 that binds all forms of VEGF-A along with the related placental growth factor. Based on VIEW 1 and VIEW 2 clinical trials, it would be now possible to inject VEGF Trap Eye every two months against the use of contemporary therapy of ranibizumab every four weeks. Further, VEGF Trap Eye was found to be well tolerated following intravitreal injections.  Recently, FDA has delayed its decision on VEGF Trap Eye for the treatment of wet macular degeneration. Bayer Healthcare has also submitted an application to European Medicines Agency for marketing approval of VEGF Trap Eye for the treatment of wet macular degeneration.

Jerini AG (German biopharmaceutical company), has developed an anti-angiogenic compound, JSM6427, which has shown positive results and offers a more convincing treatment option. Intraocular implanted osmotic pump results in slow release of formulation for an extended period of six months. Phase I clinical trials have begun. 

TargeGen, Inc. announced that topical administration of the prodrug, TG100801, may be effective for the treatment of retinal disease and may also be used in combination with approved products. TG100801 demonstrated the ability to reduce VEGF-mediated retinal leakage, angiogenesis and inflammation after topical instillation. TG100801 converts to the active drug TG100572 as it penetrates the eye. The active drug, TG100572, was shown to overcome neovascularization and inflammation, both of which are characteristics of DR and wet macular degeneration. 

CoMentis, Inc. (formerly Athenagen), announced the initiation of a Phase II clinical study of ATG3, a topical drop, for neovascular AMD. ATG3 acts as antagonist of the nicotinic acetylcholine receptor pathway which mediates angiogenesis. The drug was developed to effectively penetrate into the retina and choroid following topical eye drop administration as shown in animal experimental data. Further, ATG3 was evaluated in a randomized, double-masked, placebo-controlled Phase I study which enrolled 80 healthy volunteers in single and multiple dose ascending regimens for up to 14 days of therapy. ATG3 study demonstrated excellent ocular tolerability of ATG3 with no systemic side-effects.

GlaxoSmithKline is investigating Pazopanib, oral, once-daily angiogenesis inhibitor targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and c-kit. Phase III studies are being planned.

Vitreolytic Agents

Vitrase (hyaluronidase ovine, ISTA Pharmaceuticals, Inc.) is the first and only pure, preservative-free, thimerosal-free, ovine hyaluronidase, which is FDA-approved as a spreading agent. Intravitreal vitrase has shown efficacy and safety in a Phase III clinical trial to investigate its promotion of the clearance of vitreous hemorrhage from PDR, although the agent is not FDA-approved for this purpose. 

The induction of a posterior vitreous detachment also could be beneficial in the treatment of DME and PDR. A randomized, double-masked, sham-injection controlled, dose-ascending clinical trial primarily designed by Thrombogenics NV (Belgium) to compare multiple doses of intravitreal microplasmin versus sham injection for treatment of patients with DME (MIVI-II) has been completed.  With this preliminary study the company believes that microplasmin may represent a major advance in this area, as detaching the vitreous from the retina has been associated with greatly reducing neovascularization of the retina, which plays a fundamental role in the loss of vision in many diabetic patients.

Two trials of MIVI-TRUST Phase III program for Focal Vitreomacular Adhesion showed that microplasmin: (1) was successful in resolving vitreomacular adhesion, (2) was able to cure full thickness macular hole without the need for surgery, (3) delivered an improvement in the vision of patients without the need for surgery, and (4) was safe and well-tolerated. 

Effects of Systemic Agents on Diabetic Retinopathy

Various systemic agents which are actually not designed for the management of DR have shown evidence-based results in reducing the progression of DR. So, these agents should be considered as extra value, while they are primarily used for treating dyslipemia and hypertension in diabetic patients. Before these can be used clinically, further studies are warranted to elucidate their mechanisms in the prevention of DR.

Hypoglycemic Agents

Insulin

The main goal of insulin therapy is to limit the progression of long-term diabetic complications with either Type 1 or Type 2 diabetes mellitus. Further, various studies have justified that good glycemic control helps in delaying the progression of DR. 

Multiple studies, for example Diabetes Control and Complications Trial (DCCT), have reported retinal pro-angiogenic effects of insulin following the initiation of intensive insulin therapy for couple of years, therefore, DR can worsen for short span of time. However, over the long term, intensive glycemic control is associated with improvement in DR. 

Thiazolidinediones

Thiazolidinediones are oral hypoglycemic agents used either as monotherapy or in combination with other hypoglycemic agents. According to the recommendations of the United Kingdom Prospective Diabetes Study (UKPDS), thiazolidinediones are extensively used for the improvement of glycemic control in Type 2 diabetic patients resulting in 1% reduction in % HbA _1C values.  

Thiazolidinediones result in the activation of peroxisome proliferator-activated receptor (PPAR) γ - a transcription factor responsible for regulating the expression of genes primarily located in the adipose tissue and also evident in the retina. The thiazolidinedione rosiglitazone, apart from its effect on glycemic control, possibly delays PDR by its anti-angiogenic effects through PPAR γ agonist activity. 

Biguanides

Metformin is a good hypoglycemic agent and has known cardioprotective effects. Metformin is indicated in obese and overweight Type 2 diabetic patients prone for the development of cardiovascular complications. Various studies have shown the anti-inflammatory and anti-angiogenic activity of metformin by decreasing the concentration of plasminogen activator inhibitor 1 and increasing fibrinolytic activity. 

Hypolipidemic agents

Fibrates

Fenofibrate is most commonly used for the treatment of hyperlipidemia. Its main action is to lower triglyceride levels, but it also reduces total and low density lipoprotein (LDL) cholesterol, raises high density lipoprotein (HDL) cholesterol, and decreases concentration of small LDL cholesterol particles and apolipoprotein B. The FIELD study shows that subjects treated with fenofibrate required less photocoagulation in PDR by 30% and DME by 31%.  In the ophthalmology sub-study, fenofibrate reduces the progression of retinopathy by 22% in all patients and 79% in patients with pre-existing retinopathy. This result was unrelated to serum lipid levels, which were statistically similar in both, the group treated with fenofibrate and the control group.  

Apart from its beneficial hypolipidemic effects, fenofibrate also acts via various nonlipidemic mechanisms, being a PPAR-α agonist, for prevention of DR are: (1) PPAR-α is present in retinal endothelial cells , and its activation through PPAR-α agonists (fenofibrate) inhibits expression of VEGF receptor 2 and neovascularization in human umbilical endothelial cells, (2) fenofibrate induces expression and activation of antioxidant enzymes, such as superoxide dismutase and glutathione peroxidise, and activation of PPAR-α induces apoptosis of human monocyte-derived macrophages, (3) PPAR-α activation has neuroprotective effects. 

Statins

Collaborative Atorvastatin Diabetes Study (CARDS), a randomized controlled trial in Type 2 diabetics, reported atorvastatin to be ineffective in reducing DR. However, there was a decrease in the need for laser treatment with atorvastatin.  ACCORD Eye substudy evaluated the effect of fenofibrate in combination with simvastatin on the risk of three-stage progression of retinopathy using a modified ETDRS (Early Treatment Diabetic Retinopathy Study) severity scale or laser photocoagulation over a duration of four years. The result in comparison to placebo shows a 40% reduction in the relative risk of DR progression. The decrease in risk was related to a significant decrease in triglyceride levels and an increase in HDL levels. 

ANTIHYPERTENSIVE AGENTS

Angiotensin-converting enzyme inhibitors

It is very much evidenced from a large number of clinical trials that blood pressure is the major culprit for the development of diabetic retinopathy and efficient control of blood pressure may reduce the development of DR in both Type 1 and 2 patients. ACE inhibitors are the most preferred modalities for the treatment of hypertension in diabetic patients. Further, it has been proved that the rennin-angiotensin system is expressed in diabetic retina as well. ^[68],[69]The RAS study (RASS) was conducted to evaluate the effect of rennin-angiotensin system blockage with either ACE inhibitor (Enalpril) or ARB (losartan) as compared to placebo for a period of five years on both renal and retinal morphologic characteristics in normotensive Type 1 diabetics. The ratio of progression of DR by two or more steps was reduced by 65% with enalpril and by 70% with losartan, this effect was seen independent of changes in blood pressure or glycemic control. 

Angiotensin-2 receptor blockers

The Diabetic Retinopathy Candesartan Trial (DIRECT) program was conducted to check blockade of renin angiotensin system with AT1-receptor blocker (candesartan) could prevent the progression of DR in both Type 1 and 2 diabetes independent of their hypotensive effect. It is divided into three randomized double-blind placebo-controlled parallel-group studies: (1) A primary prevention study involving Type 1 diabetic patients without DR (DIRECT-Prevent 1), (2) A secondary prevention study involving Type 1 diabetic patients with DR (DIRECT-Protect 1), (3) A secondary prevention study involving Type 2 diabetic patients with diabetic retinopathy (DIRECT-Protect 2). In each trial patients were randomized to receive candesartan (16-32 mg/day) or placebo and the median follow-up was 4.7 years. Results of both studies, DIRECT-Prevent 1 and DIRECT-Protect 1, suggested that candesartan is not beneficial for the prevention of DR. DIRECT-Protect 2 showed a non-significant reduction in the progression of DR. However, a significant increase in diabetic retinopathy regression was observed-this effect was even more pronounced in patients with mild DR. Thus, data analysis suggests an overall protective effect of candesartan in DR. 

MISCELLANEOUS AGENTS

Ruboxistaurin

Ruboxistaurin (Arxxant^® , Eli Lilly and Company) is an investigational agent which has shown results for the treatment of moderate to severe NPDR. It acts by limiting the over-activation of protein kinase C beta, which is directly involved in the pathogenesis of DR. It is a new class of compounds being tested for the management of moderate to severe NPDR.^[73],[74] 

Therapy with ruboxistaurin is associated with a reduction in the progression of DME and a reduction in the rate of vision loss in patients with DME, although ruboxistaurin has not received FDA approval. 

Somatostatin derivatives

Octreotide (Sandostatin®, Novartis) is approved for acromegaly, carcinoid tumors, and vasoactive intestinal peptide tumors. Somatostatin is an endogenous growth hormone inhibitor with known anti-angiogenic properties. The somatostatin analogue octreotide has been associated with decreased rates of progression to high-risk PDR, vitreous hemorrhage and the need for vitrectomy in patients with at least severe NPDR

Antiplatelet agents

It has been seen that in chronic hyperglycemia-induced retinal inflammation, platelet activation, aggregation and thromboxane A2 has been increased. Further, leucocytes start adhering to the endothelial surface resulting in increased propensity for microthrombus formation and finally capillary occlusion, leading to retinal ischemia and severe DR. The EDTRS study evaluated the effect of aspirin on the progression of diabetic retinopathy and showed no beneficial or deleterious effect either on disease progression or on the rates of vitreous hemorrhage. In another study, combinations of aspirin and dipyridamole have suggested possible benefits for slowing the progression of diabetic retinopathy.  The Dipyridamole, Aspirin, Microangiopathy of Diabetes (DAMAD) study showed a small but statistically significant reduction in the formation of micro-aneurysms

Herbal drugs for the management of diabetic retinopathy

Various plant-based drugs have shown promising results in experimental studies for the prevention of diabetic retinopathy. The advantage of herbal drugs over current therapies is that, apart from their safety, they are producing hypoglycemic effects in addition to their retinoprotective effect. Recently, Gupta et al., have shown the effect of chronic oral administration of curcumin in rats for prevention of DR.  Curcumin inhibited the over-expression of retinal VEGF levels in rats. Moreover, electron microscopy study has shown that curcumin prevented the thickening of the basement membrane by its anti-oxidant and anti-inflammatory mechanisms as measured in retinas of treated rats. Overall, they have found good preventive effect of curcumin in DR.

Pycnogenol^® is a natural plant extract from the bark of the maritime pine tree which grows exclusively along the coast of southwest France in Les Landes de Gascogne. The extract possesses powerful anti-oxidant and anti-inflammatory properties. Various experimental and clinical studies have shown the efficacy of Pycnogenol® in the management of DR.

In another study, Nakajima et al.,  have shown that chronic oral genistein can significantly reduce retinal vascular leakage in an animal model of DR. Further, it has been studied that genestein possesses good tyrosine kinase inhibitory activity. In a perspective study published earlier has proved that drinking green tea lessened the incidence of DR.  Similarly, one experimental study showed that green tea can potentially prevent the onset of DR.  Further, hesperetin has shown a preventive effect on DR in an experimental rat model.  So there is lot of scope coming out of the herbal world.

CONCLUSION

The scientific principles for the treatment of DR and prevention of blindness have been known for the past three decades. In spite of this, DR remains a major public health problem with large numbers of people with diabetes going blind worldwide (especially in India), which can be preventable. Patients are not going blind for lack of technology or treatment options. They are going blind because they are not receiving treatment that has been well established for more than a quarter of a century.

Certainly, in the last one decade there have been significant developments in the pharmacotherapy of retinal-related disorders and many such innovations are still in the pipeline which we can expect in the near future. But, still we cannot depend on the innovations of the future. So there is a need for improving the present system using existing techniques and options.

In conclusion, it can be stated that for the present scenario systematic use of available pharmacotherapy as an adjunct to laser photocoagulation , which is the gold standard therapy, can be a useful tool in the prevent

The Red Face and Its Management

The Problem(s)

Red face is commonly seen, can be transient and come and go (flushing), or be persistent. Sometimes it can be scaly (dermatitis), or there may be papules and pustules (rosacea) present. Red face is occasionally seen in infants or neonates.

Flushing/Blushing

·        Transient redness of face and/or neck and upper trunk due to vasodilatation

·        Blushing is flushing due to emotion.

Causes of Flushing

·        Emotional (blushing)

·        Menopausal

·        Neurologic

o   e.g., migraine, Parkinson’s disease

·        Foods and food additives

·        Drugs

o   Vasodilators including alcohol

o   Calcium channel blockers

o   Corticosteroids

·        Systemic Disease

o   Carcinoid

o   Pheochromocytoma

o   Mastocytosis

o   Cushing’s syndrome

o   Polycythemia vera

o   Hyperthyroidism

·        Rosacea

o   Persistent and transient

Common Causes of Red Face

·        Rosacea (erythema, papules, pustules, telangiectatic vessels, swelling, rhinophyma)

·        Acne

·        Seborrheic Dermatitis (other types of dermatitis or psoriasis are less common)

·        Emotions

·        Menopause

·        Sunburn

·        Keratosis Pilaris

·        Systemic Lupus Erythematosus (SLE) (less common)

·        Dermatoheliosis/photoaging

·        Psoriasis

Important Questions to Ask

·        Does the redness come and go or is it persistent?

·        Is it exacerbated by temperature change, food, drugs, or emotions?

·        Are there visible vessels on the face?

·        Is there scaling in addition to redness?

·        Is this acne-like with papules and pustules?

·        Any symptoms? (e.g., itchy with dermatitis)

·        Is the patient menopausal?

·        What creams are being applied to the face?

·        Are other areas of the body involved?

·        Is flushing more generalized?

o   Systemic causes

o   Superior vena caval obstruction

Make a Diagnosis

·        History

o   Food, drugs, other diseases

o   Physical exam

·        Acne-like, suggestive of rosacea

·        Scaly eyebrows and sides of nose, suggestive of seborrheic dermatitis

·        Butterfly distribution of acne, suggestive of SLE

·        Other areas involved, suggestive of:

o   Psoriasis (nails, scalp, extensor limbs)

o   Keratosis pilaris (upper arms)

o   Atopic dermatitis (other atopic features)

Acne and Rosacea

Acne can be confused with, or coexist with, rosacea particularly in fair-skinned individuals. In some of these patients topical retinoids can be irritating and increase redness. Anecdotally, topical gels combining benzoyl peroxide and antibiotics, e.g., clindamycin 1% + benzoyl peroxide 5% (BenzaClin^®); erythromycin 3% + benzoyl peroxide 5% gel (Benzamycin®) and 1% clindamycin phosphate + 5% benzoyl peroxide (Clindoxyl^®) may be helpful.

Treatment of Red Face

·        Camouflage make up (Cover Fx^®, Covermark^®, Dermablend^®, Dormer^®)

·        An esthetician may be helpful

·        Stop the flush:

o   Clonidine, 0.05mg, twice daily

o   Treat other symptoms, e.g., scaling/dermatitis

o   Weak, non-fluorinated topical steroids for short term flare

o   Moisturize with non-comedogenic products

·        Control

o   Hydrocortisone 1%, (Desonide^®)

o   Topical calcineurin inhibitors

o   Tacrolimus (Protopic^®), Pimecrolimus (Elidel^®)

·        Rule out underlying disease, e.g., SLE, carcinoid

Red Face in Infants or Neonates

Vascular Abnormality

·        Hemangiomas

·        Port wine stain/nevus flammeus

·        Vascular malformations

Inflammatory

·        Dermatitis

o   seborrheic

o   atopic

·        Keratosis Pilaris

·        Uncommon: acute contact dermatitis, psoriasis, erythroderma, etc.

Treatment of Rosacea

Treatment of Rosacea (Acne-like features and flushing)

·        Keep cool

·        Topical applications

o   Metronidazole cream (Noritate® 1%; MetroCream® 0.75%), lotion (MetroLotion^®0.75%), gel (MetroGel® 1%)

§  A cornerstone for the treatment of rosacea

o   Sulfacetamide sodium (Sulfacet-R^® 25g, Novacet^® 30g and 60g generic)

o   Rosacure^®, Rosaliac^®

·        Non-comedogenic make up and cosmetic products

·        Systemic medications

o   Tetracycline, doxycycline, minocycline

o   Clonidine

o   Isotretinoin (Accutane^®)

·        Stop topical corticosteroids

·        Trigger avoidance: Avoid hot foods, fluids, alcohol, spicy foods

·        Sunscreen use

·        BLU-U^® + photodynamic therapy (Levulan^®)

Treatment of Rosacea (flushing, erythema, telangiectatic vessels)

·        Lasers

o   Pulse dye

o   ND:Yag

o   KTP

o   CO2, Erbium-Yag for rhinophyma

·        Intense Pulsed Light (IPL)

Note: One can treat the entire red face with laser or IPL, or one can trace out only the prominent vessels by laser.

Treatment of Infants, Children With Red Face

Vascular Abnormalities

·        • May need workup for underlying abnormalities.

·        • Laser, e.g., pulsed dye for port wine stain and some hemangiomas

·        • Rapidly growing hemangiomas require expert assessment and treatment.

Inflammatory

·        Mild topical steroids for dermatitis

Key Points

·        Make a diagnosis and follow up for results of treatment

·        Many of these causes are common, e.g.,

o   Rosacea

o   Seborrheic Dermatitis

o   Emotions and menopause

o   Flushing

·        Take a good history

o   Drugs, foods, and food additives

·        Look for other underlying diseases.

·        Camouflage redness while deciding on diagnosis and treatment.

·        Definitive treatment (topical, systemic, or laser/IPL) may be lengthy and involve several treatment sessions (laser/IPL) and/or several modalities.

·        Redness may occur and require additional treatment in the future (topical, systemic, laser/IPL).