Bioinformatics Institute of India: Pharma Department

Anti-HIV agent as a Vaccine

2015-02-26T01:08:00.000-08:00

Anti-HIV agent as a Vaccine

In a remarkable new advance against the virus that causes AIDS, scientists from the Jupiter, Florida campus of The Scripps Research Institute (TSRI) has announced the creation of a novel drug candidate that is so potent and universally effective, it might work as part of an unconventional vaccine.

The research, which involved scientists from more than a dozen research institutions, was published February 18 online ahead of print by the journal Nature.

The study shows that the new drug candidate blocks every strain of HIV-1, HIV-2 and SIV (simian immunodeficiency virus) that has been isolated from humans or rhesus macaques, including the hard-to-stop variants. It also protects against much-higher doses of virus than occur in most human transmission and does so for at least eight months after injection.

"Our compound is the broadest and most potent entry inhibitor described so far," said Michael Farzan, a TSRI professor who led the effort. "Unlike antibodies, which fail to neutralize a large fraction of HIV-1 strains, our protein has been effective against all strains tested, raising the possibility it could offer an effective HIV vaccine alternative."

Figure Showing electron micrograph of HIV particles infecting a human T-cell

Blocking a Second Site

When HIV infects a cell, it targets the CD4 lymphocyte, an integral part of the body's immune system. HIV fuses with the cell and inserts its own genetic material -- in this case, single-stranded RNA -- and transforms the host cell into a HIV manufacturing site.

The new study builds on previous discoveries by the Farzan laboratory, which show that a co-receptor called CCR5 contains unusual modifications in its critical HIV-binding region, and that proteins based on this region can be used to prevent infection.

With this knowledge, Farzan and his team developed the new drug candidate so that it binds to two sites on the surface of the virus simultaneously, preventing entry of HIV into the host cell.

"When antibodies try to mimic the receptor, they touch a lot of other parts of the viral envelope that HIV can change with ease," said TSRI Research Associate Matthew Gardner, the first author of the study with Lisa M. Kattenhorn of Harvard Medical School. "We've developed a direct mimic of the receptors without providing many avenues that the virus can use to escape, so we catch every virus thus far."

The team also leveraged preexisting technology in designing a delivery vehicle -- an engineered adeno-associated virus, a small, relatively innocuous virus that causes no disease. Once injected into muscle tissue, like HIV itself, the vehicle turns those cells into "factories" that could produce enough of the new protective protein to last for years, perhaps decades, Farzan said.

Data from the new study showed the drug candidate binds to the envelope of HIV-1 more potently than the best broadly neutralizing antibodies against the virus. Also, when macaque models were inoculated with the drug candidate, they were protected from multiple challenges by SIV.

"This is the culmination of more than a decade's worth of work on the biochemistry of how HIV enters cells," Farzan said. "When we did our original work on CCR5, people thought it was interesting, but no one saw the therapeutic potential. That potential is starting to be realized."

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Bioinformatics Depatment

Parkinson’s disease: a dose-finding study

2015-02-12T03:19:00.001-08:00

Parkinson’s disease: a dose-finding study

In advanced stages of Parkinson’s disease, serotonergic terminals take up L-DOPA and convert it to dopamine. Abnormally released dopamine may participate in the development of L-DOPA-induced dyskinesias. Simultaneous activation of 5-HT1A and 5-HT1B receptors effectively blocks L-DOPA-induced dyskinesias in animal models of dopamine depletion, justifying a clinical study with eltoprazine, a 5-HT1A/B receptor agonist, against L-DOPA-induced dyskinesias in patients with Parkinson’s disease. A double-blind, randomized, placebo-controlled and dose-finding phase I/IIa study was conducted. Single oral treatment with placebo or eltoprazine, at 2.5, 5 and 7.5 mg, was tested in combination with a suprathreshold dose of L-DOPA (Sinemet®) in 22 patients with Parkinson’s disease (16 male/six female; 66.6 ± 8.8 years old) with L-DOPA-induced dyskinesias.

Figure: Brain Regions Affected by PD

Figure: PD Treatment Steps

A Wilcoxon Signed Rank Test was used to compare each eltoprazine dose level to paired randomized, placebo on the prespecified primary efficacy variables; area under the curve scores on Clinical Dyskinesia Rating Scale for 3 h post-dose and the maximum change of Unified Parkinson’s Disease Rating Scale part III for 3 h post-dose. Secondary objectives included effects on maximum Clinical Dyskinesia Rating Scale score, area under the curve of Rush Dyskinesia Rating Scale score for 3 h post-dose, mood parameters measured by Hospital Anxiety, Depression Scale and Montgomery Asberg Depression Rating Scale along with the pharmacokinetics, safety and tolerability profile of eltoprazine. A mixed model repeated measures was used for post hoc analyses of the area under the curve and peak Clinical Dyskinesia Rating Scale scores. It was found that serum concentrations of eltoprazine increased in a dose-proportional manner. Following levodopa challenge, 5 mg eltoprazine caused a significant reduction of L-DOPA-induced dyskinesias on area under the curves of Clinical Dyskinesia Rating Scale [–1.02(1.49); P = 0.004] and Rush Dyskinesia Rating Scale [–0.15(0.23); P = 0.003]; and maximum Clinical Dyskinesia Rating Scale score [–1.14(1.59); P = 0.005].

The post hoc analysis confirmed these results and also showed an antidyskinetic effect of 7.5 mg eltoprazine. Unified Parkinson’s Disease Rating Scale part III scores did not differ between the placebo and eltoprazine treatments. The most frequent adverse effects after eltoprazine were nausea and dizziness. It can be concluded that a single dose, oral treatment with eltoprazine has beneficial antidyskinetic effects without altering normal motor responses to L-DOPA. All doses of eltoprazine were well tolerated, with no major adverse effects. Eltoprazine has a favourable risk-benefit and pharmacokinetic profile in patients with Parkinson’s disease. The data support further clinical studies with chronic oral eltoprazine to treat L-DOPA-induced-dyskinesias.

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Bioinformatics Department

Swine Flu Virus (H1N1) Prognosis: Epidemic or Pandemic

2015-02-03T23:05:00.002-08:00

H1N1, or swine flu, first appeared during the 2009 flu season and quickly caused fear and confusion around the world. The virus spreads when you touch an infected surface or breathe cough and sneeze droplets in the air. If you are infected, you can be contagious for up to 10 days. The symptoms are the same as the seasonal flu -- cough, sore throat, and body aches. Young children, pregnant women, and older adults are more likely to develop complications. Tamiflu and Relenza can treat or prevent swine flu. The CDC recommends for the 2014-2015 flu season that everyone 6 months old and older should get a flu shot to prevent or reduce the chance of getting the flu. The best way to prevent novel H1N1 swine flu is vaccination. The 2014 CDC recommendations that apply to H1N1, H3N2, and other flu viruses are almost identical to those above-mentioned recommendations for patients at risk when vaccine doses are limited and are as follows.

· Are aged 6 months through 4 years (59 months)

· Are aged 50 years and older

· Have chronic pulmonary (including asthma), cardiovascular (except hypertension), renal, hepatic, neurologic, hematologic, or metabolic disorders (including diabetes mellitus)

· Are immunosuppressed (including immunosuppression caused by medications or by human immunodeficiency virus)

· Are aged 6 months through 18 years and receiving long-term aspirin therapy and who therefore might be at risk for experiencing Reye's syndrome after influenza virus infection

A newly approved inactivated trivalent vaccine containing 60 mcg of hemagglutinin antigen per influenza vaccine virus strain (Fluzone High-Dose [Sanofi Pasteur]) is an alternative inactivated vaccine for people 65 years of age and older.

But an annual flu shot is your best bet against this virus. In the wake of a swine flu outbreak, which has so far claimed 191 lives, the Centre on Monday said mortality on account of the flu can be contained with immediate medical intervention. There have been 2038 cases of swine flu reported across the country in 2015, with Telangana reporting the highest number of cases at 629 and 34 deaths, followed by Delhi with 488 cases and 5 deaths, Gujarat with 309 cases and 38 deaths and Rajasthan with 205 cases and 49 deaths.

Picture Showing the Prevalence of Swine Flu in India

Health Ministry officials said the Delhi's low mortality is attributable to the high awareness about the flu, which led to early detection and timely treatment. “Despite having a very high number of cases reported, Delhi has had fewer deaths only because of quick diagnosis and treatment,”said Dr. Arun Kumar Panda, additional secretary in the Health Ministry.

Dr. Panda said swine flu is a seasonal flu and can be managed with treatment, but he cautioned against using Tamiflu against medical advice. “The drug should not be taken as a precaution and without the prescription of a doctor, as it can lead to resistance of the drug.”

In 2012 there were 5044 cases of swine flu reported and 405 deaths, in 2013, the swine flu cases were 5253 and 699 deaths, in 2014, there were 937 cases and 238 deaths.

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Bioinformatics Department

Combining Machine Learning Systems and Multiple Docking Simulation Packages to Improve Docking Prediction Reliability for Network Pharmacology

2015-01-19T01:57:00.001-08:00

Increased availability of bioinformatics resources is creating opportunities for the application of network pharmacology to predict drug effects and toxicity resulting from multi-target interactions. Here we present a high-precision computational prediction approach that combines two elaborately built machine learning systems and multiple molecular docking tools to assess binding potentials of a test compound against proteins involved in a complex molecular network. One of the two machine learning systems is a re-scoring function to evaluate binding modes generated by docking tools. The second is a binding mode selection function to identify the most predictive binding mode. Results from a series of benchmark validations and a case study show that this approach surpasses the prediction reliability of other techniques and that it also identifies either primary or off-targets of kinase inhibitors. Integrating this approach with molecular network maps makes it possible to address drug safety issues by comprehensively investigating network-dependent effects of a drug or drug candidate.

Figure: Illustration of a systems docking simulation. It is mainly used to dock a small molecule to a protein structure and to evaluate its potential to bind.

Docking simulation, a screening method to rapidly assess a test compound's binding activity, is especially helpful in early stage pharmacology studies. We developed a docking method using machine learning approach, which integrates features of structure-based rational drug design and QSAR into the learning models to enhance performance in molecular recognition. Docking simulation conducted by machine learning systems A + B provides improved reliability in predicting binding potentials and the capability of identifying potential targets. To achieve more accurate prediction, further integration of other computer-aided technology is feasible, such as the application of molecular dynamics (MD) after docking. Together with a curated signaling map, the network-based screening approach is able to comprehensively characterize the underlying mechanism of a drug candidate's activity and also to interpret the cascade effects of modulated targets. Adverse side effects constitute an enormous cost in drug development. By applying network-based screening, drug developers can reduce the possibility of marketing a drug with unfavorable drug-target interactions. On the other hand, it also provides an opportunity to rationally optimize inhibitor polypharmacology for treating complex diseases, such as cancer, neurodegenerative disorders, cardiovascular disease, and metabolic syndromes.

Altered milk protein can deliver aids drug to infants

2014-11-16T23:44:00.000-08:00

A novel method of altering a protein in milk to bind with an antiretroviral drug promises to greatly improve treatment for infants and young children suffering from HIV/AIDS, according to a researcher in Penn State's College of Agricultural Sciences.

That's critical because an estimated 3.4 million children are living with HIV/AIDS, the World Health Organization reports, and nine out of 10 of them live in resource-limited countries in sub-Saharan Africa, where effective antiretroviral treatments still are not widely accessible or available. International medical experts believe less than a third of affected children worldwide receive an antiretroviral drug.

Complicating treatment is that most antiretroviral drugs are not well tolerated by very young children. One of the most commonly prescribed antiretroviral drugs for treating and preventing HIV infection, Ritonavir, has undesirable side effects and important oral-delivery problems. Its physicochemical properties challenge its administration to infants, explained Federico Harte, associate professor of food science.

"Ritonavir has a high hydrophobicity and low solubility in water, which lead to a low dissolution rate in the gastrointestinal fluid and, hence, to insufficient bioavailability. The liquid formulation used to treat infants over one month of age contains 43 percent ethanol and has an awful flavor that has been described as bitter-metallic, medicinal, astringent, sour and burning," he said.

"Moreover, when coming into contact with the stomach mucosa, Ritonavir causes nausea, vomiting and diarrhea. Therefore, we need to develop alternative pediatric formulations of Ritonavir and overcome its poor water solubility to improve its oral administration to infants and children."

To solve that problem, Harte looked to a group of proteins in cow's milk celled caseins. Casein proteins form spherical aggregates called casein micelles, which are responsible, incidentally, for the white color of milk. The casein micelles in mammals' milk are natural delivery systems for amino acids and calcium from mother to young, and Harte reasoned, might deliver Ritonavir molecules as well.

Altered milk protein can deliver aids drug to infants

"He have been working with bovine casein micelles for a few years now, and we have investigated the structure and functionality of these proteins. "What he found is these micelles are able to carry molecules that have very little solubility in water, that have low molecular weight and that are very hydrophobic -- such as Ritonavir."

Significantly, Harte discovered in his research recently published online in the Journal of Pharmaceutical Research that subjecting milk to ultrahigh-pressure homogenization enhances the binding properties of the casein micelles. Normal milk is homogenized at 10 to 15 megapascals, he pointed out. Milk in this research was homogenized at between 400 and 500 megapascals, disassociating the casein micelles and improving the protein's binding qualities to attach to drug molecules.

"As a result of this enhanced binding of molecules, they believe a milk powder containing Ritonavir can be used as baby formula, providing a transport system for a drug that is not very soluble in water.

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Biotechnology Department

Diabetes researchers find faster way to create insulin-producing cells

2014-09-22T01:18:00.002-07:00

University of British Columbia, in collaboration with BetaLogics Venture, a division of Janssen Research & Development, LLC, has published a study highlighting a protocol to convert stem cells into insulin-producing cells. The new procedure could be an important step in the fight against Type 1 diabetes. The protocol can turn stem cells into reliable, insulin-producing cells in about six weeks, far quicker than the four months it took using previous methods. The protocol transforms stem cells into insulin-secreting pancreatic cells via a cell-culture method. The conversion is completed after the cells are transplanted into a host. An important next step for UBC researchers and their industry collaborators is to determine how to prevent the insulin-producing cells' from being rejected by the body.

Advances over the last decade suggest that generating functional beta-cells from human PSCs is achievable. However, there are aspects of beta-cell development that are not well understood and are hampering generation of PSC-derived beta-cells. In particular, the signaling pathways that instruct endocrine progenitor cells to differentiate into mature and functional beta-cells are poorly understood. Other significant obstacles remain, including the need for safe and cost-effective differentiation methods for large-scale generation of transplantation quality beta-cells, methods to prevent immune rejection of grafted tissues, and amelioration of the risks of tumorigenesis. Transplantation of pancreatic progenitors or insulin-secreting cells derived from human embryonic stem cells (hESCs) has been proposed as a therapy for diabetes. Stage (S) 7 cells expressed key markers of mature pancreatic beta cells, including MAFA, and displayed glucose-stimulated insulin secretion similar to that of human islets during static incubations in vitro. Additional characterization using single-cell imaging and dynamic glucose stimulation assays revealed similarities but also notable differences between S7 insulin-secreting cells and primary human beta cells. Nevertheless, S7 cells rapidly reversed diabetes in mice within 40 days, roughly four times faster than pancreatic progenitors. Therefore, although S7 cells are not fully equivalent to mature beta cells, their capacity for glucose-responsive insulin secretion and rapid reversal of diabetes in vivo makes them a promising alternative to pancreatic progenitor cells or cadaveric islets for the treatment of diabetes.

BY:-

BII Noida

Pharmacokinetics Drug-Design Interaction Study of Dovitinib (TKI258)

2014-07-07T03:58:00.000-07:00

This is a multi-center, open-label, phase I study to assess the effects of dovitinib (TKI258) on the pharmacokinetics of a cocktail of caffeine, diclofenac, omeprazole and midazolam in patients with advanced solid tumors, excluding breast cancer.

The aim of this study is to evaluate the potential effect of dovitinib (TKI258) on the metabolism of the probe drugs caffeine, diclofenac, omeprazole and midazolam, which are metabolized by CYP1A2, CYP2C9, CYP2C19 and CYP3A4 respectively (Cytochrome P450 isoenzyme), comparing the single-dose pharmacokinetics (AUCtlast, AUCinf and Cmax parameters) of each of the individual probe drug co-administered with and without multiple dose of dovitinib (TKI258) 500 mg under a 5 days on / 2 days off dose schedule.

The study foresees two treatment phases: DDI (drug-druginteraction) followed by post-DDI. During the DDI phase patients receive treatment with the probe drug cocktail and dovitinib (TKI258). During the post-DDI phase patients may continue to receive treatment with dovitinib (TKI258) until disease progression (assessed by RECIST 1.1), unacceptable toxicity, death or discontinuation from the study treatment for any other reason.

Condition

Intervention

Phase

Advanced Solid
Tumors,
Excluding Breast
Cancer

Drug: caffeine
Drug: diclofenac
Drug: omeprazole
Drug: midazolam
Drug: TKI258

Phase 1

BY

Keerti Mishra

Faculty of Biotechnology

FDA Approves Natesto (testosterone) Nasal Gel to Treat Men with Low Testosterone

2014-06-09T21:54:00.000-07:00

TORONTO (May 28, 2014) – Trimel Pharmaceuticals Corporation (TSX: TRL) announced today that the United States Food and Drug Administration (FDA) has approved Natesto (testosterone), formerly CompleoTRT™, the first and only testosterone nasal gel for replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone. Natesto is self-administered via a nasal applicator thereby minimizing the risk of secondary exposure to testosterone of women or children.

“In my practice I regularly encounter men demonstrating symptoms of hypogonadism and physicians will increasingly see this as the North American population ages,” said Dr. Jeffrey Rosen, the medical director and founder of Clinical Research of South Florida (CRSA). “For these patients seeking to restore their testosterone levels, Natesto™ will offer an alternative delivery system that is safer and more convenient than the other options currently available on the market.”

It is conservatively estimated that nearly 13 million American men may have low testosterone levels. Current treatment guidelines focus on the restoration of the physiological testosterone level through the use of exogenous testosterone preparations, which include topical gels applied by the hands, subcutaneous pellets, transdermal patches, intramuscular injections, oral tablets, as well as a buccal patch.

“The FDA approval for Natesto is a major achievement for our company, as it validates our clinical research and development efforts, as well as reinforces our commitment to provide innovative treatment options for patients,” said Tom Rossi, Trimel Pharmaceuticals Corporation President and CEO. “Men suffering from “Low T” will now have a different option to raise their testosterone levels. This novel route of administration will enable men to take this therapy in mere seconds, without worrying about the risk associated with transferring the product to women or children. We are now focused on getting Natesto to market as expeditiously as possible so that appropriate patients can have access to it.”

About Male Hypogonadism

Male hypogonadism, or low testosterone, is a condition in which the testicles, hypothalamus or pituitary gland is affected by disease or damage that results in inhibiting hormone and testosterone secretion. Signs and symptoms associated with male hypogonadism include erectile dysfunction and decreased sexual desire, fatigue and loss of energy, depressed mood, osteoporosis and regression of secondary sexual characteristics.

About the Natesto Phase III Study

Natesto was evaluated in a multicenter, open-label, 90-day Phase III trial that enrolled 306 hypogonadal men at 39 clinical research centers in the United States. The mean age of patients was 54 years with a range of 28 to 80 years. Of the 306 patients, 271 (89%) were Caucasian, 18 (6%) were African-American, 16 (5%) were Asian, and 1 (less than 1%) had race recorded as “Other.” Patients were instructed to administer Natesto™ intranasally. During the Natesto™ treatment period (Days 1 to 90), 78 patients were treated with 33 mg of testosterone daily. Of these, a total of 73 men were included in the statistical evaluation of efficacy on Day 90 based on the intent-to-treat (ITT) population with last observation carried forward (LOCF). Ninety percent (90%) of these patients had Cavg within the normal range (300 to 1050 ng/dL) on Day 90. The percentage of patients with Cavg below the normal range (less than 300 ng/dL) on Day 90 was 10% and no subject had a Cavg value exceeding 1050 ng/dL.

Posted By:
Ankita Nagpal

IISc professor’ virtual liver product gets patent in US

2014-04-16T00:10:00.004-07:00

Source:TOI

Banglore: Strand Life Sciences, founded by professors at the Indian Institute of Science (IISc), Bangalore, was awarded a patent in the US last week for its two-year-old virtual liver product, used by pharmaceuticals companies across the world to test new drug toxicity in the liver.

The virtual liver—a ready-to-use software simulation—mimics normal liver functions and generates likely outcomes of new drugs before the drug is tested on animals and humans.
Industry estimates suggest that nearly 50% of new drugs fail to pass through the clinical trial stage as the drugs are shown to have side effects, in particular, toxicity issues. Of that, 60% of the cases relate to liver injuries, given that the liver is responsible for flushing out toxins from the body.
"The software will also be awarded patent right in the European region shortly," said Kalyanasundaram Subramanian, chief scientific officer of Bangalore-based Strand Life Sciences.

Founded in 2000 by a clutch of computer science and mathematics professors, Strand has captured a 30% share of the global genomic (the discipline related to genetics) market through its core business of selling software that allows research labs, academics, and pharmaceutical companies to do biological data mining and interpretation.
Last year, the US-based Biomark Capital, a dedicated life-sciences fund, bought out early investors in Strand, including West Bridge and UTI Ventures, to become the single largest non-promoter investor in the firm.

The company generates over 90% of its business from global markets, and has revenues of about Rs 45 crore, with scientific software sales accounting for 50% of the revenues. Two other businesses—consulting and diagnostic testing—contribute the remaining 50%.
In 2007, Strand began work on the virtual liver, which falls under the consulting business vertical, and applied for patent rights in 2011. The virtual liver allows the pharmaceutical industry to reduce the number, time, and expenditure associated with animal and human trials and yet be able to understand the side effects of drugs on the liver.

"We wanted to combine simulation along with experimental methods to predict toxicity early on. The simulation is made on a rat model and a human model. Based on their outcomes, we know how a drug will react," said Subramanian.
With the patent being approved, the company expects business to increase and their labs to get busier. He said that in the first year of commercializing the virtual liver, pharma companies only ran pilot projects to test the software and subsequently placed small drug testing orders.
On the lines of the virtual liver, Strand has partnered with cosmetic companies to help them test their products on virtual software created for skin and hair.

Subramanian said though the company's hands were full, "going forward if we do anything like virtual liver we would look at the cardiac segment because that's another major area of toxicity."
Strand has close to 200 employees with around 80 computer scientists and 90 life scientists, including a strategic team based out of the US.

Posted by: Gauri Shah

Faculty BII

Building new drugs just got easier

2014-03-18T11:47:00.000-07:00

Source: Scripps Research Institute

Sientists at The Scripps Research Institute (TSRI) have developed a method for modifying organic molecules that significantly expands the possibilities for developing new pharmaceuticals and improving old ones.

A method for modifying organic molecules has been developed that significantly expands the possibilities for developing new pharmaceuticals and improving old ones. The innovation makes it easier to modify existing organic compounds by attaching biologically active "functional group" to drug molecules. A typical small-molecule drug derives its activity from such functional groups, which are bound to a relatively simple backbone structure consisting chiefly of carbon atoms.

Pushing the Boundaries

Chemists over the past half-century or so have devised various methods for adding functional groups to carbon atoms, to make new compounds and to modify old ones. But a certain type of modification has remained largely out of reach.

Known as a "meta" C-H activation, this modification involves the temporary attachment of a helper molecule to one carbon atom, in such a way that the helper molecule extends past the nearest-neighbor carbon atom to the next-nearest carbon atom, and there mediates the addition of a functional group. It is a tricky task for a number of reasons, but mostly because the targeted attachment site is so far away and inaccessible. The carbon in the backbone of a typical organic compound is arranged in rings of six or so carbon atoms -- and thus to reach from one such carbon over a second to a third means reaching almost to the far side of the ring.

In 2012, Yu and his colleagues published a landmark paper, also in Nature, which described a way to accomplish this feat with one set of compounds. They devised a helper molecule, with a long segment called a nitrile, that could attach to one carbon atom on the compound, arch over the next-door carbon atom, and in effect swing a palladium atom at its far end back -- a bit like a crane swinging a wrecking ball -- to the targeted carbon atom. There the palladium atom would act as a catalyst to dislodge the existing occupant, a hydrogen atom, enabling the attachment of the new functional group.

Following the same principle, Yu's team recently came up with a new template for making meta-C-H activations on a much more challenging set of organic compounds. Now, in the new study, the researchers have demonstrated the same task with a major family of compounds known as amines, including medicinally important heterocyclic amines. In so doing, the researchers found a way to use a helper molecule -- also called a template -- that is chemically simpler and more user-friendly than the ones they have described in previous work.

A Boost to Drug Discovery

Unusually for such a project, the TSRI chemists analyzed the 3D atomic structure of their template compound using X-ray crystallography as well as nuclear magnetic resonance spectroscopy. These studies revealed that the new template's ability to mediate the attachment of a new functional group to a distant carbon atom can be "tuned" by making slight changes to its chemical composition, including the choice of the proper metal catalyst at its working end.

"The key is to tune the shape of the template to create a subtle bias towards the targeted carbon hydrogen bond," said Yu. "At the same time the template's movement towards the target site has to be exploited effectively by a super-reactive catalyst."

Compounds that can be modified using the new technique include tetrahydroquinoline, benzooxazines, anilines, benzylamines, 2-phenylpyrrolidines and 2-phenylpiperidines. "All these are commonly used in medicinal chemistry either as final drug compounds or intermediate compounds from which the final compounds are made," Yu said.

"Techniques like this one that enable controlled, remote C-H activation are just beginning to be adopted by industry, and should provide a boost to drug discovery and development efforts for many years to come," Yu said.

Posted by:

Gauri Shah

Faculty BII

Flies in Ranbaxy's Toansa plant's sample storage room, says FDA

2014-02-03T23:20:00.000-08:00

PTI Hyderabad

Presence of flies in sample storage room, un-calibrated instruments in laboratory and non-adherence to sample analysis procedure were among the lapses found in Ranbaxy's Toansa plant that led to US health regulator FDA banning imports of drugs made at the facility.According to the report released by the US Food and Drug Administration (FDA) inspection teams, as many as eight lapses were identified, including "Too Numerous To Count (TNTC) flies" in sample storage room, inadequate control over samples and non-adherence of procedures in sample analysis, during their visit to the Toansa, Punjab facility.

Other lapses included usage of un-calibrated and unqualified instruments in laboratory, said the report, which was released two days ago."Our inspection of QC Analytical and Microbiological laboratories found the facility to be in significant disrepair. Laboratories windows within the instrumentation (eg: HPCL) rooms were found to be un-closeable.

"Too Numerous To Count (TNTC) flies were observed throughout the sample preparation room, and laboratory re-agent/equipment/documentation storage cabinets were found to be broken and un-closeable," FDA inspection report said. Earlier this week, FDA banned the import of Ranbaxy products from its Toansa plant, halting the shipment of all the company's drugs to the US from India. This is the company's fourth plant to face regulatory action from the American health regulator after Mohali, Paonta Sahib amd Dewas plants. Citing manufacturing norm violations, the USFDA prohibited Ranbaxy Laboratories from distributing drugs produced at the Toansa unit, including medicines made by the company's Ohm Laboratories facility in New Jersey.

Expressing disappointment over the FDA ban, Ranbaxy had said it will cooperate with the FDA and "comply with Consent Decree in both letter and spirit".
The FDA inspection report further said that the Indian drug maker repeated the same errors which were cited by the regulator in its earlier inspection in December 2012.

"Appropriate controls are not established over computerised systems..This is a repeat observation from the previous FDA inspection in 12/2012."Specifically the standalone computerised system controlling GC# 6 does not have sufficient controls to prevent unauthorised access to, changes to, or omission of data files and folders," the report said.

The audit team said that the raw material, intermediates and finished API (active pharma ingredients) analytical results found to be failing specifications or otherwise retested until acceptable results are obtained. These results are not reported.The FDA notice said Ranbaxy is required to hire a third- party expert to thoroughly inspect the Toansa facility and certify to the FDA that the facility and its methods and controls are adequate to ensure continuous compliance with cGMP (Current Good Manufacturing Practices).

"Ranbaxy will not be permitted to resume manufacturing and distributing API for FDA-regulated drugs from the Toansa facility until the agency is satisfied that Ranbaxy has addressed its manufacturing quality issues at that facility," it further said.

Posted by:

Gauri Shah (faculty)

New Guidelines for Preventing, Treating Opportunistic Infections in HIV+ Children

2014-01-21T00:49:00.000-08:00

From Reuters Health Information CME

News Author: Megan Brooks
CME Author: Laurie Barclay, MD

CLINICAL CONTEXT

A panel of specialists in pediatric HIV infection and infectious diseases from the National Institutes of Health, the Centers for Disease Control and Prevention, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics issued clinical guidelines for the prevention and treatment of opportunistic infections (OIs) in HIV-exposed and HIV-infected US children.

For bacterial and specific fungal and viral infections, pediatric specialists expert in each condition reviewed the literature for new publications since the previous guidelines in 2009. The full panel and endorsing organizations reviewed proposed revisions. These guidelines target clinicians and other healthcare workers providing medical care for HIV-exposed and HIV-infected children in the United States, whereas a separate document offers guidelines for prevention and treatment of OIs in HIV-infected adults and postpubertal adolescents.

STUDY SYNOPSIS AND PERSPECTIVE

A US expert panel has issued updated guidelines for preventing and treating opportunistic infections (OIs) in HIV-exposed and infected children.

Jointly created by the National Institutes of Health, the Centers for Disease Control and Prevention, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics, the new guidelines update previous recommendations issued in 2009.The document includes updated immunization recommendations for HIV-exposed and HIV-infected children, including pneumococcal, human papillomavirus (HPV), meningococcal, and rotavirus vaccines."Ideally, HPV vaccine should be administered before an individual becomes sexually active," the guidelines state. "HIV-infected individuals should use latex condoms during every act of sexual intercourse to reduce the risk of exposure to sexually transmitted pathogens, including HPV."

And for influenza, "The approach to evaluation and treatment of HIV-infected children on stable combination antiretroviral therapy with suspected or confirmed influenza should be similar to that of HIV-uninfected children," the guidelines say. "Prevention of influenza in HIV-infected children aged 6 months and older should include annual administration of trivalent inactivated influenza vaccine, according to Advisory Committee on Immunization Practices recommendations."

They further advise, "Influenza-specific antiviral chemoprophylaxis should be considered for HIV-infected children based on level of immunosuppression and other preexisting co-morbidities, influenza vaccination status, and degree of exposure to suspected or confirmed influenza, according to CDC guidelines. HIV-infected children with confirmed influenza should be considered for prompt antiviral therapy, according to CDC guidelines."

Panel member Dr. George Siberry, who is with the Eunice Kennedy Shriver National Institute of Child Health and Human Development in Bethesda, Maryland, told Reuters Health by email that the new recommendations complement other US federal guidelines covering OIs in adults with HIV, as well as antiretroviral treatment of children, pregnant women, and adolescents and adults, "all of which are available at www.aidsinfo.nih.gov."He said "selected key updates" to the guidelines include a greater emphasis on the importance of ART for prevention and treatment of OIs, especially those OIs for which no specific therapy exists, and guidance about managing ART in children with OIs, including potential drug-drug interactions.

The guidelines panel notes in a 16-page executive summary, published online November 27 in the Journal of the Pediatric Infectious Diseases Society, that "licensure of drugs for children and their application in clinical care often relies on efficacy data from adult trials in combination with pharmacokinetic, safety, and/or observational data in children." Therefore, recommendations sometimes rely on trials in adults with only supporting data in children.

The update also includes "increased information about the diagnosis and management of immune reconstitution inflammatory syndrome (IRIS)," Dr. Siberry said, and "updated recommendations on discontinuation of OI prophylaxis after immune reconstitution in children."

Posted by: Gauri Shah

Faculty Biotechnology

Bioinformatics Institute of India

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Advanced Solid Tumors, Excluding Breast Cancer	Drug: caffeine Drug: diclofenac Drug: omeprazole Drug: midazolam Drug: TKI258	Phase 1