BREATHING NEW LIFE INTO OLD MEDICINES

Discovering and developing new treatments for disease is a challenging, time-consuming, and expensive endeavor. For every drug that eventually makes it to the pharmacy, hundreds of compounds fail to deliver results and millions of dollars are spent without a direct return on investment. However, in these economically challenging times, existing drugs and compounds—whether in development, already on the market, or even ones that have failed clinical trials due to lack of efficacy—are being re-examined by pharmaceutical companies and research institutions. The goal of this approach—called drug repurposing— is to find potential new uses for these drugs.

High-throughput drug screening platforms in Sanford-Burnham's Conrad Prebys Center for Chemical Genomics will be used to screen existing drugs for new applications.

There are three main benefits to drug repurposing—it’s safer, faster, and cheaper. Since a repurposed drug has already passed a significant number of toxicity and other tests, its risks are better known and the chance of failure is reduced. More than 90 percent of new drugs fail during development, contributing to the high cost of pharmaceutical research and development. A new therapy based on a repurposed drug could benefit patients sooner—ultimately saving and improving more lives.

In the past, drug repurposing efforts were hampered by the lack of a complete drug collection. Fortunately, a comprehensive listing of clinically approved drugs was recently made available by the NIH. Now, in order to make the promise of drug repurposing a reality, Sanford-Burnham researchers are building the world’s most comprehensive library (collection) of repurposed drugs, which can be leveraged against our strengths in stem cell biology, phenotypic cell-based screening, and high-throughput drug screening. Moreover, this library will be made available to other non-profit research institutions to advance translational medicine.

Despite the promise of drug repurposing, serendipitous discovery of new applications for existing drugs happens rarely, and only at the point when people are actually taking them. With the advent of stem cell-based human disease models—called disease in a dish—researchers can now test large numbers of approved drugs for their efficacy against a number of diseases before they reach clinical testing in humans. In this technique, researchers at Sanford-Burnham and elsewhere take skin samples from a patient or healthy volunteer, dial them back developmentally to stem cells, and induce their differentiation into the desired cell type (neurons, for example, if studying Alzheimer’s disease). The advantage to disease-in-a-dish modeling is that it generates large numbers of otherwise hard-to-access cell types, complete with an individual’s genetic and epigenetic make-up—making it a valuable tool for discovering and developing therapies that are more personalized to the individual.

Using cells from a patient with muscular dystrophy and a small library of FDA-approved drugs, Sanford-Burnham scientists have already identified a series of agents that reverse the functional defect causing the disease, providing an initial proof-of-concept for this approach. Spurred on by this exciting data, the team is now developing disease-in-a-dish screens for other genetic diseases.

While we are making substantial progress, one challenge is the incompleteness of the current drug repurposing library available to us. The more complete this library, the greater the chance we will find a drug that can potentially be repurposed to treat a child with a genetic condition like muscular dystrophy or other diseases.

“Regrettably, pharmaceutical companies are not likely to engage in drug repurposing efforts for rare childhood diseases,” Sanford-Burnham’s Layton Smith told Drug Discovery News. “This is in part due to the smaller patient populations and challenges in running clinical trials in these indications. In addition, competition with generic drugs makes this effort commercially unviable, in spite of its great potential to benefit human health. Even if companies were motivated to engage in these efforts, it is very difficult for the pharmaceutical industry to perform the type of screens Sanford-Burnham is doing because of their limited access to patient samples.”

Non-profit research institutes such as Sanford-Burnham, on the other hand, are well positioned to respond to this market and research opportunity.

Source: Drug News

by

AKSHAYA SRIKANTH

Pharm.D

India

ADVERSE DRUG REACTION CASE REPORTS IN ELDERS

Ciprofloxacin Delirium and myoclonus in an elderly patient: case report

An 85 year old man received oral ciprofloxacin 500mg daily for an infected right hip joint. On the seventh day he experienced generalized myoclonic jerks, hallucination and delirium which improved with a small dose of clonazepam. Ciprofloxacin was permanently withdrawn after his symptoms recurred twice following re-administration. No further episodes of delirium myoclonic jerks occurred.

Jayathissa S. Eet al. Myoclonus and delirium associated with ciprofloxacin. Age and Ageing 39: 762, No. 6, Nov 2010.

Metformin Lactic acidiosis and vision loss in an elderly patient: case report 

A 67 year old woman developed lactic acidiosis and transient vision loss during treatment with metformin for type 2 diabetes mellitus. The woman, who had a history of coronary disease, hypertension and osteoarthritis, and who had been receiving metformin (dosage, route and duration of treatment not stated), presented to an emergency department with acute bilateral vision loss. Her vision loss had started the previous afternoon. Examination revealed a rectal temperature of 32.3o, a HR 55 beats/min, a BP of 117/94mm Hg, a respiratory rate of 34 breaths/min and a pulse oximeter reading of 98%. She was awake and alert but her visual acuity and fields were not intact and she had mid-sized pupils that were slow to react. Laboratory tests showed a pH OF 6.65 and a lactate level of 10.9mmol/L. Her creatinine level was 7.0 mg/dL from a baseline of 1.3 mg/dL and her serum metformin concentration was 28 microgram/mL. She also had hyperkalaemia with a potassium level of 7.1mmol/L. The woman was treated with calcium gluconate, insulin and glucose for hyperkalaemia and sodium bicarbonate for her metabolic acidiosis. Following a lack of response, emergency haemodialysis was initiated. Her vision returned 10 hours after admission with an acuity of 20/30 bilaterally. Her blood pH increased to 7.48, her hypothermia resolved and her laboratory values normalized. She was discharged without metformin therapy. Author comment: ‘’This patient’s metabolic acidiosis resulted from long-term metformin use in the setting of an elevated creatinine, which ultimately caused decreased excretion of the drug. Her presenting complaint was vision loss’’.

Kreshak AA, et al. Transient vision loss in a patient with metformin-associated lactic acidiosis. American Journal of Emergency Medicines 28: 1059e5-1059e7, No.9, Nov 2010.

Corticosteroids/methotrexate Kaposi’s sarcoma in an elderly patient: case report

A 65-year old man developed kaposi’s sarcoma with colonic and skin lesions, following treatment with methotrexate and corticosteroids, including prednisone for ulcerative colitis(UC).

Following a diagnosis of left sided UC and spondyloarthropathy in November 1993, immunomodulatory therapy with mercaptopurine and azathioprine was initiated; treatment was subsequently withdrawn due to gastrointestinal intolerance. In June 2001, methotrexate (dosage and route not stated) was introduced but was suspended in November 2007 to prevent potential drug-related toxicities; prednisone 5mg/day (route not stated) was administered continuously throughout this period. In August 2008, he was admitted for IV steroid therapy (details not stated) following an acute disease episode. During admission he developed violaceous reddish-brown nodules on both legs (time to reaction onset not clearly stated). Investigation revealed active UC with multiple reddish elevated lesions in the last 25cm of the colon, and thickening of the rectum and sigmoid colon walls. Skin histology showed a small, non-encapsulated dermal lesion composed of dilated, irregular and spiculated blood vessels, lined by few prominent endothelial cells; lymphocytes and macrophages comprised an associated infiltrate. Immunohistochemistry with CD34 and CD31 were positive; staining for human herpes virus 8 (HHV-8) showed moderate and focal nuclear positivity. Colonic kaposi’s sarcoma was the preliminary diagnosis. Anti-HHV-8 serology demonstrated an IgG antibody titre of 1/40. A protocolectomy was performed, confirming the presence of multiple nodular lesions of the sigmoid colon and rectum. Labelling for HHV-8 was positive. Multifocal kaposi’s sarcoma of the colon was the final diagnosis. The man’s skin lesions resolved after surgery and steroid withdrawal. At 12 months follow-up, he had no symptoms and no recurrence of skin lesions.
Rodriguez-Pelaez M, et al. kaposi’s sarcoma: An opportunistic infection by human herpesvirus-8 in ulcerative colitis. Journal of Crohn’s and colitis 4: 586-590, No.5, Nov 2010.

Influenza virus vaccine/influenza A virus vaccine H1N1 Guillain-Barre syndrome in an elderly patient: case report

A 75 year old man, with severe chronic obstructive pulmonary disease and dyspnoea, was hospitalized with worsening dyspnoea, cough and purulent expectoration. He reported a progressive debility in his lower limbs for the past week. Neurological examinations revealed grade 4/5 debility in his lower limbs and loss of osteotendinous reflexes. He had received a seasonal influenza virus vaccine 8 weeks earlier and an influenza A viral vaccine, H1N1 vaccine 2 weeks before the onset of the symptoms (route and doses not stated ). A lumber puncture and an electromyogram revealed albumino-cytological dissociation and acute demyelinating neuropathy affecting his lower limbs, respectively. Guillain-Barre syndrome secondary to influenza vaccine was suspected. He received immunoglobulins and rehabilitation. The weakness in his extremities and his respiratory process improved markedly; he was discharged and monitored. Author comment: There was casual effect between the vaccinations and Guillain-Barre syndrome, although it was not possible to determine which of the two was supposed to be responsible, whether it was the result of a sum of probabilities or a cumulative effect of antigen stimulation. Nieto ML, et al. Gullain-Barre syndrome secondary to H1N1 influenza vaccine.

Revista Clinica Espanola 210: 485-486, No. 9, Oct 2010.

by

Akshaya Srikanth

Pharm.D Resident

Hyderabad, India

HEART DISEASE PASSES FROM FATHER TO SON

Coronary artery disease, which kills tens of thousands each year, may be passed genetically from father to son, according to a new study.

The study, led by the University of Leicester, shows that the Y chromosome - a part of DNA only present in men - plays a role in the inheritance of the disease.

Coronary artery disease involves the narrowing of blood vessels delivering blood to the heart, and can lead to angina symptoms, such as constriction of the chest, and heart attacks.

Scientists analysed DNA from over 3,000 men enrolled in a heart health study and found that 90 per cent of British Y chromosomes belong to one of two major groups.  

The risk of coronary artery disease among men who carry a Y chromosome in one of the two groups is 50 per cent higher than for other men, and is independent of traditional risk factors such as high cholesterol, high blood pressure and smoking.  

The researchers believe the increased risk is down to the specific group's influence on the immune system and inflammation.  

Principal investigator Dr Maciej Tomaszewski said:

“We are very excited about these findings as they put the Y chromosome on the map of genetic susceptibility to coronary artery disease. We wish to further analyse the human Y chromosome to find specific genes and variants that drive this association.

“The major novelty of these findings is that the human Y chromosome appears to play a role in the cardiovascular system beyond its traditionally perceived determination of male sex.

Dr Hélène Wilson, research advisor at the British Heart Foundation (BHF), which was the main funder of the study, said:

“Lifestyle choices such as poor diet and smoking are major causes, but inherited factors carried in DNA are also part of the picture.

"The next step is to identify specifically which genes are responsible and how they might increase heart attack risk."

“This discovery could help lead to new treatments for heart disease in men, or tests that could tell men if they are at particularly high risk of a heart attack.

The study is published in The Lancet in February 2012 . LINK: LANCET

by

AKSHAYA SRIKANTH

Pharm.D Resident

Hyderabad, India