Monday On The Blog:
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Big Pharma
HIV
Tenofovir, Leading HIV Medication, Linked with Risk of Kidney Damage
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Hall Of Shame
Duke Experimental Cancer Treatment:Medical research fraud?
Tenofovir, Leading HIV Medication, Linked with Risk of Kidney Damage
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Hall Of Shame
Duke Experimental Cancer Treatment:Medical research fraud?
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Hepatitis C
Citation: El-Shamy A, Shoji I, Kim S-R, Ide Y, Imoto S, et al. (2012) Sequence Heterogeneity in NS5A of Hepatitis C Virus Genotypes 2a and 2b and Clinical Outcome of Pegylated-Interferon/Ribavirin Therapy. PLoS ONE 7(2): e30513. doi:10.1371/journal.pone.0030513
Editor: John E. Tavis, Saint Louis University, United States of America
Received: August 1, 2011; Accepted: December 16, 2011; Published: February 2, 2012
Editor: John E. Tavis, Saint Louis University, United States of America
Received: August 1, 2011; Accepted: December 16, 2011; Published: February 2, 2012
Abstract
Pegylated-interferon plus ribavirin (PEG-IFN/RBV) therapy is a current standard treatment for chronic hepatitis C. We previously reported that the viral sequence heterogeneity of part of NS5A, referred to as the IFN/RBV resistance-determining region (IRRDR), and a mutation at position 70 of the core protein of hepatitis C virus genotype 1b (HCV-1b) are significantly correlated with the outcome of PEG-IFN/RBV treatment. Here, we aimed to investigate the impact of viral genetic variations within the NS5A and core regions of other genotypes, HCV-2a and HCV-2b, on PEG-IFN/RBV treatment outcome. Pretreatment sequences of NS5A and core regions were analyzed in 112 patients infected with HCV-2a or HCV-2b, who were treated with PEG-IFN/RBV for 24 weeks and followed up for another 24 weeks. The results demonstrated that HCV-2a isolates with 4 or more mutations in IRRDR (IRRDR[2a]≥4) was significantly associated with rapid virological response at week 4 (RVR) and sustained virological response (SVR). Also, another region of NS5A that corresponds to part of the IFN sensitivity-determining region (ISDR) plus its carboxy-flanking region, which we referred to as ISDR/+C[2a], was significantly associated with SVR in patients infected with HCV-2a. Multivariate analysis revealed that IRRDR[2a]≥4 was the only independent predictive factor for SVR. As for HCV-2b infection, an N-terminal half of IRRDR having two or more mutations (IRRDR[2b]/N≥2) was significantly associated with RVR, but not with SVR. No significant correlation was observed between core protein polymorphism and PEG-IFN/RBV treatment outcome in HCV-2a or HCV-2b infection.
Conclusion: The present results suggest that sequence heterogeneity of NS5A of HCV-2a (IRRDR[2a]≥4 and ISDR/+C[2a]), and that of HCV-2b (IRRDR[2b]/N≥2) to a lesser extent, is involved in determining the viral sensitivity to PEG-IFN/RBV therapy.
Pegylated-interferon plus ribavirin (PEG-IFN/RBV) therapy is a current standard treatment for chronic hepatitis C. We previously reported that the viral sequence heterogeneity of part of NS5A, referred to as the IFN/RBV resistance-determining region (IRRDR), and a mutation at position 70 of the core protein of hepatitis C virus genotype 1b (HCV-1b) are significantly correlated with the outcome of PEG-IFN/RBV treatment. Here, we aimed to investigate the impact of viral genetic variations within the NS5A and core regions of other genotypes, HCV-2a and HCV-2b, on PEG-IFN/RBV treatment outcome. Pretreatment sequences of NS5A and core regions were analyzed in 112 patients infected with HCV-2a or HCV-2b, who were treated with PEG-IFN/RBV for 24 weeks and followed up for another 24 weeks. The results demonstrated that HCV-2a isolates with 4 or more mutations in IRRDR (IRRDR[2a]≥4) was significantly associated with rapid virological response at week 4 (RVR) and sustained virological response (SVR). Also, another region of NS5A that corresponds to part of the IFN sensitivity-determining region (ISDR) plus its carboxy-flanking region, which we referred to as ISDR/+C[2a], was significantly associated with SVR in patients infected with HCV-2a. Multivariate analysis revealed that IRRDR[2a]≥4 was the only independent predictive factor for SVR. As for HCV-2b infection, an N-terminal half of IRRDR having two or more mutations (IRRDR[2b]/N≥2) was significantly associated with RVR, but not with SVR. No significant correlation was observed between core protein polymorphism and PEG-IFN/RBV treatment outcome in HCV-2a or HCV-2b infection.
Conclusion: The present results suggest that sequence heterogeneity of NS5A of HCV-2a (IRRDR[2a]≥4 and ISDR/+C[2a]), and that of HCV-2b (IRRDR[2b]/N≥2) to a lesser extent, is involved in determining the viral sensitivity to PEG-IFN/RBV therapy.
Introduction Hepatitis C virus (HCV) is a major cause of chronic liver disease, such as chronic hepatitis, liver cirrhosis and hepatocellular carcinoma, with180 million people being currently infected with HCV worldwide. It is estimated that 70% of acute infections become persistent [1]. As a consequence of the long-term persistence of HCV infection, the number of patients with hepatocellular carcinoma is expected to increase further over the next 20 years. More than two decades have passed since the discovery of HCV, and yet therapeutic options remain limited. Standard regimens for treatment of chronic hepatitis C include pegylated interferon alpha (PEG-IFN) and ribavirin (RBV) [2]. In addition, two protease inhibitors (telaprevir and boceprevir) were approved in May 2011 by the U. S. Food and Drug Administration (FDA) for clinical use in combination with PEG-IFN/RBV to treat chronic hepatitis C patients with HCV genotype 1 [3], [4].
In Japan, about 70% of HCV-infected patients are infected with HCV genotype 1b (HCV-1b) and most of the remaining patients are infected with HCV-2a (25%) or HCV-2b (5%) [5]. When treated with PEG-IFN/RBV, the sustained virological response (SVR) rate is ca. 50% in HCV-1b infection, and ca. 80% in HCV-2a and -2b infections [2], [6]. The mechanism(s) underlying the different responses among patients with different HCV genotypes and subtypes is still unclear. However, this suggests that viral genetic heterogeneity could affect, at least to some extent, the sensitivity to IFN-based therapy. In this context, sequence heterogeneity of the viral NS5A protein has been widely discussed for its correlation with IFN responsiveness. Sequence variations within a region in NS5A of
HCV-1b defined as the IFN sensitivity-determining region (ISDR) is correlated with IFN responsiveness [7]. In HCV-2a infection, the influence of sequence heterogeneity in and around a region corresponding to ISDR on the IFN responsiveness was also suggested [8]–[10]. Recently, we identified a new region near the C-terminus of NS5A of HCV-1b, which we refer to as the IFN/RBV resistance-determining region (IRRDR) [11], [12]. The degree of sequence variation within IRRDR was significantly correlated with the clinical outcome of PEG-IFN/RBV combination therapy. The significance of IRRDR of other HCV genotypes, however, has not been investigated yet.
In addition to the NS5A sequence variation, HCV core protein polymorphism was also proposed as a pretreatment predictor of poor virological response in HCV-1b-infected patients treated with PEG-IFN/RBV therapy [13]. It is not clear at this stage whether core protein polymorphism could be used to predict the treatment outcome in HCV-2a and -2b infections. In the present study, we investigated the impact of viral genetic heterogeneity in the NS5A and core regions of HCV-2a and -2b on PEG-IFN/RBV treatment outcome. To the best of our knowledge, this is the first report describing the possible correlation between PEG-IFN/RBV responsiveness and NS5A-IRRDR heterogeneity of HCV-2a and -2b.
In Japan, about 70% of HCV-infected patients are infected with HCV genotype 1b (HCV-1b) and most of the remaining patients are infected with HCV-2a (25%) or HCV-2b (5%) [5]. When treated with PEG-IFN/RBV, the sustained virological response (SVR) rate is ca. 50% in HCV-1b infection, and ca. 80% in HCV-2a and -2b infections [2], [6]. The mechanism(s) underlying the different responses among patients with different HCV genotypes and subtypes is still unclear. However, this suggests that viral genetic heterogeneity could affect, at least to some extent, the sensitivity to IFN-based therapy. In this context, sequence heterogeneity of the viral NS5A protein has been widely discussed for its correlation with IFN responsiveness. Sequence variations within a region in NS5A of
HCV-1b defined as the IFN sensitivity-determining region (ISDR) is correlated with IFN responsiveness [7]. In HCV-2a infection, the influence of sequence heterogeneity in and around a region corresponding to ISDR on the IFN responsiveness was also suggested [8]–[10]. Recently, we identified a new region near the C-terminus of NS5A of HCV-1b, which we refer to as the IFN/RBV resistance-determining region (IRRDR) [11], [12]. The degree of sequence variation within IRRDR was significantly correlated with the clinical outcome of PEG-IFN/RBV combination therapy. The significance of IRRDR of other HCV genotypes, however, has not been investigated yet.
In addition to the NS5A sequence variation, HCV core protein polymorphism was also proposed as a pretreatment predictor of poor virological response in HCV-1b-infected patients treated with PEG-IFN/RBV therapy [13]. It is not clear at this stage whether core protein polymorphism could be used to predict the treatment outcome in HCV-2a and -2b infections. In the present study, we investigated the impact of viral genetic heterogeneity in the NS5A and core regions of HCV-2a and -2b on PEG-IFN/RBV treatment outcome. To the best of our knowledge, this is the first report describing the possible correlation between PEG-IFN/RBV responsiveness and NS5A-IRRDR heterogeneity of HCV-2a and -2b.
Effects of Telaprevir on Cyclosporine and Tacrolimus Pharmacokinetics Make Utility in Post-OLT Setting Uncertain
John M. Vierling, MD, FACP
John M. Vierling, MD, FACP
Posting Date: December 13, 2011
Professor of Medicine and Surgery
Chief of Hepatology
Department of Medicine and Surgery
Baylor College of Medicine
Director, Advanced Liver Therapies
St Luke's Episcopal Hospital
Houston, Texas
Professor of Medicine and Surgery
Chief of Hepatology
Department of Medicine and Surgery
Baylor College of Medicine
Director, Advanced Liver Therapies
St Luke's Episcopal Hospital
Houston, Texas
Chronic hepatitis C is the leading cause of orthotopic liver transplantation (OLT) in the United States and Europe, accounting for 30% to 50% of adult liver transplantations.[1] Hepatitis C virus (HCV) infects the transplanted allograft in virtually 100% of recipients who are viremic at the time of OLT.[2]
Recurrent chronic hepatitis C is a significant cause of morbidity and mortality and results in decompensated cirrhosis in approximately 20% of transplantation recipients within 4-7 years.
Transplant hepatologists have attempted to treat chronic hepatitis C post-OLT using off-label peginterferon/ribavirin, attaining only marginal success. Thus, the possibility of adding a direct-acting antiviral agent, such as the HCV NS3/NS4 protease inhibitors telaprevir and boceprevir, post-OLT is of great interest.
An understanding of drug-drug interactions (DDI) between direct-acting antiviral agents and tacrolimus and cyclosporine, the primary immunosuppressants used in OLT, is a minimal prerequisite before either telaprevir or boceprevir can be used post-OLT. This is especially true for telaprevir since this agent is a potent substrate and inhibitor of cytochrome P450 3A (CYP3A), which also metabolizes both cyclosporine and tacrolimus. Moreover, telaprevir also can saturate and inhibit the major gut transporter, P-glycoprotein (P-gp). To provide these essential DDI data, Garg and colleagues[3] assessed the effect of telaprevir on the single-dose pharmacokinetic (PK) parameters of tacrolimus and cyclosporine.
There are 4 important results of this rigorously conducted study. First, coadministration of telaprevir with cyclosporine significantly increased the dose-normalized (DN) exposure compared with administration of cyclosporine alone. Specifically, the DN concentration maximum (Cmax) increased by approximately 1.4-fold, the DN area under the curve (AUC) increased approximately 4.6-fold, and the half-life increased 4-fold. Thus, the intervals between cyclosporine doses would need to be substantially longer if coadministered with telaprevir. Second, coadministration of telaprevir with tacrolimus yielded much greater effects. The DN Cmax increased approximately 9.3-fold, the DN AUC increased approximately 70-fold, and the half-life increased approximately 5-fold. These results indicate that coadministration of telaprevir and tacrolimus would be potentially hazardous unless low doses of tacrolimus were administered very infrequently. Third, since the PK of cyclosporine or tacrolimus was assessed only after single doses of the immunosuppressants, the increased elimination half-life for both cyclosporine and tacrolimus strongly suggests that further increases in blood levels would occur if multiple doses were administered in combination with telaprevir. Fourth, the fact that food is required for intestinal absorption of telaprevir could further impact the PK of cyclosporine and tacrolimus, since food decreases blood exposure of both immunosuppressants. Thus, the impact of telaprevir coadministration every 7-9 hours with a (not low-fat) meal on cyclosporine or tacrolimus remains unknown.
The principal clinical implication of this study is that the magnitude of the effects of telaprevir on the PK of cyclosporine and tacrolimus preclude its safe use for the treatment of chronic hepatitis C post-OLT without additional data from trials of dosing to prove that safe coadministration is possible. Even with such data, coadministration would require very careful selection of eligible patients by transplant hepatologists experienced in the management of complex DDIs, as well as the informed consent of the patient. The potential to do harm is underscored by evidence that both HCV infection and abnormal hepatocyte function in a necroinflammatory milieu would independently affect metabolism of cyclosporine and tacrolimus and, likely, would also impact telaprevir metabolism. Once telaprevir was discontinued, the duration of its inhibitory effect on CYP3A and P-gp would need to be ascertained to adjust the dosages and dose intervals of cyclosporine or tacrolimus.
The magnitude of the impact of coadministration of telaprevir and single doses of either cyclosporine or tacrolimus is a disappointment for transplant hepatologists who were eager to use telaprevir to treat recurrent chronic hepatitis C post-OLT. In addition, calculating dosages and dosing intervals of cyclosporine or tacrolimus with coadministered telaprevir would be even more problematic in the presence of other potential DDIs with other coadministered medications metabolized through CYP3A or transported by P-gp. Examples of medications metabolized by CYP3A that are used commonly post-OLT include corticosteroids, sirolimus, mycophenolic acid, calcium-channel blockers, statins, analgesics, and antiretrovirals for HIV.
Importantly, a comparable study of the impact of boceprevir on the PK of cyclosporine and tacrolimus was recently conducted in healthy volunteers and the data were presented in December 2011 at HEP DART.[4] In contrast to telaprevir, boceprevir is primarily metabolized by aldo-keto reductase with a lesser contribution from CYP3A4. In a study of 10 healthy volunteers, coadministration of boceprevir with cyclosporine induced a 2.01-fold increase in Cmax and a 2.70-fold increase in AUC from time 0 to infinity after single dosing (AUCinf) of cyclosporine. By contrast, coadministration of boceprevir and tacrolimus caused a 9.9-fold increase in Cmax and a 17.1-fold increase in AUCinf of tacrolimus. These data indicate that coadministration of boceprevir with either cyclosporine or tacrolimus would require significant dose adjustments of the calcineurin inhibitors and attentive monitoring of their trough concentrations and of renal function.
Despite these informative data, important needs remain unaddressed. First, studies of the effects of telaprevir or boceprevir on the PK of sirolimus, another immunosuppressant metabolized by CYP3A, are urgently needed, as patients are increasingly converted to sirolimus immunosuppression to retard deterioration of renal function caused by the nephrotoxicity of cyclosporine or tacrolimus.
The effects of either telaprevir or boceprevir on the PK of cyclosporine and tacrolimus should be studied in phase Ib protocols in post-OLT noncirrhotic patients with chronic hepatitis C and stage 1-3 fibrosis to address the applicability of the PK changes in the setting of abnormal liver tests and advanced fibrosis. The focus of attention will likely be on coadministration of telaprevir or boceprevir with cyclosporine because the data suggest that it may be the safer immunosuppressant with either direct-acting antiviral agent. If the data from studies of telaprevir or boceprevir in post-OLT noncirrhotic patients are favorable, similar PK studies should be performed in compensated post-OLT cirrhotic patients with the additional variable of significant portal systemic shunting.
1. Berenguer M. Management of hepatitis C virus in the transplant patient. Clin Liver Dis. 2007;11:355-376.
2. Terrault NA. Treatment of recurrent hepatitis C in liver transplant recipients. Clin Gastroenterol Hepatol. 2005;3:S125-S131.
3. Garg V, van Heeswijk R, Lee JE, Alves K, Nadkarni P, Luo X. Effect of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus. Hepatology. 2011;54:20-27.
4. Hulskotte EJG, Gupta S, Xuan F, et al. Pharmacokinetic interaction between the HCV protease inhibitor boceprevir and the calcineurin inhibitors cyclosporine and tacrolimus. 16th Annual Meeting of HEP DART; December 4-8, 2011; Koloa, Hawaii.
Link to the original abstract
HIV
Larger belly linked to memory problems in people with HIV
ST. PAUL, Minn. – A larger waistline may be linked to an increased risk of decreased mental functioning in people infected with the AIDS virus HIV, according to research published in the February 14, 2012, print issue of Neurology®, the medical journal of the American Academy of Neurology.
"Interestingly, bigger waistlines were linked to decreased mental functioning more than was general obesity," said study author J. Allen McCutchan, MD, MSc, of the University of California, San Diego. "This is important because certain anti-HIV drugs cause weight gain in the center of the body that is most dramatic in the abdomen, neck, chest and breasts."
The study was performed in 130 HIV positive people from six clinics. Participants were around the age of 46 with HIV infection for an average of 13 years. Most participants were taking combinations of anti-HIV drugs called antiretroviral therapy. Impaired mental functions such as poor memory and concentration, called neurocognitive impairment (NCI), was diagnosed in 40 percent of study participants.
People with NCI had waist circumferences of an average of 39 inches, compared to 35 inches for those without memory difficulties. NCI was also linked to older age, a longer time living with HIV and diabetes in people older than 55 years. For example, five times as many people with memory problems also had diabetes compared to those with no memory problems (15 percent compared to 3 percent).
"Avoiding those HIV drugs that cause larger waistlines might protect or help to reverse NCI," said McCutchan. "We don't know if central obesity is causing NCI directly or is just a marker for exposure to a more direct cause such as anti-HIV drugs. People with HIV should talk to their doctors before considering changes in their anti-HIV medications."
To learn more about cognitive impairment, visit http://www.aan.com/patients.
The American Academy of Neurology, an association of more than 25,000 neurologists and neuroscience professionals, is dedicated to promoting the highest quality patient-centered neurologic care. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as Alzheimer's disease, stroke, migraine, multiple sclerosis, brain injury, Parkinson's disease and epilepsy.
For more information about the American Academy of Neurology, visit http://www.aan.com or find us on Facebook, Twitter, Google+ and YouTube.
Media Contacts:
Rachel Seroka, rseroka@aan.com, (651) 695-2738
Angela Babb, APR, ababb@aan.com, (651) 695-2789
New HIV-vaccine tested on people
Scientists from the Antwerp Institute of Tropical Medicine, Antwerp University Hospital and Antwerp University have tested a new 'therapeutic vaccine' against HIV on volunteers. The participants were so to say vaccinated with their own cells. The researchers filtered certain white blood cells out of the volunteer's blood, 'loaded' them outside the body and then gave them back. The immune system of the testees was better than before in attacking and suppressing the virus, the scientists reported in the top journal AIDS. But they still cannot cure the disease.
Actually, medical science can control an HIV-infection quite well, with a medicine cocktail. 'Seropositive' people (people who are infected with the HIV virus) now can lead a reasonably normal life, but their virus is not exterminated. When they stop the treatment it immediately rebounds.
Science knows what the problem is: the 'special forces' in our blood (the CD8 cells, in medical lingo) get not enough support from the general staff (the dendritic cells, that show the combat units what to attack). Dendritic cells exhibit on their exterior typical parts of the virus to be attacked. But human dendritic cells are not that good in getting the right information on the HIV virus and to transform it into good examples for the CD8 battle cells.
The virologists and HIV-physicians of the Institute of Tropical Medicine and the haematologists of Antwerp University Hospital have cooperated for years on that problem. Together they succeeded to 'load' dendritic cells of seropositive volunteers in the lab with the building instructions (genetic information in the form of so-called messenger RNA) for HIV proteins. They could make the dendritic cells to execute the instructions and to exhibit the resulting typical part of the HIV virus on their surface. Subsequent research in test tubes demonstrated that the 'loaded' dendritic cells were able to activate battle cells.
Time had come to proceed to humans. Flemish, Belgian and French research foundations provided grants. Six seropositive persons who for a long time already used the drug cocktails, were prepared to volunteer. The scientists filtered the dendritic cells from a large volume of their blood, cultivated them in test tubes in the cell-therapy unit of the Antwerp University Hospital and provided them with the genetic instructions of an HIV virus. They then froze the loaded cells.
The volunteers received four times, with four-week intervals, a small quantity of their own reworked dendritic cells. And indeed, after each vaccination the CD8 battle cells in their bodies recognised the virus better and better, while the vaccination had virtually no side effects. The most important result was that the vaccine-activated battle cells became better and better in suppressing the virus, in test tubes for the moment. But HIV remains a disguise artist; it still succeeds in changing its proteins sufficiently fast and often to let at least a few viruses escape the attack.
So it remains impossible to cure AIDS, but the results are encouraging: the vaccine, made of the participant's own dendritic cells, is safe and has some therapeutic effect, be it a limited one. But sufficiently strong for a publication in the most renowned journal for HIV researchers, AIDS. And more than sufficient to enthuse and motivate the Antwerp scientists.
New research reveals how protein protects cells from HIV infection
Finding offers potential new drug targets aimed at slowing progression of disease
NEW YORK -- A novel discovery by researchers at NYU Langone Medical Center and colleagues reveals a mechanism by which the immune system tries to halt the spread of HIV. Harnessing this mechanism may open up new paths for therapeutic research aimed at slowing the virus' progression to AIDS. The study appears online ahead of print today in Nature Immunology.
"A lot of research on viruses, especially HIV, is aimed at trying to understand what the body's mechanisms of resistance are and then to understand how the virus has gotten around these mechanisms," said co-lead investigator Nathaniel R. Landau, PhD, a professor of microbiology at the Joan and Joel Smilow Research Center at NYU School of Medicine.
The research focused on a protein called SAMHD1. Recent studies have found that immune cells, called dendritic cells, containing the protein are resistant to infection by HIV. Since the discovery, scientists have sought to understand how SAMHD1 works to protect these cells, with hopes that science might find a way to synthetically apply that protection to other cells.
Dr. Landau and his team are now able to provide an answer:
When a virus, like HIV, infects a cell, it hijacks the cell's molecular material to replicate. That molecular material is in the form of deoxynucleotide triphosphates (dNTPs), which are the building blocks for DNA. Once the virus replicates, the resulting DNA molecule contains all the genes of the virus and instructs the cell to make more virus.
Researchers wanted to understand how cells containing the SAMHD1 protein are protected from such hijacking. They found that SAMHD1 protects the cell from viruses by destroying the pool of dNTPs, leaving the virus without any building blocks to make its genetic information – a process researchers call nucleotide pool depletion. "SAMHD1 essentially starves the virus," Dr. Landau said. "The virus enters the cell and then nothing happens. It has nothing to build and replicate with, so no DNA is made."
As a result, the most common form of HIV does not readily infect these cells. Instead, the virus has evolved to replicate mainly in a different kind of cell, called CD4 T-cells, which do not contain SAMHD1 and therefore have a healthy pool of dNTPs. Dr. Landau explained that the virus has evolved in such a way that it may deliberately avoid trying to infect immune cells with SAMHD1 to avoid alerting the greater immune system to activate a variety of antiviral mechanisms to attack the virus. Viruses that are related to HIV, like HIV-2 and SIV, have developed a protein called viral protein X (VPX) that directly attacks SAMHD1. This allows the virus to infect dendritic cells, an important type of immune cell.
"Viruses are remarkably clever about evading our immune defenses," Dr. Landau said. "They can evolve quickly and have developed ways to get around the systems we naturally have in place to protect us. It's a bit of evolutionary warfare and the viruses, unfortunately, usually win. We want to understand how the enemy fights so that we can outsmart it in the end."
Understanding the mechanism by which SAMHD1 provides protection to cells may provide a new idea about how to stop or slow the virus' ability to spread, Dr. Landau explained. Potential future research efforts, for example, might focus on finding a way to increase the amount of SAMHD1 in cells where it does not exist, or to reduce the amount of dNTPs in cells vulnerable to infection.
"Over the past few years, a number of these natural resistance mechanisms have been identified, specifically in HIV, but some have potential applications to other viruses, as well," he said. "This is a very exciting time in HIV research. Many of the virus' secrets are being revealed through molecular biology, and we're learning a tremendous amount about how our immune system works through the study of HIV."
About NYU School of Medicine:
NYU School of Medicine is one of the nation's preeminent academic institutions dedicated to achieving world class medical educational excellence. For 170 years, NYU School of Medicine has trained thousands of physicians and scientists who have helped to shape the course of medical history and enrich the lives of countless people. An integral part of NYU Langone Medical Center, the School of Medicine at its core is committed to improving the human condition through medical education, scientific research and direct patient care. The School also maintains academic affiliations with area hospitals, including Bellevue Hospital, one of the nation's finest municipal hospitals where its students, residents and faculty provide the clinical and emergency care to New York City's diverse population, which enhances the scope and quality of their medical education and training. Additional information about the NYU School of Medicine is available at http://school.med.nyu.edu/.
Perspective
New England Journal Of Medicine
Reza Mirnezami, M.R.C.S., Jeremy Nicholson, Ph.D., and Ara Darzi, M.D.
N Engl J Med 2012; 366:489-491
N Engl J Med 2012; 366:489-491
Ultimately, precision medicine should ensure that patients get the right treatment at the right dose at the right time, with minimum ill consequences and maximum efficacy. But it will change how medicine is practiced and taught and how health care is delivered and financed. It will change the way research and development are financed and regulated. It will deeply affect public trust and the nature of the patient–clinician relationship, and it will require unprecedented collaboration among health care stakeholders...Continue Reading
Bath Salts
February 12, 2012
Fake speed is new to the drug scene, and like K-2 or synthetic marijuana or synthetic cocaine, it is legal, but by no means safe.
It can be purchased online or in head shops and is a white or yellowish powder labeled as "bath salts" or "plant food." It is sold in packets or small containers and contains mephadrone, or MDPV (methylenedioxypyrovalerone), a psychoactive drug with stimulant properties. It can be snorted or injected into a vein. Mephadrone is created by pseudo-chemists in uncontrolled settings and can cause serious, immediate and long-term damage.
On March 1, 2011, the Drug Enforcement Agency banned the chemicals used to make these synthetic drugs. Possession and sale of these chemicals or products that contain them is illegal in the United States.
Synthetic cannabinoids are an alternative to THC, the psychoactive chemical found in marijuana. "Aloha," one of the synthetic cannabinoids, has a fruity smell and comes in small round containers holding 4 grams. It is a green herb with the texture of ground marijuana. One man had a terrible experience. He said that after smoking the stuff his mind was blown and he virtually lost control. The world was spinning and he lost control of his legs. The high became unbearable. He couldn't focus on anything. Then he had extreme nausea and began throwing up non-stop. He was not aware of his surroundings, where he was, or what was going on.
After emptying his stomach, he sat down, and things got worse. Colors looked too vibrant and unreal. The world was unrecognizable. He couldn't focus his eyes and saw multiple objects. He was unable to move his arms, and everything he wanted to do was delayed. He had terrific pain in his head and chest, and felt like he would drop dead. He felt like he was going through a seizure, and his life flashed before his eyes. There was still no feeling in his arms for 30 minutes. He passed out and woke up in a daze. The feeling in his arms was returned, but his head was pounding and he was beyond tired.
Do not use this or even try it. It has the extreme potential to kill or cause serious damage.
Maddox, of Charleston, is founder and president of Drug and Alcohol Presentations.
It can be purchased online or in head shops and is a white or yellowish powder labeled as "bath salts" or "plant food." It is sold in packets or small containers and contains mephadrone, or MDPV (methylenedioxypyrovalerone), a psychoactive drug with stimulant properties. It can be snorted or injected into a vein. Mephadrone is created by pseudo-chemists in uncontrolled settings and can cause serious, immediate and long-term damage.
On March 1, 2011, the Drug Enforcement Agency banned the chemicals used to make these synthetic drugs. Possession and sale of these chemicals or products that contain them is illegal in the United States.
Synthetic cannabinoids are an alternative to THC, the psychoactive chemical found in marijuana. "Aloha," one of the synthetic cannabinoids, has a fruity smell and comes in small round containers holding 4 grams. It is a green herb with the texture of ground marijuana. One man had a terrible experience. He said that after smoking the stuff his mind was blown and he virtually lost control. The world was spinning and he lost control of his legs. The high became unbearable. He couldn't focus on anything. Then he had extreme nausea and began throwing up non-stop. He was not aware of his surroundings, where he was, or what was going on.
After emptying his stomach, he sat down, and things got worse. Colors looked too vibrant and unreal. The world was unrecognizable. He couldn't focus his eyes and saw multiple objects. He was unable to move his arms, and everything he wanted to do was delayed. He had terrific pain in his head and chest, and felt like he would drop dead. He felt like he was going through a seizure, and his life flashed before his eyes. There was still no feeling in his arms for 30 minutes. He passed out and woke up in a daze. The feeling in his arms was returned, but his head was pounding and he was beyond tired.
Do not use this or even try it. It has the extreme potential to kill or cause serious damage.
Maddox, of Charleston, is founder and president of Drug and Alcohol Presentations.
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Off The Cuff
Glaxo studies traditional Chinese medicine
Scientists from GlaxoSmithKline are to study how traditional Chinese medicine can be applied to modern drugs as part of a revamp of the company’s research and development
Scientists from GlaxoSmithKline are to study how traditional Chinese medicine can be applied to modern drugs as part of a revamp of the company’s research and development
Britain’s biggest drug maker last week unveiled the outcome of a review of its 38 groups of scientists, known as Discovery Performance Units (DPU), saying it would close three units and open four.
The Sunday Telegraph can reveal the new units will look at traditional Chinese medicines, investigating how their principles can be applied to making new, synthetic, molecules.
Continue Reading...
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The analytical fisticuff over how expensive research and development is for pharmaceutical companies flared up again today with a new estimate that pegs the cost of inventing a new medicine at well over the $1 billion price tag often tossed around in the industry. After factoring in money spent on drug failures, Bernard Munos of the InnoThink Center for Research In Biomedical Innovation says that the average cost to bring a drug to market closer to a staggering $4 billion.
Small firms that don’t go bust tend to be the most cost-effective. But among big pharma, some drugmakers manage to stretch their dollars further than others. Amgen, of Thousand Oaks, California, gets the most bang for its buck at just over $3.7 billion per approved drug—calculated by dividing the company’s total R&D spending by the number of approved agents—while UK-based AstraZeneca is the least efficient, spending closer to $12 billion per agent thanks to several recent late-stage clinical trial failures involving treatments for diabetes, depression, and ovarian cancer.
Experts remain divided about the accuracy of these new estimates, though. “A grand average doesn’t have much to do with the real world of cost,” Donald Light, a health policy researcher at the University of Medicine and Dentistry of New Jersey in Stratford, told Nature Medicine. Last year, Light used estimates of clinical trial costs submitted by pharmaceutical companies to the Internal Revenue Service to come to the conclusion that the overall cost to develop a new drug was closer to $60 million (see ‘Drugs development is cheaper than widely claimed, experts say’). He says that numbers as high as $12 billion are not useful measures of R&D costs because they do not take into account the cost that society bears on behalf of the drug company in the form of subsidies and tax credits.
Regardless of who’s right, “the high cost of developing drugs shouldn’t be a badge of honor for drug firms,” writes reporter Matthew Herper, who broke the story in Forbes. “There’s no reason it has to be this expensive.” Now, there’s one point all the experts can agree upon.
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