Good news for those who have chronic hepatitis C, which affects people with addictions much more frequently than others. Two new drugs have been shown to substantially improve sustained remission rates in the Genotype I type of the virus, which is the most common type of infection in the US. Importantly, although the response rate was lower in African Americans (due to genetic factors limiting the drug effectiveness), these drugs improved response rates to respectable levels. The new medications are awaiting approval by the FDA and may be on the market as early as last 2011.
MW
New drug boosts hepatitis C treatments
Experimental medication passes key test on road to FDA approval for treating virus By Nathan Seppa
Science News
Web edition : 10:35 am
Adding an experimental drug to standard treatment more than doubles the likelihood of knocking out hepatitis C in patients with the chronic liver infection, two studies in the March 31 New England Journal of Medicine show.
The new drug, boceprevir, and a similar drug called telaprevir (SN: 5/23/09, p. 12) have now shown the ability to wipe out the virus in many patients. Both drugs are currently under review by the Food and Drug Administration, and scientists feel that both are destined for approval.
“This is the first time I can remember being so optimistic about this really difficult virus,” says Donald Jensen, a hepatologist at the University of Chicago School of Medicine who wasn’t involved in the new studies. Hepatitis C can lead to liver cirrhosis and cancer.
Both new boceprevir trials started with hundreds of hepatitis C patients receiving a four-week course of the current standard medication, a one-two punch of drugs called peginterferon alfa-2b and ribavirin. The patients were then randomly assigned to get boceprevir or a placebo added to this regimen, without knowing which they were getting.
After receiving treatment for up to 44 weeks, those getting boceprevir were two to three times more likely to knock the virus down to undetectable levels in the blood as were those getting only the standard dual-drug therapy, researchers report.
The two trial groups weren’t identical: One recruited previously treated hepatitis C patients, while the other enlisted only patients who hadn’t yet been treated. But both studies showed viral clearance rates of nearly two-thirds among those getting the triple therapy, compared with only 21 to 38 percent success among those getting the standard regimen.
A patient who clears the virus is often cured, says Fred Poordad, a hepatologist at Cedars-Sinai Medical Center in Los Angeles, who coauthored both studies. He cites 10 years of follow-up data from people who had cleared the virus after getting the standard peginterferon/ribavirin treatment. If the virus doesn’t reappear within six months after treatment, he says, close to 100 percent of them remain free of virus for good.
But 25 to 30 percent of those receiving standard treatment typically experience such a relapse shortly after treatment. With boceprevir added to the mix, that figure can be expected to fall below 10 percent, Poordad says.
The results thus indicate that 60 to 70 percent of patients getting the triple therapy “are now cured,” says Bruce Bacon, a hepatologist at Saint Louis University School of Medicine who coauthored both of the new studies.
The treatment does carry side effects. In both trials, nearly half of patients getting boceprevir developed anemia, compared with 20 to 29 percent of those on the standard dual treatment. Anemia is treatable, Bacon says. Nearly all patients in both trials reported some other side effects — including fatigue, headache and nausea — while taking the drug regimen. Bacon acknowledges these adverse effects, but adds that most hepatitis C patients “are willing to tough it out.”
Black patients didn’t benefit as much from the treatment as did other racial groups because some blacks carry a genetic variant that limits the effect of the drugs, Jensen says. Even so, roughly half of blacks getting the triple treatment saw their virus fall below detectable levels, a substantially better rate than those on dual therapy.
Merck makes boceprevir and sponsored these two trials. Vertex Pharmaceuticals makes telaprevir. Bacon notes that these studies now show that the effectiveness of boceprevir and telaprevir are similar. That’s not surprising since both drugs inhibit protease enzymes. While protease enzymes play vital roles in the body, thwarting specific proteases can stall virus replication.
The drugs work only on genotype 1 hepatitis C, but that form accounts for about three-fourths of all hepatitis C in the United States.
Thursday, March 31, 2011
Tuesday, March 29, 2011
How Cocaine Changes the Brain
This new research identifies how cocaine changes the configuration of receptors and function in the reward areas of the brain. It adds to the evidence that an increase in glutamate is a key feature of addiction. Some of the medications currently used for alcohol dependence, such as topiramate, baclofen and acamprosate, may work by helping to restore the balance between glutamate and GABA.
MW
Cocaine inverts rules for synaptic plasticity of glutamate transmission in the ventral tegmental area
Manuel Mameli, Camilla Bellone, Matthew T C Brown & Christian Lüscher
Nature Neuroscience (2011) 14, 414-416
The manner in which drug-evoked synaptic plasticity affects reward circuits remains largely elusive. We found that cocaine reduced NMDA receptor excitatory postsynaptic currents and inserted GluA2–lacking AMPA receptors in dopamine neurons of mice. Consequently, a stimulation protocol pairing glutamate release with hyperpolarizing current injections further strengthened synapses after cocaine treatment. Our data suggest that early cocaine-evoked plasticity in the ventral tegmental area inverts the rules for activity-dependent plasticity, eventually leading to addictive behavior.
MW
Cocaine inverts rules for synaptic plasticity of glutamate transmission in the ventral tegmental area
Manuel Mameli, Camilla Bellone, Matthew T C Brown & Christian Lüscher
Nature Neuroscience (2011) 14, 414-416
The manner in which drug-evoked synaptic plasticity affects reward circuits remains largely elusive. We found that cocaine reduced NMDA receptor excitatory postsynaptic currents and inserted GluA2–lacking AMPA receptors in dopamine neurons of mice. Consequently, a stimulation protocol pairing glutamate release with hyperpolarizing current injections further strengthened synapses after cocaine treatment. Our data suggest that early cocaine-evoked plasticity in the ventral tegmental area inverts the rules for activity-dependent plasticity, eventually leading to addictive behavior.
Sunday, March 27, 2011
Treating Pain Is a Real Pain
Our current tools for treating chronic severe pain are inadequate at best. Opioids such as morphine or methadone reduce chronic pain on average about 30%, with a range of perhaps 0-50%. And of course they come with multiple liabilities, such as constipation, sweating, nausea and physiological tolerance which means that symptoms occur if the drug is suddenly stopped. Although unproven there is concern that chronic use of these medications could actually increase pain sensitivity. Other methods such as cognitive behavioral therapy, moderate exercise, physical therapy, injections, surgery, neurostimulators, biofeedback, etc., have a modest impact if any. We desperately need new tools. This article describes new research on a compound that may reduce pain without the disadvantages of opioids. Cannabinoid receptors, by the way, are those that responde to drugs like marijuana and hashish. There are more of these receptors in peripheral tissues than the brain. It is possible that the effect of cannabis on pain are due to their effects on these peripheral receptors.
MW
Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism
Jason R Clapper, Guillermo Moreno-Sanz, Roberto Russo, Ana Guijarro, Federica Vacondio, Andrea Duranti, Andrea Tontini, Silvano Sanchini, Natale R Sciolino, Jessica M Spradley, Andrea G Hohmann, Antonio Calignano, Marco Mor, Giorgio Tarzia & Daniele Piomelli
Nature Neuroscience 13, 1265–1270 (2010) doi:10.1038/nn.2632
Peripheral cannabinoid receptors exert a powerful inhibitory control over pain initiation, but the endocannabinoid signal that normally engages this intrinsic analgesic mechanism is unknown. To address this question, we developed a peripherally restricted inhibitor (URB937) of fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of the endocannabinoid anandamide. URB937 suppressed FAAH activity and increased anandamide levels outside the rodent CNS. Despite its inability to access brain and spinal cord, URB937 attenuated behavioral responses indicative of persistent pain in rodent models of peripheral nerve injury and inflammation and prevented noxious stimulus–evoked neuronal activation in spinal cord regions implicated in nociceptive processing. CB1 cannabinoid receptor blockade prevented these effects. These results suggest that anandamide-mediated signaling at peripheral CB1 receptors controls the access of pain-related inputs to the CNS. Brain-impenetrant FAAH inhibitors, which strengthen this gating mechanism, might offer a new approach to pain therapy.
MW
Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism
Jason R Clapper, Guillermo Moreno-Sanz, Roberto Russo, Ana Guijarro, Federica Vacondio, Andrea Duranti, Andrea Tontini, Silvano Sanchini, Natale R Sciolino, Jessica M Spradley, Andrea G Hohmann, Antonio Calignano, Marco Mor, Giorgio Tarzia & Daniele Piomelli
Nature Neuroscience 13, 1265–1270 (2010) doi:10.1038/nn.2632
Peripheral cannabinoid receptors exert a powerful inhibitory control over pain initiation, but the endocannabinoid signal that normally engages this intrinsic analgesic mechanism is unknown. To address this question, we developed a peripherally restricted inhibitor (URB937) of fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of the endocannabinoid anandamide. URB937 suppressed FAAH activity and increased anandamide levels outside the rodent CNS. Despite its inability to access brain and spinal cord, URB937 attenuated behavioral responses indicative of persistent pain in rodent models of peripheral nerve injury and inflammation and prevented noxious stimulus–evoked neuronal activation in spinal cord regions implicated in nociceptive processing. CB1 cannabinoid receptor blockade prevented these effects. These results suggest that anandamide-mediated signaling at peripheral CB1 receptors controls the access of pain-related inputs to the CNS. Brain-impenetrant FAAH inhibitors, which strengthen this gating mechanism, might offer a new approach to pain therapy.
Friday, March 25, 2011
More on treatment for opioid addiction
Here is the text of a letter I sent today to a reporter at Minnesota Public Radio. They had previously run a program that was neither accurate nor complete.
MW
Dear Kerri,
I'm writing about your recent program on painkiller addiction. Unfortunately, I was not able to join the call, but became aware of it after the fact. I appreciate your attention to this problem, as it is particularly affecting young people.
I have been an addiction psychiatrist for over 30 years, and I have treated something like 1500 opioid addicts including about 30 in my current practice. In addition, I am an expert in treating highly complex pain patients who are using opioids. I used to run the addiction program at the VAMC in Minnepolis, which included a methadone maintenance clinic and eventually Suboxone treatment. From 2004 to 2009 I was Director of the Division of Treatment and Recovery Research at the National Institute on Alcohol Abuse and Alcoholism. (Not to brag, but I wanted to give you some sense of bona fides.)
One area where addiction treatment in the US really lags is in making scientifically based treatment available to people who need it, or even informing them of the evidence and their options. This is no where more true than opioid addiction. There are now multiple well done randomized controlled trials that have unequivocally and without exception found that for established (>1 year) opioid addiction, the only proven effective treatment is long-term opioid maintenance with either methadone or Suboxone. The most recent study, reported last spring at the American Psychiatric Association, focused on prescription opioid addicts, not heroin addicts. (Most previous research has been on heroin addicts.) This large and very well done study found that even after 9 months of Suboxone maintenance, along with enhanced psychosocial (behavioral) treatment of a quality far in excess of that available in the community, the relapse rate after tapering off of Suboxone was 95%. A recent naturalistic study in the UK followed opioid addicts who sought treatment. Those choosing abstinence had twice the mortality rate in the following year as compared to maintenance. These are only two of the most recent studies. There are dozens more. Among experts on opioid dependence, there is no controversy about this. (To anticipate a possible counterargument, there is evidence that an injectible drug that blocks the effects of opioids may be effective during the period when someone is on probation under the condition of agreement. However it is also true that almost all relapse as soon as they are off probation.)
Here's the problem. Due to devotion to 12-step concepts of addiction (which are not scientifically grounded), most treatment programs in the US fail to inform people of this evidence, let alone offer to provide it. Opioid dependence continues to be treated with an abstinence based approach grounded in the 12 steps. When the predictable relapse occurs, patients and families are told that the individual needs more abstinence-based rehab. The patient is held responsible for the failure of the treatment. There is an implication that if a person only accepts the program whole cloth and practices it religiously, then success is assured. In fact, it is the treatment that is ineffective, not the patient. Addiction treatment is the only place in modern health care where providers are not held responsible to give full informed consent to their patients, or for the success of their treatment. I currently have several patients who have been through multiple abstinence programs at a cost of tens of thousands of dollars each, who are now doing well on maintenance treatment.
This is not merely about infighting among the experts. Active opioid dependence has a high fatality rate; in one study 50% of the sample died between the mid-twenties and mid-fifties! And in the UK study, there was a mortality difference detectable after only one year. In addition, insurance companies and families spend millions of dollars on treatment clearly demonstrated to be ineffective, as much as $30-60,000 per month for residential treatment. Maintenance treatment, on the other hand is not only much more effective, it is much cheaper, on the order of a few hundred dollars per month. If we use $300 has an average maintenance cost, then one month for one patient in a residential program that cost $30,000 would buy actually effective maintenance treatment for 8 patients for a whole year! And that doesn't factor in the increased health care, criminal justice costs and loss of productivity that occurs with the higher relapse rate for abstinence based treatment. One study estimated the cost of maintenance treatment yielded savings more than 7 times a much.
I apologize for the long email, but I strongly feel that the public needs to have this information available to them. After being involved in research for over thirty years, I decided when I left NIH that the research didn't matter if there wasn't a vehicle for making it available to the people who are suffering with the disorder. So I am now devoted full time to transforming the treatment system into one that is based on science, professionalism, and cost-effectiveness and that is dedicated to offering consumers choice.
Thank you for reading this (if you get this far before pressing Delete). Of course references are available on request. I have had a lot of media experience and I have appeared on Mid-Morning before I went to Washington (I'm back in this area now.) I would be more than happy to participate in a program that presented a more balanced view. I could possibly suggest a patient or two who might be willing to talk about this on air as well.
Warm regards,
Mark
MW
Dear Kerri,
I'm writing about your recent program on painkiller addiction. Unfortunately, I was not able to join the call, but became aware of it after the fact. I appreciate your attention to this problem, as it is particularly affecting young people.
I have been an addiction psychiatrist for over 30 years, and I have treated something like 1500 opioid addicts including about 30 in my current practice. In addition, I am an expert in treating highly complex pain patients who are using opioids. I used to run the addiction program at the VAMC in Minnepolis, which included a methadone maintenance clinic and eventually Suboxone treatment. From 2004 to 2009 I was Director of the Division of Treatment and Recovery Research at the National Institute on Alcohol Abuse and Alcoholism. (Not to brag, but I wanted to give you some sense of bona fides.)
One area where addiction treatment in the US really lags is in making scientifically based treatment available to people who need it, or even informing them of the evidence and their options. This is no where more true than opioid addiction. There are now multiple well done randomized controlled trials that have unequivocally and without exception found that for established (>1 year) opioid addiction, the only proven effective treatment is long-term opioid maintenance with either methadone or Suboxone. The most recent study, reported last spring at the American Psychiatric Association, focused on prescription opioid addicts, not heroin addicts. (Most previous research has been on heroin addicts.) This large and very well done study found that even after 9 months of Suboxone maintenance, along with enhanced psychosocial (behavioral) treatment of a quality far in excess of that available in the community, the relapse rate after tapering off of Suboxone was 95%. A recent naturalistic study in the UK followed opioid addicts who sought treatment. Those choosing abstinence had twice the mortality rate in the following year as compared to maintenance. These are only two of the most recent studies. There are dozens more. Among experts on opioid dependence, there is no controversy about this. (To anticipate a possible counterargument, there is evidence that an injectible drug that blocks the effects of opioids may be effective during the period when someone is on probation under the condition of agreement. However it is also true that almost all relapse as soon as they are off probation.)
Here's the problem. Due to devotion to 12-step concepts of addiction (which are not scientifically grounded), most treatment programs in the US fail to inform people of this evidence, let alone offer to provide it. Opioid dependence continues to be treated with an abstinence based approach grounded in the 12 steps. When the predictable relapse occurs, patients and families are told that the individual needs more abstinence-based rehab. The patient is held responsible for the failure of the treatment. There is an implication that if a person only accepts the program whole cloth and practices it religiously, then success is assured. In fact, it is the treatment that is ineffective, not the patient. Addiction treatment is the only place in modern health care where providers are not held responsible to give full informed consent to their patients, or for the success of their treatment. I currently have several patients who have been through multiple abstinence programs at a cost of tens of thousands of dollars each, who are now doing well on maintenance treatment.
This is not merely about infighting among the experts. Active opioid dependence has a high fatality rate; in one study 50% of the sample died between the mid-twenties and mid-fifties! And in the UK study, there was a mortality difference detectable after only one year. In addition, insurance companies and families spend millions of dollars on treatment clearly demonstrated to be ineffective, as much as $30-60,000 per month for residential treatment. Maintenance treatment, on the other hand is not only much more effective, it is much cheaper, on the order of a few hundred dollars per month. If we use $300 has an average maintenance cost, then one month for one patient in a residential program that cost $30,000 would buy actually effective maintenance treatment for 8 patients for a whole year! And that doesn't factor in the increased health care, criminal justice costs and loss of productivity that occurs with the higher relapse rate for abstinence based treatment. One study estimated the cost of maintenance treatment yielded savings more than 7 times a much.
I apologize for the long email, but I strongly feel that the public needs to have this information available to them. After being involved in research for over thirty years, I decided when I left NIH that the research didn't matter if there wasn't a vehicle for making it available to the people who are suffering with the disorder. So I am now devoted full time to transforming the treatment system into one that is based on science, professionalism, and cost-effectiveness and that is dedicated to offering consumers choice.
Thank you for reading this (if you get this far before pressing Delete). Of course references are available on request. I have had a lot of media experience and I have appeared on Mid-Morning before I went to Washington (I'm back in this area now.) I would be more than happy to participate in a program that presented a more balanced view. I could possibly suggest a patient or two who might be willing to talk about this on air as well.
Warm regards,
Mark
Here's a recent synthesis of studies on the course and remission rate for amphetamine, cannabis, cocaine and opioid dependence. Importantly they calculated remission rates using the assumption that drop outs from the studies were using and dependent (relapsed). This will result in an overly pessimistic view, since it is almost certain that not all of the study dropouts are still dependent. However, they do point that although addiction is frequently described as a "chronic, relapsing disease," there are surprisingly few studies that examine that.
MW
Systematic review of prospective studies investigating 'remission' from amphetamine, cannabis, cocaine or opioid dependence.
Calabria B., Degenhardt L., Briegleb C. et al. Request reprint
Addictive Behaviors: 2010, 35, p. 741–749.
Review synthesises evidence on how many people recover each year (with or without treatment) from their dependence on stimulants, heroin-type drugs or cannabis, providing a baseline against which to assess improvement efforts.
Original abstract Aims To review and summarise prospective studies reporting on remission from dependence on amphetamines, cannabis, cocaine or opioids.
Methods Systematic searches of the peer-reviewed literature were conducted to identify prospective studies of people dependent on amphetamines, cannabis, cocaine or opioids like heroin, which followed them up for at least three years to investigate how many experienced remission from their dependence. Treatment trials were excluded, but studies of patients who entered treatment in the normal way were included along with non-treatment and general population samples. Remission was defined as abstinence from the drug of dependence or no longer meeting diagnostic criteria for drug dependence. The remission rate was estimated for each drug type, allowing pooling across studies with varying follow-up times. Searches were limited to publications between 1990 and 2009. Reference lists of review articles and important studies were searched to identify additional studies.
Results There were few studies examining the course of psychostimulant dependence that met inclusion criteria (one for amphetamines and four for cocaine). There were ten studies of opioid dependence, none of which were of general population samples, and three of cannabis dependence, all of which were of general population samples. Definitions of remission varied and most studies did not clearly assess remission from dependence. Where possible, data from the studies was used to calculate the annual proportion of patients who remitted, firstly as proportions of the patients who could be followed up. A figure for cannabis was not calculated. Based on a single US study of methamphetamine users, amphetamine dependence had the highest annual remission rate (0.45 or 45% a year no longer dependent), followed by opioid (0.22 or 22%) and cocaine dependence (0.14 or 14%). The single study (from the USA) of a general population sample of cocaine-dependent people found that 39% had remitted four years after initially surveyed.
However, studies reporting remission rates based solely on the followed-up sample inflate remission estimates, given that people who drop out are probably less likely to have remitted. The data was recalculated on the conservative assumption that every patient who could not be followed up was still dependent or had died dependent. These estimates differed quite markedly from the levels typically reported in papers. On this basis, remission rates were highest for cannabis dependence (0.17 or 17% a year no longer dependent) followed by amphetamine (just under 0.17 or 17%), opioids (0.092 or 9%) and cocaine dependence (0.05 or 5%).
Conclusions Despite the fact that drug dependence is commonly described as a "chronic" disorder, surprisingly few follow-up studies have documented the course of this disorder. In addition definitions used are often imprecise and inconsistent across studies. There remains considerable uncertainty about the longitudinal course of dependence upon these most commonly used illicit drugs. The limited prospective evidence suggests that 'remission' from dependence may occur relatively frequently but rates differ across drugs. Remission from amphetamine dependence was highest overall with almost one in two persons remitting during a given year; the conservative estimate of remission from amphetamine or cannabis dependence was one in six annually. Remission from opioid dependence ranged from one to two in ten each year; and remission from cocaine dependence ranged from one in twenty to one in eight. The findings of this review for cannabis are similar to the results of retrospective surveys (when people are asked to look back to recall whether they were dependent on the drugs rather than followed up) that have found cannabis to have the highest rates of cessation of use. The results are not consistent for opioid dependence, which has been found in retrospective surveys to have the lowest remission rates.
Last revised 16 March 2011
MW
Systematic review of prospective studies investigating 'remission' from amphetamine, cannabis, cocaine or opioid dependence.
Calabria B., Degenhardt L., Briegleb C. et al. Request reprint
Addictive Behaviors: 2010, 35, p. 741–749.
Review synthesises evidence on how many people recover each year (with or without treatment) from their dependence on stimulants, heroin-type drugs or cannabis, providing a baseline against which to assess improvement efforts.
Original abstract Aims To review and summarise prospective studies reporting on remission from dependence on amphetamines, cannabis, cocaine or opioids.
Methods Systematic searches of the peer-reviewed literature were conducted to identify prospective studies of people dependent on amphetamines, cannabis, cocaine or opioids like heroin, which followed them up for at least three years to investigate how many experienced remission from their dependence. Treatment trials were excluded, but studies of patients who entered treatment in the normal way were included along with non-treatment and general population samples. Remission was defined as abstinence from the drug of dependence or no longer meeting diagnostic criteria for drug dependence. The remission rate was estimated for each drug type, allowing pooling across studies with varying follow-up times. Searches were limited to publications between 1990 and 2009. Reference lists of review articles and important studies were searched to identify additional studies.
Results There were few studies examining the course of psychostimulant dependence that met inclusion criteria (one for amphetamines and four for cocaine). There were ten studies of opioid dependence, none of which were of general population samples, and three of cannabis dependence, all of which were of general population samples. Definitions of remission varied and most studies did not clearly assess remission from dependence. Where possible, data from the studies was used to calculate the annual proportion of patients who remitted, firstly as proportions of the patients who could be followed up. A figure for cannabis was not calculated. Based on a single US study of methamphetamine users, amphetamine dependence had the highest annual remission rate (0.45 or 45% a year no longer dependent), followed by opioid (0.22 or 22%) and cocaine dependence (0.14 or 14%). The single study (from the USA) of a general population sample of cocaine-dependent people found that 39% had remitted four years after initially surveyed.
However, studies reporting remission rates based solely on the followed-up sample inflate remission estimates, given that people who drop out are probably less likely to have remitted. The data was recalculated on the conservative assumption that every patient who could not be followed up was still dependent or had died dependent. These estimates differed quite markedly from the levels typically reported in papers. On this basis, remission rates were highest for cannabis dependence (0.17 or 17% a year no longer dependent) followed by amphetamine (just under 0.17 or 17%), opioids (0.092 or 9%) and cocaine dependence (0.05 or 5%).
Conclusions Despite the fact that drug dependence is commonly described as a "chronic" disorder, surprisingly few follow-up studies have documented the course of this disorder. In addition definitions used are often imprecise and inconsistent across studies. There remains considerable uncertainty about the longitudinal course of dependence upon these most commonly used illicit drugs. The limited prospective evidence suggests that 'remission' from dependence may occur relatively frequently but rates differ across drugs. Remission from amphetamine dependence was highest overall with almost one in two persons remitting during a given year; the conservative estimate of remission from amphetamine or cannabis dependence was one in six annually. Remission from opioid dependence ranged from one to two in ten each year; and remission from cocaine dependence ranged from one in twenty to one in eight. The findings of this review for cannabis are similar to the results of retrospective surveys (when people are asked to look back to recall whether they were dependent on the drugs rather than followed up) that have found cannabis to have the highest rates of cessation of use. The results are not consistent for opioid dependence, which has been found in retrospective surveys to have the lowest remission rates.
Last revised 16 March 2011
Subscribe to:
Posts (Atom)