text:
- Individualized Care
- Why Treatments Fail
- Reasons for Treatment Failure
- Resistance
- Considerations When Changing Antiretroviral Therapy
- Resistance Testing
- Drug Potency
- Suboptimal Drug Levels
- Adherence
- Drug Toxicity
- Salvage Therapy Strategies
- Experience Counts
- Summary
- Selected Sources
Salvage therapy is an approach taken when previous anti-HIV treatments fail to achieve desired goals, which include undetectable viral load, CD4 cell levels above 200 cells/mm3, and the prevention of HIV disease progression. It is one of the most difficult situations to face as a patient, and one of the most problematic challenges for healthcare providers. Though sometimes euphemistically referred to as "management of treatment-experienced patients," many HIV positive people, having already exhausted the benefits of at least a couple of drug combinations, think of their next regimen as salvage or "rescue" therapy.
A few physicians argue that due to cross-resistance among different drugs within the same class, people with HIV infection have only one good shot at treating it, and that any treatment regimen beyond the first is therefore salvage therapy. Others see salvage therapy as literally the end of the line -- when an individual's HIV has developed extensive resistance to all currently available treatments. But most providers consider salvage therapy to be somewhere in between these extremes. Understanding that the term can refer to different treatment situations is important. Nevertheless, most of the information in this article will be relevant for anyone changing a drug regimen, no matter where that person is on the treatment path.
Individualized Care
Salvage therapy is one of the most difficult topics to write about because every statement must be qualified in relation to an individual's personal treatment history. Although this should be the case with any medical decision, choices about HIV treatment should be tailored for each person. As therapeutic options become more limited, the stakes are arguably higher. More than at any other time in a person's treatment history, salvage therapy requires highly individualized care.
It is important for people to keep their own treatment history file that includes CD4 cell count, viral load, and resistance test results, together with a list of drugs previously used, medication allergies, past side effects, and adherence levels (frequency of taking doses as prescribed). As antiretroviral therapies become more effective, it is clear that we now need to plan for 30 years or more of treatment. Keeping complete treatment records is especially important when changing providers or hospitals.
Whether an individual has failed an initial regimen, has been HIV positive for many years and has used all the available drugs, or has been recently infected with a multi-drug-resistant HIV strain, the approach will be similar. It involves looking at five or six key areas, each of which must be addressed to optimize the chances of success with a subsequent regimen. This highly individualized approach is not based on new science, and in fact has changed very little over the past three or four years.
Why Treatments Fail
Although the range of antiretroviral therapies has expanded, the basic principles of HIV treatment have been understood for some time and remain fairly constant. Apart from a few exceptions, such as recent research on viral fitness (replication capacity), most of the approaches discussed in this article are not new or recently discovered.
John Mellors, M.D., of the University of Pittsburgh outlined the foundations of HIV therapy in a keynote speech opening the 1999 Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in San Francisco. The multidisciplinary approach he described was also stressed at the Workshop on Management of Treatment Experienced Patients held in San Diego, California, this past September.
Both lectures emphasized that there are only a limited number of known reasons why treatment might fail: drug resistance, inadequate drug potency, suboptimal drug levels, poor adherence, and drug toxicity. At least one -- and possibly a combination -- of these factors are responsible for the failure of each treatment regimen used in the past, whether it was the first or the fifth combination. To avoid repeating the same mistakes with salvage therapy, it is important to understand why each previous treatment attempt failed.
|Reasons for Treatment Failure
Drug resistance is recognized as the reason most combination regimens fail, but how resistance develops is still often misunderstood.
The medical explanation for the development of resistance is that ongoing viral replication occurs in the presence of a drug regimen that does not adequately suppress the virus. This means that if a person has a detectable viral load (over 50 copies/mL) while on treatment, enough new virus is produced each day for resistance to develop by chance due to random viral mutations (genetic changes). Once resistance develops by chance, however, if a person continues to take the drugs to which HIV is no longer susceptible, the resistant virus will continue to replicate until it becomes established as the majority strain.
Resistance, therefore, does not cause a treatment to fail, but rather develops if one or more of the other key factors related to treatment failure are present. If a combination regimen is not potent enough, if drugs are poorly absorbed, if adherence is not perfect, or if the drugs are not effective due to pre-existing resistance, a person may not achieve or maintain a viral load under 50 copies/mL. Then, as a result of continuing treatment with a detectable viral load, viral mutations may develop and resistance can follow.
However, studies show that if viral load is reduced to an undetectable level (usually below 50 or 25 copies/mL, depending on the assay) and all other factors related to treatment success are taken into account, then a combination regimen will continue to work and the virus is much less likely to develop further resistance. Individuals who achieve and maintain undetectable viral load levels with any drug combination, first-line or salvage, are in the best position to see their viral load remain this low for many years. The magnitude of the drop in viral load -- even if it is reduced by hundreds of thousands of copies -- is not as important as getting viral load as low as possible. Some studies suggest that it may be beneficial to aim for a viral load below 5 copies/mL; ongoing research should clarify whether this is important for long-term health.
Another important concept is that resistance rarely acts like an on-off switch. Think of resistance more as being on a continuum, with completely sensitive or even hypersensitive virus at one end and completely resistant virus at the other. In between these two extremes, other factors come into play. For example, HIV generally slowly accumulates mutations that gradually limit how effective protease inhibitors (PIs) are against the virus. But even with extensive resistance, the drugs still can have some clinical benefit. If a person with drug-resistant HIV discontinues treatment and viral load increases further, this is evidence that the drugs were providing some anti-HIV activity. Since resistance is on a continuum, increasing the dose or concentration of a drug often can overcome resistance -- although doing so may also increase drug toxicity.
Resistance Testing
Resistance tests are used to identify drugs that are not effective against an individual's specific strains of HIV. There are two main types of resistance tests. Genotypic tests look for genetic changes in a person's virus and match these mutations against a database of known mutations that in clinical trials have been associated with resistance to different drugs. Phenotypic tests look at how viral replication is affected when increasing concentrations of different drugs are added to an individual's HIV in a test tube. A third variation called a "virtual phenotype" compares genotypic results with a large database of phenotypic results.
Both genotypic and phenotypic tests only detect resistance once it is relatively extensive. The tests are less sensitive to minority drug-resistant strains of HIV that are present in the body at low levels. For the most reliable results, the viral load should be above 1,000 copies/mL and the individual should currently be taking anti-HIV therapy. While several studies have shown that resistance tests can help physicians select an optimal drug regimen, other studies have not shown a dramatic benefit in terms of clinical outcome. This is likely because as a person's HIV becomes more resistant, there are fewer effective treatment options available. Resistance tests can tell which drugs are no longer active, but someone whose virus is no longer sensitive to any drugs will not be able to construct an effectively suppressive regimen.
Experts have begun to recognize the value of resistance tests at every important change in a person's HIV disease progression. Julio Montaner, M.D., of the University of British Columbia in Vancouver has referred to the combined history of all of an individual's worst resistance profiles over time as "virtual resistance." Compiling such a profile involves blood tests when HIV is originally diagnosed and before starting treatment, a complete history of all drugs a person has taken, and viral load test results for the periods during which those drugs were used. It also requires knowing the exact timing of previous resistance tests and what drugs were being taken at the time of these tests.
Short-term treatment benefit has been observed when resistance testing is used in conjunction with therapeutic drug monitoring (TDM) to ensure optimal drug levels (discussed below). Long-term TDM data for anti-HIV medications are not yet available.
Drug Potency
Potency refers to the strength of drugs in a combination regimen -- how effective they are at reducing viral replication and maintaining a response. On a basic level, drug potency refers to how much of a viral load reduction a drug generates by itself. The greater the potency of each drug in a combination, the greater the magnitude and durability of viral load reduction.
Anti-HIV drugs are approved only when they show a clear antiretroviral effect; even the newest drugs that have been studied for use in salvage therapy must show this effect. For example, results from a recent study of the fusion inhibitor T-20 (enfuvirtide, Fuzeon) showed that T-20 added to the best available existing choice of therapy produced a 1.7 log reduction in viral load, while the best existing regimen alone produced only a 0.7 log reduction. The European/Australian segment of this study (TORO 2) showed slightly less of an effect (1.4 log and 0.6 log reductions with and without T-20, respectively) in people who had more resistance to existing drugs before they started the study. From this, it appears that T-20 can produce an approximate 1 log reduction in viral load, although this will of course vary among individuals.
The reason combination antiretroviral therapy includes three or more drugs is largely linked to the issue of potency. The potency of a regimen is determined not only by the activity of each drug, but also by the combined activity of the regimen as a whole. The overall potency of a combination regimen must be strong enough to reduce viral load from baseline to an undetectable level and to maintain this response for months and, ideally, years.
If a single drug could produce a 5 log or 6 log reduction in viral load on its own, it could theoretically be used without other drugs in a combination (although resistance is more likely when a drug is used alone). However, existing drugs produce viral load reductions only of about 0.4 to about 2.5 logs. Therefore, at least three highly suppressive drugs are generally required to reduce viral load from baseline to an undetectable level. By definition, people who require salvage therapy do not have three potent drugs available, so regimens with larger numbers of drugs -- sometimes up to nine -- may be needed to achieve adequate potency. Even drugs that are not very potent by themselves can still contribute some antiretroviral activity to a combination.
Potency depends not only on the effectiveness of a drug itself and the other drugs it is used with, but also on the specific virus it is used against. A few drugs can be more effective against drug-resistant virus than against wild-type (nonmutated) HIV, but in general, resistance and previous treatment experience render new drugs less potent. For example, studies have shown that the recently approved nucleotide reverse transcriptase inhibitor (NtRTI) tenofovir DF (TDF, Viread) produces an average 0.6 log viral load reduction in treatment-experienced people compared with a 1.1 log drop in those who are treatment-naive. Tenofovir may therefore contribute more potency as part of a first-line regimen than as part of a salvage regimen.
Suboptimal Drug Levels
A third important reason for treatment failure is suboptimal drug levels in the body. Suboptimal drug levels may be due to inadequate dosing, but may also be related to individual differences in pharmacokinetics (drug absorption, metabolism, and excretion). How drugs are absorbed in the body is highly individual, and blood drug levels are subject to significant variation among different people taking exactly the same dose. For some drugs used for conditions other than HIV this is not a problem, because their generally low toxicity means the drugs can be given in sufficiently high doses to allow for this variability. But this is not the case for most anti-HIV medications. Due to the toxicity of antiretroviral drugs, the highest tolerable dose may be only just above the minimum dose required to avoid resistance.
Many antiretroviral drugs are metabolized in the liver by the cytochrome P450 (CYP450) enzyme system. Some people naturally metabolize drugs more slowly or more rapidly than others. For example, those with existing liver damage often have impaired drug metabolism. People who metabolize drugs faster than average run the risk of developing resistance due to suboptimal drug levels. Those who metabolize drugs more slowly than average may experience increased side effects due to high drug levels. Among people who metabolize drugs quickly or do not achieve adequate concentrations in the body for other pharmacokinetic reasons, even perfect adherence will not ensure safe levels.
In addition, drugs that are metabolized by the CYP450 pathway can interact. When multiple drugs that use the same pathway are present, metabolism may be slowed, leading to higher drug levels. In other cases, certain drugs can stimulate CYP450 metabolism, leading to more rapid drug processing and lower levels. Every recent medical conference on AIDS has included reports about drug interactions, often involving medications that have been licensed for many years. Some foods and herbal remedies (for example, grapefruit juice and St. John's wort) can also affect drug metabolism.
Peak and trough levels and area under the curve (AUC) are important concepts in understanding drug levels. The peak level is the highest drug level in the body after taking a dose. The trough level is the lowest drug level between doses, usually reached right before the next scheduled dose is taken. On a graph, the line that joins peak and trough levels is a curve; therefore, the amount of drug exposure over a dosing interval is represented by the "area under the peak/trough curve," or AUC.
It is best to have a constant therapeutic drug level in the body over time, since high levels can cause increased side effects and low levels can promote resistance. Several new antiretroviral drug formulations are designed to last longer in the body and achieve steady drug levels with a single daily dose.
Sometimes low drug levels and resulting drug resistance can be overcome with higher doses. Increasing drug dosages can produce a stronger antiviral effect, but also heighten the risk of side effects. For example, it is well known that the first studies of AZT (zidovudine, Retrovir) -- which used three or four times the current accepted dose -- led to side effects that were very difficult to tolerate. What is less well known is that AZT monotherapy at these high doses produced about a 4 log reduction in viral load. Using such high doses as part of salvage therapy is not common, but may be useful on an individual basis (though only in consultation with a physician).
With regard to T-20, it should be noted that maximum dose cut-offs for efficacy or tolerability were not reached in the registrational studies due to supply problems and the difficulty of asking subjects to inject the drug more than twice per day. There may therefore be a subgroup of people using T-20 in the context of salvage therapy who could benefit from the potentially greater antiviral activity of higher doses.
Drug Boosting
One way to increase the antiretroviral activity of a drug is to add another medication that "boosts" the blood level of the first drug. As discussed above, this works because certain medications inhibit drug metabolism in the liver.
Ritonavir (Norvir) is used most often to boost the levels of other PIs. Numerous studies have shown that using ritonavir to boost indinavir (Crixivan) can overcome indinavir resistance; however, as blood levels of indinavir increase, so too does the incidence of side effects. The new PI Kaletra includes a small amount of ritonavir in the pill to increase levels of lopinavir. The added ritonavir boosts lopinavir well above the minimum concentration needed to inhibit 50% or 95% of viral replication (called the IC 50 or IC 95 , respectively; IC refers to the "inhibitory concentration" as determined in laboratory tests). This is one of the reasons Kaletra has proven to be so effective against HIV that is resistant to older PIs. Lopinavir itself has a resistance profile similar to that of other PIs, but boosting with ritonavir can overcome this resistance.
As another example, a recent study suggested that using a low dose (300 mg) of hydroxyurea (Hydrea) twice daily could enhance the activity of ddI (didanosine, Videx) while reducing ddI toxicity. It has also been suggested that mycophenolate (mycophenolic acid, CellCept; used in organ transplantation) can similarly increase the potency of abacavir (Ziagen) and a few other nucleoside reverse transcriptase inhibitor (NRTI) drugs, although clinical benefit from this approach has not been clearly shown in recent studies.
Therapeutic Drug Monitoring
Therapeutic drug monitoring (TDM) refers to measuring the levels of medications in the body. The goal of TDM is to help achieve optimal drug levels on an individualized basis. The technique can provide protection against excessively low or high drug levels, and thereby improve virological outcomes and reduce toxicity. TDM is most useful with PIs and may also be used with non-nucleoside reverse transcriptase inhibitors (NNRTIs); however, it is not recommended for NRTIs due to current technological limitations. Results from a large European trial (named ATHENA) of subjects taking their first antiretroviral regimen showed that TDM led to lower rates of treatment discontinuation and higher rates of virological response. Some clinicians believe TDM may be beneficial for people taking salvage regimens as well.
By helping to optimize treatment, TDM can lead to the use of very different dosing regimens in different individuals. For example, indinavir/ritonavir is often dosed at 400 mg/100 mg twice daily in France, where TDM is widely used. (The typical dose in the U.S. is 800 mg indinavir with 100 or 200 mg ritonavir twice daily.) People in the Netherlands using the original formulation of saquinavir (Invirase) with the benefit of TDM received "double dosing" and avoided the early failures seen in the U.S. due to suboptimal drug levels. And in the UK, a patient whose damaged liver allowed only extremely slow metabolism of efavirenz (Sustiva) was given a low dose of 200 mg twice weekly prior to a liver transplant.
Such individualized dosing is possible only when drug levels can be monitored and adjusted on a person-by-person basis; it is not possible simply to guess drug levels. Further research needs to be done in this area, however, as optimal drug levels are not precisely understood and drug level tests have not been standardized.
Scientific opinions about TDM differ considerably between Europe and the U.S., as does access to it. Countries in Europe with leading research programs on drug metabolism already have laboratories that can analyze blood drug levels in people receiving antiretroviral therapy. In the Netherlands TDM is part of the standard of care; all people starting anti-HIV regimens that include a PI or an NNRTI have their levels of these drugs measured. In France TDM is not universal, but it is widely used, especially for people receiving salvage therapy. In the UK TDM is available to a wide range of people, mainly those using PIs. Use varies by clinic, and some offer TDM to all patients; due to the efforts of treatment advocates in the UK, the additional cost of the tests is covered by drug manufacturers.
Availability of TDM in the U.S. has increased over the past few years, although it is still uncommon. U.S. clinicians generally are ambivalent about the benefits of TDM for anti-HIV therapy due to the wide variability of drug levels within a single individual (especially due to timing of doses, food requirements, and varying adherence levels over time), uncertain therapeutic ranges of anti-HIV medications, lack of standardization of drug level measurements, variability in laboratory accuracy, and difficulties in interpreting TDM results. Some providers also question the value of measuring boosted PI combinations (that is, regimens with minimized peak/trough variability).
Yet clinicians such as Steve Miles, M.D., of the University of California at Los Angeles (UCLA) nevertheless believe that TDM can help individualize HIV treatment, including in people whose previous regimens have failed and in those with few therapeutic options, for whom "a mistake in drug levels could doom a regimen." (Dr. Miles also noted that TDM is reimbursed by Medicare and Medi-Cal at approximately $40 per assay.)
In a position paper published in the August 10, 2002 issue of AIDS Research and Human Retroviruses, the Adult Pharmacology Committee of the U.S. Adult AIDS Clinical Trials Group (AACTG) stated that "data generally support the use of TDM." While acknowledging difficulties in this rapidly changing area of treatment, the committee also provided guidelines to assist clinicians, particularly when using TDM in conjunction with phenotypic testing for people receiving salvage therapy. Encouragingly, Edward Acosta, Pharm.D., from the AACTG committee, in a lecture on TDM use in the U.S. at the September 2002 ICAAC, concluded that "TDM will likely be incorporated into treatment, especially in salvage therapy ... and especially if the rate of new drug development is unable to keep pace with the development of resistance." (See also "Therapeutic Drug Monitoring," BETA, Autumn 2000. For information on a currently enrolling trial studying TDM, see "Open Clinical Trials for HIV/AIDS Treatments" in this issue.)
Combining TDM and Resistance Testing
While the benefits of resistance testing and TDM on clinical outcome have been evaluated separately, two important resistance studies showed that both drug sensitivity and optimal drug levels are necessary to achieve a sustained virological benefit from treatment.
In the GART study, Douglas Mayers, M.D., of Henry Ford Hospital in Detroit, Michigan, and colleagues studied 153 subjects who experienced a greater than three-fold rise in HIV viral load while using a regimen containing a PI and two NRTIs for over 16 weeks. Subjects were randomized to receive either treatment recommendations based on genotypic testing or else no genotypic test results. In a pharmacokinetic substudy, blood levels of all drugs (including NRTIs) from random (untimed) samples from 147 participants were measured using the VircoPK assay at baseline and at weeks 4, 8, and 12. The week 12 results were used to determine whether individual subjects had drug levels above or below the median. Genotypic and phenotypic test results were also used to determine the number of more active and less active drugs for each participant. Researchers calculated viral load changes from baseline to week 12 and their relation to drug levels. Inhibitory quotients (IQs, see table below) were calculated as drug level at week 12 divided by fold change of IC 50 at baseline, and were also classified as being above or below the median for the group.
Suboptimal levels of more active drugs led to a reduced antiviral effect compared with higher concentrations of less active drugs, reaching statistical significance for the genotypic analysis. A clear relationship was also found between the average change in viral load at week 12 and the number of drugs with mean IQ above the group median. For the cohort as a whole, the additional viral load reduction was 0.2 logs for each drug with an IQ above the median. Even though the differences in this study may appear small, they can be significant in a salvage setting in which any added viral suppression is likely to contribute to a longer duration of response to treatment.
The VIRADAPT study showed a virological benefit when using genotypic resistance test results to guide treatment choices for second-line and salvage therapy combinations. Results were presented by Rodolphe Garraffo, Pharm.D., and colleagues from Nice, France, at the September 1999 ICAAC and published in the July 7, 2000 issue of AIDS. Drug level monitoring for PIs was also done in this study to determine the impact of medication levels on therapeutic success or failure.
Eighty-five participants (49 in the genotypic testing arm and 36 in the control arm) received 575 PI drug level measurements. Participants were considered to have optimal drug concentrations if two or more measurements were greater than the IC 50 for the specific PI they were receiving. Subjects who had two or more measurements below the IC 50 were considered to have suboptimal drug concentrations. Participants with suboptimal drug concentrations achieved a 0.3 log reduction in viral load at week 48, compared with a 1.2 log decrease in those with optimal drug concentrations. In a multivariate analysis, drug concentrations above the IC 50 , the use of genotypic testing, and the presence of primary resistance mutations for PIs were independently associated with virological response.
Some providers believe that adherence is often the likeliest cause of treatment failure; drugs cannot be effective if people are unable to take them as prescribed. As discussed above, due to toxicity the highest tolerable dose of an antiretroviral drug may be only just above the amount needed to avoid resistance. Missing even an occasional dose can cause drug levels between doses to fall so low that the drug no longer suppresses the virus. This is a particular concern with once-daily medications, since more time passes between doses and the virus therefore has more time to replicate in the absence of an adequate concentration of the drug in the event of a missed dose. Following the dietary requirements for a medication is also important.
While some people can be 100% adherent and still experience treatment failure due to pre-existing resistance, suboptimal drug levels, or an insufficiently potent regimen, many others will not have been as adherent as they wanted or needed to be.
Adherence rates among people taking anti-HIV therapy are probably higher than for practically any other condition -- including other life-threatening infections -- yet even this high adherence rate is not high enough. Although the importance of adherence may be widely recognized, it remains problematic in day-to-day practice. For many people, the need for salvage therapy may provide an opportunity to take treatment more seriously than ever before.
If adherence has been very poor, a person may have avoided resistance because of insufficient continuous drug levels. That is, the concentration of a medication may have been too low to pressure the virus to develop drug-resistant mutations. This possibility should be taken seriously. Before choosing new drugs, people who are considering changing their treatment regimens due to viral load rebound should tell their healthcare providers how they were actually taking their medications. Resistance testing may be another way to confirm whether drug resistance has developed.
Getting adherence right should be the primary focus for people on any therapy until they develop good habits. Support programs and adherence teams (i.e., peer advocates, social workers, pharmacists, and nurses) can be more helpful than many doctors, and often are more trusted by patients. These adherence experts can provide tips and tools such as timers, phone reminders, and beeping pillboxes. Support for adherence should be included as part of every treatment plan. Designing a strategy for near-perfect adherence when taking salvage therapy can be as beneficial as having access to a new drug.
Drug Toxicity
Drug toxicity leading to discontinuation is another possible cause of treatment failure. For a minority of people, severe or life-threatening reactions to anti-HIV medications can eliminate these drugs as options, and therefore can be seen as medically responsible for treatment failure. Hypersensitivity reactions to abacavir and nevirapine (Viramune), hepatotoxicity (liver toxicity), seriously elevated lipid levels, and manifestations of mitochondrial toxicity (for example, muscle aches and weakness) can all lead to drug discontinuation.
Less serious toxicities may also lead to treatment failure if they are not managed properly. For example, diarrhea and vomiting can prevent adequate drug absorption. Any side effects that have a negative impact on quality of life may lead to problems with adherence. Close monitoring and effective management of side effects can only increase the chances of successful treatment. In some cases, switching drugs to improve tolerability may also be important.
A session at the Workshop on Management of Treatment-Experienced Patients this past September highlighted the importance of drawing upon specialized expertise to prevent and manage both side effects and opportunistic illnesses (OIs). This may become increasingly important in the case of side effects that are outside the realm of expertise of most clinicians trained in infectious disease management, such as elevated blood lipid levels and loss of bone mineral density.
Salvage Therapy Strategies
Addressing the various factors that contribute to treatment failure can improve the likelihood of successful salvage therapy. Two management approaches will be discussed below: whether or not to interrupt therapy before starting a new salvage regimen, and whether there is a benefit to using multiple drugs in salvage therapy. Both approaches have been used in salvage therapy settings in well-publicized cohort studies from London, Frankfurt, Montreal, and Paris. They are being further studied in a large, randomized international trial called OPTIMA. (The future of this study is currently unclear due to slow enrollment; many researchers and participants are reluctant to accept randomization in the context of salvage therapy.) For more information about OPTIMA and other salvage therapy trials, see "Open Clinical Trials for HIV/AIDS Treatments" in this issue.
To Interrupt or Not to Interrupt?
There are several reasons underlying the strategy of interrupting therapy before starting a new salvage regimen. These include allowing a reversion from resistant to wild-type virus, a break from side effects, and a short period to psychologically prepare to cope with a subsequent mega-HAART combination (a regimen containing five or more drugs).
The French GIGHAART study showed that a treatment break of eight weeks prior to optimized salvage therapy could dramatically increase the chances of subsequently achieving virological benefit. Results were presented by Christine Katlama, M.D., of Hôpital Pitié-Salpêtrière in Paris and colleagues at the 8th European Conference on Clinical Aspects and Treatment of HIV Infection in October 2001, and again at more recent conferences. In this randomized study, the arm that took a break before resuming treatment and the arm that immediately started salvage therapy both experienced a viral load decrease greater than 1 log over the first two weeks. However, viral load gradually rebounded in the immediate treatment arm, leaving only a 0.4 log drop from baseline at week 12. The deferred treatment arm experienced continued viral load decline to 1.9 logs below baseline. The greater benefit seen in the deferred therapy arm led to the early termination of the study.
Taking these results back to individualized care, the prospect of better results with deferred therapy is exciting, but the potential risks are also very real. Treatment-experienced people who interrupt therapy will need more frequent monitoring and possibly prophylaxis drugs to protect them from developing OIs if their CD4 cell counts are at risk for dropping below 200 or even 100 cells/mm3. However, the cost savings from not using antiretroviral drugs during this period should easily cover the expense of additional monitoring.
Other studies of treatment interruption have shown that a CD4 cell decrease of more than 100 cells/mm3 may be expected, and that the optimum time to defer therapy appears to be 8-12 weeks. These results are from averaged data and, as always, treatment decisions should be individualized. Some people may need to start salvage therapy earlier, while others may be able to delay resuming treatment for longer periods.
The second main salvage therapy strategy is to increase the number of drugs in an antiretroviral regimen. Some studies have used combinations of up to nine drugs. Such studies looked at multidisciplinary approaches to salvage therapy in people who had run out of other treatment options and were happy to try a new strategy. Participants in the French GIGHAART study, for example, had CD4 cell counts under 200 cells/mm3, resistance to three classes of antiretroviral drugs, and a median viral load of over 50,000 copies/mL. It is notable that major studies of mega-HAART have used TDM to confirm the levels of each PI and NNRTI, and have adjusted doses appropriately on an individualized basis.
Combinations used in the GIGHAART study included three to five NRTIs (ddI, d4T [stavudine, Zerit], AZT, 3TC [lamivudine, Epivir], and/or abacavir) plus one NNRTI (nevirapine, delavirdine [Rescriptor], or efavirenz) plus three PIs (either 400 mg ritonavir/600 mg amprenavir [Agenerase] twice daily or 300 mg ritonavir/400 mg lopinavir twice daily, plus either 400 mg indinavir, 600 mg saquinavir, or 1,250 mg nelfinavir, all twice daily). Hydroxyurea (500 mg twice daily) was also included in 48 (71%) of the regimens. Of the 62 subjects included in the preliminary evaluation, one (2%) used six drugs, 40 (64%) used seven drugs, and 21 (34%) used eight drugs.
By week 8, those in the deferred treatment arm showed some evidence of reversion to wild-type virus similar to that observed in previous short-term treatment interruption studies. For example, 21%, 38%, and 24% of participants, respectively, showed evidence of a loss of at least one resistance mutation to the PI, NRTI, or NNRTI classes. Furthermore, 14%, 24%, and 7% of participants, respectively, experienced loss of resistance mutations to one, two, or three classes of drugs. However, 55% showed no evidence of reversal of resistance mutations.
Therapeutic drug monitoring of trough PI and NNRTI levels revealed that a slightly lower proportion of participants achieved adequate drug levels in the immediate arm compared with the deferred arm (74% vs. 80%). When results from resistance testing were correlated with either adequate or low drug levels, a better virological response was associated with reversal of resistance mutations when adequate drug levels were achieved.
Safety and tolerability are always a concern when dealing with regimens containing numerous drugs. Participants in this study generally experienced a low level of toxicity for a group with such advanced disease. Rates of grade 3 (severe) toxicities and HIV-related OIs were similar in the immediate and deferred arms, with slightly more events reported in the immediate treatment arm (although numbers were small).
Data from Dr. Montaner's mega-HAART cohort were presented at the XIV International AIDS Conference in Barcelona this past July. The results showed that this multi-drug approach may produce a durable response with tolerable side effects. In this study 248 participants with multi-drug-resistant HIV received regimens containing up to nine drugs (median of six). TDM was used to ensure adequate drug levels.
Using an intent-to-treat (ITT) analysis in which all participants were analyzed whether or not they continued in the study, 69% achieved viral loads below 400 copies/mL on at least two consecutive measurements and about 40% achieved viral load levels below 50 copies/mL by week 48. This response was sustained out to 24 months in 80% of those who achieved undetectable viral loads.
Dr. Montaner concluded that aiming for undetectable viral load in treatment-experienced people is both realistic and sustainable. Even more optimistically, he showed that using this aggressive, multi-drug approach in individuals with highly drug-resistant HIV produced a survival benefit similar to that seen in treatment-naive people using normal HAART regimens.
|Expanded Access Programs
Once new drug candidates have been shown to be generally safe and effective -- but before they have been fully licensed -- expanded access programs (EAPs) often make new medications available to people who need them most urgently. Availability of new drugs varies widely, and the timelines for expanded access can be difficult to predict. Activist organizations such as the Coalition for Salvage Therapy (CST) and the AIDS Treatment Activists Coalition (ATAC) lobby for EAPs. Reports on their progress can be found at www.atac-usa.org.
Strategies for Using New Drugs
Access to new drugs may provide the best hope for many people with HIV, especially those who continue to experience rising viral load levels after trying a mega-HAART combination. But the use of new medications requires careful consideration. In particular, it is important to avoid simply adding new drugs sequentially to an existing regimen as they become available. Adding a new drug to a regimen in which the existing medications are no longer effective is similar to using the new drug as monotherapy -- a recipe for resistance. Some drugs in the development pipeline hold great promise, but they will produce better results if they are supported by other effective drugs in a combination regimen. (See "The HIV/AIDS Drug Pipeline," BETA, Summer/Autumn 2002.)
For each individual, weighing how long one can delay treatment with a new drug compared with how urgently one needs the medication can be very difficult. For people who have no other options and whose clinical health is at risk, any new drug may provide an important benefit -- even if it is only for the short term.
Study results presented by Steven Deeks, M.D., of the University of California at San Francisco (UCSF) and colleagues at the February 2002 Conference on Retroviruses and Opportunistic Infections (CROI) support the argument against changing treatment in the face of high-level resistance. Instead, people with high CD4 cell counts who are clinically well may stay on a "failing" PI combination, perhaps for several years. After 2-3 years on PI-based regimens, a subset of subjects who retained high CD4 cell counts (approximately 100 cells/mm3 above their nadir, or lowest ever count) despite viral load rebound have apparently maintained stable counts due to the reduced fitness of their drug-resistant virus. These individuals, who remain NNRTI-naive, will soon be able to use two drug classes in their next combination: NNRTIs and fusion inhibitors.
Delaying use of certain drugs in the hope of constructing a viable future regimen is not a straightforward option. Prediction of the timelines for pipeline drugs and expanded access programs is notoriously unreliable, and the cost of progressive accumulation of PI and NRTI resistance mutations is still not clear. Nevertheless, the results of Dr. Deeks's study introduce the importance of viral fitness (see table below). Reports on viral fitness will likely increasingly become available for use in conjunction with the results of resistance and drug level tests, adding one more tool to help tailor antiretroviral treatment to each individual.
Experience Counts
The experience of physicians is an important factor in the success of salvage therapy. This past summer Mike Youle, M.D., of the Royal Free and University College Hospital in London, who has been at the forefront of many new strategies to individualize patient care in the UK, began a presentation to the UK Community Advisory Board on salvage therapy by stating, "There are lots of bad doctors, bad nurses, bad drugs, and bad patients," and that if each of these problems were addressed, there would be little demand for salvage therapy. Dr. Youle clarified that lack of experience on the part of healthcare providers, or an unwillingness to keep completely up-to-date on HIV treatment advances, directly affects the health and care of patients, an observation that has been supported by several studies.
People receiving HIV therapy -- especially those with extensive treatment experience -- should be treated by a physician who is aware of the most current research and is willing and able to develop individualized approaches to treatment. People with HIV should also keep up with the latest advances in treatment strategy and the availability of new drugs, so that decisions will be based on the best research available. Successful outcomes are often the result of collaboration and teamwork between informed patients and their physicians.
Look at lifetime resistance -- keep a history of drugs used in the past and previous resistance test results. These can be used to develop a worst-case "virtual resistance" profile.
Maximize potency -- even if each drug only works a little, a mega-HAART combination can provide the combined potency many people need to reduce their viral load to an undetectable level.
Consider TDM -- suboptimal drug levels may explain why a past treatment regimen failed despite perfect adherence. Therapeutic drug monitoring may help determine optimal doses to overcome resistance or safely allow for drug interactions when using mega-HAART combinations.
Focus on adherence -- starting salvage therapy can be a good opportunity to devote attention to improved adherence. Count pills each day and keep a strict pill diary. Think about nothing else until you get it right!
Try to improve tolerability -- when using multiple drugs, careful management of side effects such as nausea, diarrhea, and interrupted sleep becomes more important than ever. Report all adverse events to a healthcare provider. Such symptoms can often be reduced using adjunct therapies such as anti-nausea or anti-diarrhea medications or sleep aids.
Consider viral fitness -- new research shows that reduced viral fitness may be an important aspect of PI-resistant mutations. The possibility of frequently rotating drugs to maintain reduced viral fitness may be an option for the future.
Selected Sources
Acosta, E.P. New approaches in HIV pharmacology: therapeutic drug monitoring. 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). San Diego, CA. September 27-30, 2002. Abstract 607f.
Acosta, E.P. and Gerber, J.G. Position paper on therapeutic drug monitoring of antiretroviral agents. AIDS Research and Human Retroviruses 18(12): 825-834. August 10, 2002.
Barditch-Crovo, P. and others. Phase I/II trial of the pharmacokinetics, safety, and antiretroviral activity of tenofovir disoproxil fumarate in HIV-infected adults. Antimicrobial Agents and Chemotherapy 45(10): 2733-2739. October 2001.
Blanchard, P. Indinavir plus ritonavir: might exposure to higher levels of indinavir overcome protease resistant HIV and prove useful to "rescue" previously failed protease inhibitor based combinations? HIV Treatment Bulletin 1(2). May 2000. www.i-base.org.uk/publications/bulletins/vol1/htb2/htb2b.html.
Burger, D. and others. Therapeutic drug monitoring of indinavir in treatment-naive patients improves therapeutic outcome after 1 year: Results from ATHENA, and Therapeutic drug monitoring of nelfinavir 1250 mg BID in treatment-naive patients improves therapeutic outcome after 1 year: Results from ATHENA. 2nd International Workshop on Clinical Pharmacology of HIV Therapy. Noordwijk, the Netherlands. April 2-4, 2001. Abstract 6.2b.
Casado, J.L. and others. Individualizing salvage therapy: the inhibitory quotient as a predictor of virological response. XIV International AIDS Conference. Barcelona, Spain. July 7-12, 2002. Abstract TuPeB4488.
Clotet, B. and others. Enfuvirtide (T-20) in combination with an optimized background (OB) regimen vs. OB alone in patients with prior experience or resistance to each of the three classes of approved antiretrovirals (ARVs) in Europe and Australia, and in North America and Brazil (TORO I and TORO II). XIV International AIDS Conference. Abstracts LbOr19a and LbOr19b.
Deeks, S. and others. Virologic and immunologic evaluation of structured treatment interruptions (STI) in patients experiencing long-term virologic failure. 7th Conference on Retroviruses and Opportunistic Infections (CROI). San Francisco. January 30-February 2, 2002. Abstract LB10.
Durant, J. and others. Importance of protease inhibitor plasma levels in HIV-infected patients treated with genotypic-guided therapy: pharmacological data from the VIRADAPT study. AIDS 14: 1333-1339. July 7, 2000.
Garraffo, R. and others. Independent benefit of sufficient drug levels and genotypic analysis in salvage therapy: pharmacological data of the VIRADAPT study. 39th ICAAC. San Francisco. September 26-29, 1999. Abstract 1166.
Havlir, D. and others. Productive infection maintains a dynamic steady-state of residual viraemia in HIV-1 infected persons treated with suppressive antiviral therapy for 5 years. Antiviral Therapy 7: S41. 2002.
Hoetelmans, R.M.W. and others. Plasma concentrations of saquinavir determine HIV-1 RNA response over a 48-week period. XII International AIDS Conference. Geneva, Switzerland. June 28-July 3, 1998. Abstract 42261.
Hsu, A. and others. The C trough inhibitory quotient predicts virologic response to ABT-378/ritonavir (ABT-378/R) therapy in treatment-experienced patients. 5th International Congress on Drug Therapy in HIV Infection. Glasgow, Scotland. October 22-26, 2000. Abstract PL9.4.
Justice, A. Determinant of failure: comorbidity. 4th International Workshop on Management of Treatment-Experienced Patients. San Diego. September 26-27, 2002. Abstract 108.
Katlama, C. and others. GIGHAART (ANRS 097): A prospective randomised trial comparing the efficacy of a salvage regimen administered with or without treatment interruption in patients with severe biological failure and extensive prior therapy. 8th European Conference on Clinical Aspects and Treatment of HIV Infection (ECCA-TH). Athens, Greece. October 27-31, 2001. Abstract O16.
Kempf, D. and others. Response to ritonavir (RTV) intensification in indinavir (IDV) recipients is highly correlated with virtual inhibitory quotient. 8th CROI. Chicago. February 4-8, 2001. Abstract 523.
Lori, F. and others. A low hydroxyurea dose (600 mg daily) is found optimal in a randomised, controlled trial (RIGHT 702). XIV International AIDS Conference. Abstract TuPeB4465.
Marzolini, C. and others. Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. AIDS 15(1): 71-75. January 5, 2001.
Mayers, D. and others. Both drug resistance and antiretroviral drug levels are associated with short-term virological responses to subsequent drug regimens in CPCRA 046 (GART Study). 5th International Workshop on HIV Drug Resistance and Treatment Strategies. Scottsdale, AZ. June 4-8, 2001. Abstract 87.
Mellors, J. Resistance to antiretroviral drugs. 39th ICAAC. Plenary lecture.
Miles, S. Personal communication. November 21, 2002.
Montaner, J. and others. Multi-drug rescue therapy (M.D.RT) in HIV-positive individuals. XIV International AIDS Conference. Abstract B10484.
Montaner, J. New challenges and perspectives in salvage therapy. XIV International AIDS Conference. Abstract WeOrB192.
Phillips, A. and others. Theoretical rationale for the use of single drug sequential antiretroviral therapy regimens. XI International HIV Drug Resistance Workshop. Seville, Spain. July 2-5 2002. Abstract 73.
Piketty, C. and others. Plasma drug levels and resistance are predictors of efficacy for the combination including saquinavir, ritonavir and efavirenz. 5th International Workshop on HIV Drug Resistance and Treatment Strategies. Abstract 120.
Squires, K. and others. Tenofovir DF: 48-week results from Phase 3 study in treatment experienced patients. 9th CROI. Seattle, WA. February 24-28, 2002. Abstract 423w.
Workman, C. Use of indinavir and ritonavir to overcome indinavir resistance. 4th International Congress on Drug Therapy in HIV Infection. Glasgow, Scotland. November 1999.
Youle, M. Approaches to salvage therapy. UK-CAB Lecture. August 2, 2002. www.i-base.org.uk/meetings/ukcab/august/UK-CAB_Salvage_aug02.htm.
Simon Collins (email@example.com) is an HIV-positive treatment advocate with HIV i-Base, an HIV-positive peer support organization based in London.
This article has been adapted from a revised version of "Changing Treatment: A Guide to Second-line and Salvage Therapy," a patient guide first produced in 1998 by HIV i-Base and updated every 4-6 months as new information becomes available. The guide is available at www.i-Base.org.uk.
Back to the SFAF BETA Winter 2002/2003 contents page.


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Patrick Garratt
GMA Legend Award goes to PC Zone – Pat's speech
Tonight during the Games Media Awards, VG247's Patrick Garratt stepped on stage to present the award for Games Media Legend – which he was the recipient of last year. By now, all of you know the award didn't go to an individual, but the now defunct PC Zone magazine, which released its final issue last […]
Patrick Garratt headlines
Latest Eurogamer podcast features Pat
Oh look, another Eurogamer podcast. Oh look, it has Pat!
VG247 podcast #8 - Blizzard lore-master Chris Metzen and JAW's Stewart Gilray
Two great interviews for you this week. I went to Irvine recently to see StarCraft II, and was lucky enough to get some face-time with Chris Metzen, Blizzard's lore boss. Despite being a proper rock star, the guy's switched on beyond belief. Hear him talk story in games, WarCraft III, SCII and loads more in […]

subset: commoncrawl


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News & Notes: Game 127
Saturday, August 20, 2011 (7:05 p.m.) – Huntington Park
Radio: WWKB AM 1520, bisons.com
Buffalo Bisons (54-72, 5th(-18.0), North)
LHP Mark Cohoon (3-8, 6.17)
Columbus Clippers (80-46, 1st(+14.0), West)
RHP Joe Martinez (8-6, 4.01)
TODAY'S GAME: Tonight, the Buffalo Bisons face the Columbus Clippers in the first game of a four-game set at Huntington Park (7:05 p.m.). Tonight's game begins an eight-game roadtrip for the Herd, who will also travel to Toledo to face the Mud Hens. The Bisons are coming off a 6-4 homestand that ending with a 3-1 series win over Toledo.
VS. THE CLIPPERS: It's been more than two months since the Bisons faced the Clippers. Columbus swept Buffalo in a four-game set, June 11-14, back at Coca-Cola Field. Prior to those four losses, the Herd had won five straight over the Clippers. Buffalo is 5-3 at Huntington Park since the Clippers opened their new stadium for the 2009 season.
ON THE HILL: LHP MARK COHOON will make his 15th start with the Bisons today. The southpaw is winless in his last five outings, but has allowed three runs or less in four of those starts. In the first game of a doubleheader on August 15 against Durham, Cohoon allowed just two runs in 6.1 innings of work but fell in a 2-1 Bisons defeat.
RALLY HERD: The Bisons earned their seventh walk-off win last night thanks to a two-run home run from INF VALENTINO PASCUCCI in the 11th inning. It was the Bisons first win this year after trailing after eight innings (previously 0-57). Five of the six wins by the Bisons on the homestand came in games the team trailed in the sixth inning or later. Despite being 18 games under the .500 mark, Buffalo is 33-32 in games decided by two runs or less.
SMOOTH AS: INF JOSH SATIN has hit in seven straight games with a .440 (11-25) average over the last week. The Triple-A rookie has hit in 24 of his 27 games since joining the Bisons on July 22. You have to go all the way back to May 29-30 while with Double-A Binghamton for the last time Satin went hitless in back-to-back games.
BISONS BITS: INF ZACH LUTZ hit .353 (12-34) with four home runs and seven RBI during the Bisons 10-game homestand…INF VALENTINO PASCUCCI is tied for 1st in the IL with 85RBI. It's the most a Bison has had since OF Jason Dubois knocked in 87 during the 2006 season.
METS UPDATE: The Mets (60-64) were defeated by the Brewers yesterday by a 6-1 score. Former Bisons OF ANGEL PAGAN had three of New York's seven hits, including two doubles. INF RUBEN TEJADA also had two hits and now has a .268 average with the Mets. New York hosts the Brewers this afternoon at 4:10 p.m.


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Black & Decker Fan/Oil Heater OR-07 Specification
|In the Box
|Main Unit, User Manual and Warranty Card
|Black & Decker Fan Heater
|Heat Settings
|1500 Watt
|One Year Warranty
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Delivery Information
Currently we are providing delivery of our products only within Kathmandu Valley. However we are soon expanding our services all over the country.
You can select one of two delivery methods:
1. Home Delivery - We will deliver the ordered products to your address.
2. Collect from our store - You can come to our store located at Bagbazar and collect your order. This method is free.
To select the delivery method of your choice, buy products and continue to the checkout process.
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Our delivery rates are based on the total price of each order. The delivery rates are given below:
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* You can add multiple products in one order. The delivery rate is calculated on the basis of total price of all the items ordered.
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- Products ordered will be deliverd with-in maximum of two business days.
- Deliveries at the address specified will be made after the confirmation of order by a telephone call to the person mentioned as a recipient.
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Black & Decker Fan/Oil Heater OR-07 Price in Nepal: Rs. 18,000.00
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Serapid on the Move
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Saturday, March 1, 2014
With an additional 18,000 sq. ft. of space, the new home of quick-die-change equipment supplier Serapid, Sterling Heights, MI, will include a sales showroom and a research and development lab. The company expected to move into its new digs—noted for its use of clean building materials such as low-VOC ceiling tiles and a white EPDM roof—in February 2014.
See also: Serapid, Inc.
Related Enterprise Zones: Tool & Die
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We're sorry your Apple TV isn't working as it should.
After you've contacted Apple for a replacement, you'll receive a kit that contains a replacement Apple TV with everything you need to return your defective Apple TV to Apple.
Important: Be sure to return your defective Apple TV so that Apple receives it within ten days of the day the replacement Apple TV shipped (check your ship date). If Apple doesn't receive your Apple TV within ten days, or if Apple technicians find that the Apple TV has accidental damage or unauthorized modifications, you'll be charged up to the full value of the replacement Apple TV. For more details, see terms and conditions.
Before you ship your Apple TV
- Reset your Apple TV to its factory settings.
- Unplug your Apple TV.
Pack your Apple TV using the included packaging materials
- Put your Apple TV in the foam bag. Do not include your power cord or Apple remote.
- Place the bagged Apple TV into the foam shipping box insert.
- Place the foam piece on top of your Apple TV so that you can see the circular cut-out on top.
- Close the box and tape it shut with the tape provided.
Ship your Apple TV to Apple
- Remove the pre-applied top label from the box (that's your copy). Make sure the return shipping label remains on the box.
- Find the name of the courier on the return shipping label.
- Visit the courier's website to schedule a pickup or find a drop-off location.*
- Get a receipt from the courier.
- In a few days, check that Apple has received your defective Apple TV.
*Apple is not responsible for any damage during shipping if the package is not properly sealed or is delivered to the courier in poor condition.
Use your replacement Apple TV
- Make note of your new Apple TV serial number. Your replacement Apple product is covered by a 90-day service warranty, or the remainder of your original product warranty or AppleCare plan, whichever is longer.
- Set up your replacement Apple TV.
© 2018 Apple Inc. All rights reserved. Apple, the Apple logo, Apple TV, and iTunes are trademarks of Apple Inc., registered in the U.S. and other countries. AppleCare and iCloud are service marks of Apple Inc., registered in the U.S. and other countries. Other product and company names mentioned herein may be trademarks of their respective companies.
1. An estimate for repairs, as required (section 9844 of the California Business and Professions Code), shall be given to the customer by the service dealer in writing. The service dealer may not charge for work done or parts supplied in excess of the estimate without the prior consent of the customer. Where provided in writing the service dealer may charge a reasonable fee for services provided in determining the nature of the malfunction in preparation of a written estimate for repair. For information, contact the Bureau of Electronic and Appliance Repair, Department of Consumer Affairs, Sacramento, CA 95814.
2. A buyer of this product in California has the right to have this product serviced and repaired during the warranty period. The warranty period will be extended for the number of whole days that the product has been out of the buyer's hands for warranty repairs. If a defect exists during the warranty period, the warranty will not expire until the defect has been fixed. The warranty period also will be extended if the warranty repairs have not been performed due to delays caused by circumstances beyond the control of the buyer, or if the warranty repairs did not remedy the defect and the buyer notifies the manufacturer or seller of the failure of the repairs within 60 days after they were completed. If, after a reasonable number of attempts, the defect has not been fixed, the buyer may return this product for a replacement or a refund subject, in either case, to deduction of a reasonable charge for usage. The time extension does not affect the protection or remedies the buyer has under other laws.


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Allah's Disempowered Daughters
Upon reading this book, it at last becomes apparent what has always been missing – from the western reader's perspective – from even the best novels from the Islamic world. Although it has never been possible to exactly put a finger on it, these novels lacked an insight into the fundamental mindset, the spiritual substructure, woven of myths and legends, of the people about whom we are reading.
On close examination, it is not really surprising that we seldom learn about these things; after all, authors and readers generally share these mindsets and do not need to subject them to any deeper examination. It takes someone like Nedim Gürsel to draw back the veil on this key fundament. On the one hand, Gürsel is writing as an author with Muslim roots for a Western audience; on the other, he writes as a westernised author for Turkish Muslims who themselves tend only to have a fractured, at best restorative relationship with their own tradition.
Born in 1951, Gürsel spent his childhood in Turkey, but his youth and years of professional training in Paris, where he now lives and works as a lecturer at the Sorbonne. And almost all of the five of his books that have been published in German testify to how Gürsel immerses himself in the Ottoman-Islamic culture of times gone by, among other things because to him, it is no longer a self-evident tradition. This is evident in the first of his novels to be published in German, which was about Mehmet II, the conqueror of Istanbul, and in his re-telling of Anatolian legends in Seven Dervishes.
Largely autobiographical account of childhood
This is particularly true of The Daughters of Allah. The novel cleverly links what is for the most part the autobiographical story of the author's childhood with a portrayal of the lost collective realm of imagination. The book covers a whole range of topics from religion and history to the nation and the wound left behind by the creation of modern Turkey – a wound that remains an open gash to this day.
The key figure in this narrative is the grandfather. As a child, Nedim grew up in his grandparents' house, which meant that he benefited from a shift in the generational and socialisation structure of modern Turkey, which his contemporaries, who were no longer exposed to Ottoman influences, did not experience, and which enabled him to gain the particular insights and impressions that we as readers now so admire.
The grandfather was called Haci, or 'Mecca pilgrim'. In truth, he only got as far as Medina, and that as a Gazi (which quite literally means "conqueror"). He was a veteran. In the First World War he fought for the tottering Ottoman Empire, and Medina was the last stop on the Berlin–Baghdad railway line, which had been built with German support and was an important target.
When has this subject ever been touched upon in Turkish literature? By dredging up this story, which has long been suppressed in Turkey, Gürsel succeeds in processing a whole bundle of traumas. As a devout Muslim, the grandfather believed he was defending Islam against the European superpowers, embodied by Lawrence's British-Arab troops. At the same time, however, he was fighting against none other than the descendants of the Prophet.
Turkish traumas
Gürsel cites his grandfather's records, which he can only decipher with the help of a specialist in Ottoman handwriting. It is not possible to tell where the thoughts of the grandfather, who loses an arm in Medina, end and Gürsel's thoughts begin. But what we read here is borne of a profoundly humane spirit; a kind of narrative reconciliation of Islam and pacifism, for the very reason that the problematic aspects of this reconciliation are not kept secret: "When he murmured to himself 'you have not killed them; Allah has killed them', he wondered whether he should not critically question this and similar verses of the Koran, but then he regretted this impulse. Only Allah could know what was best and what was right."
But there is much more to Gürsel's book than this. The evocation of a childhood spent listening to stories on his grandmother's knee results in a re-telling of the popular myths of Islam, first and foremost the legends concerning the Prophet. Gürsel writes: "And if I have stolen, then I have stolen from shared Arabic lore without taking a wrong turn." The "stolen" stories come from the "official" Mohammed "biography" by Ibn Ishaq from the eighth century. Gradually, these recollections of childhood lead to a kind of religious re-enchantment: even a writer imbued by the ideas of the French Enlightenment cannot resist the charms of the stories once told by his grandmother.
As Western readers, the appeal for us lies elsewhere, namely in the fact that we are learning about these legends at all – stories that only a specialist might otherwise be privy to. For in truth, they have greater influence on the majority of Muslims' perception of Islam than the Koran and the hadiths, which are highly inaccessible to most Muslims.
The power of myths and folklore
From a literary point of view, this re-telling of myths that are widely known in the Islamic world does, however, have a small drawback: Mohammed is swathed in such an overpowering aura of goodness, beauty and – last but not least – success that although the text is full of curiosities, it offers little in the way of suspense.
With the Daughters of Allah that give the book its title – the pagan goddesses of pre-Islamic Mecca mentioned in the infamous "Satanic Verses" – Gürsel is setting a counterpoint. The story of what happened when Islam drove the joyful world of the pre-Islamic pagans from the temple – the Kaaba – is retold from the perspective of those who lost the religious struggle.
The fact that religious zealots in Turkey took legal action over these passages is, however, surprising. Perhaps it did not suit the faithful that the pagan goddesses were suddenly given a voice. Ultimately, however, the novel maintains an affirmative relationship to the religion of the childhood evoked by the narrator.
The book's central message is that although faith can be misused by fanatics and nationalists – and Gürsel supplies numerous examples of this – it is nevertheless an integral and ultimately positive component of Turkish identity. For this reason, the novel could to a certain extent be viewed as part of the religious-imperial renaissance that has characterised Turkey since Erdogan took office, and which also includes the rediscovery of the Ottoman heritage that provides Gürsel with the material for his work while drawing on the story of his own life.
Stefan Weidner
© Qantara.de 2013
Nedim Gürsel: The Daughters of Allah published in German as "Allahs Töchter", translated from the Turkish by Barbara Yurtadas. Published by Suhrkamp Verlag, Berlin 2012.
Editor: Aingeal Flanagan/Qantara.de


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So Tour de France winner / testosterone ratio out-of-whacker Floyd Landis called a press conference today to defend himself against the charge of elevating his testosterone. His explanation, as far as we're concerned, is brilliant.
The night before Stage 17, Mr. Landis said, while gathered with friends and teammates, he prepared for the strenuous mountain stage by drinking two beers and at least four shots of whiskey.
The revelation that Mr. Landis was drinking the night before the test could be significant. According to several studies, alcohol consumption can increase the ratio between testosterone and epitestosterone, which occur naturally in the body. Mr. Landis failed the test because it showed an elevated ratio between the two.
We'll be honest: This was the first we had heard of this "elevated testosterone ratio because of heavy drinking" story. This not only changes our perception of Landis, it changes our perception of all athletes. From now on, any athlete with an unbalanced testosterone/epitestosterone ratio, we're buying his/her jersey.
Tour Winner Floyd Landis Denies Taking Drugs, Does Say He Drank [WSJ.com]
(UPDATE: Here's a very instructive look at whether Landis "failed" a drug test at all.)


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Defensive Publications are a method for the open source community to prevent the issuance of low quality software patents. These publications serve as evidence to disclose to the examiner what is new and innovative within the technology. Through Linux Defenders, developers collaborate with our team to ensure that these publications are effective in protecting the freedom to create, invent and operate.
|Publication Date
|January 12, 2015
System for designing and creating computer programs using finite state machines
The methods commonly used to develop computer software are very difficult, time consuming and error prone. Many software projects are canceled due to cost and time overruns. It is common for projects to fail to deliver all of the anticipated benefits.
|database software development Computer Programming Object Oriented Programming Transaction Processing Finite State Machine Publish and Subscribe Internet of Things Eclipse Rich Client Plugin RCP


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Doubts loom over China 'election'
CHINA'S most uncertain leadership transition in decades could catalyse lasting institutional innovations in the way leaders are chosen, analysts say.
As more than 2000 Communist Party delegates gather on Thursday to start the 18th Party Congress, observers have been surprised by reports that two respected and reformist-minded proteges of outgoing party boss Hu Jintao have failed to secure seats on the Politburo Standing Committee.
While Xi Jinping and Li Keqiang are almost certain to be promoted to party boss and premier-in-waiting, a further five seats on the committee — the inner sanctum of power — are yet to be settled.
Huang Jing, an expert in Chinese politics at the National University of Singapore, said ungainly brawling between Mr Hu and his predecessor, Jiang Zemin, has continued up until the eve of the congress.
Professor Huang said Mr Hu had ceded positions on the committee in exchange for a series of unorthodox appointments that will allow him to finally take control of the People's Liberation Army.
"I think we all underestimated Hu Jintao's ability to do conspiracy," Professor Huang said. "Hu's calculation is very simple: if he controls the gun then in one or two years Jiang Zemin will have to die and his guys on the Politburo Standing Committee will line up to kowtow to him."
Such a result would ensure Mr Hu's shadow loomed large over his successor, Xi Jinping.
Others believe the tussle for control of the committee is far from over. Some close observers say a process of limited internal elections is under discussion, because there is no other mechanism to resolve internal differences.
"For their own sakes this is the best way for them to maintain the appearance of unity and also to shoulder the blame for lingering hatreds among them," said Professor Feng Chongyi, an expert on Chinese politics at the University of Technology, Sydney.
"Hu Jintao will be extremely happy if he can finally claim to have made an innovation at the end of his term," Professor Feng said. "And it is common sense — if he cannot get the upper hand through backroom dealings."
Susan Shirk, chair of the 21st Century China Program of the University of California, San Diego, said this was the process by which institutional change occurred. "When the risks of sticking with the old method look very large, that's when people change the method," she said.
Professor Huang was more pessimistic. He said the party had actually returned to "informal politics", based entirely on personal patronage.
"From a political scientist's point of view I think that's a great step backwards," he said.
Party members will attend the week-long congress, which will "elect" a central committee of about 200 members and 170 alternate members.
The Central Committee, in turn, is expected to convene a plenum meeting on November 15 which should then anoint the new 25-member Politburo and seven or nine-member Politburo Standing Committee.
John Garnaut is Fairfax Media's Asia Pacific editor. Most recently he was China correspondent. John graduated in law and arts from Monash University and worked for three years as a commercial lawyer at Melbourne firm Hall & Wilcox before joining the Sydney Morning Herald as a cadet in 2002. He became the Economics Correspondent in the Canberra press gallery and in 2007 was posted to Beijing.


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English, est. 1793
Comport, from the dessert service Viscount Milton, c. 1867
bone china
14.6 x 23.5 cm
Collection of the Winnipeg Art Gallery; Acquired with funds from Drs. Morris C. and Jacqui F.C. Shumiatcher and the Estate of Annette and Bessie Rosenberg in memory of their parents Isaac Aaron Rosenberg and Rebecca Rosenberg
Ceramic, Decorative Arts Ceramic
This comport is part of the spectacular Viscount Milton dessert service, commemorating the overland expedition across northwestern Canada between 1862 and 1863 of William Wentworth Fitzwilliam, Viscount Milton (1839–1877) and Dr. William Butler Cheadle (1836–1910). Only two services were made, one for Viscount Milton and one for Cheadle. This arduous and challenging journey was published as The North West Passage by Land (1865) by Cheadle, based on his diary entries, his drawings, and the photographs taken en route. These same illustrations form the basis of the service's imagery, with each vessel displaying a different scene from the perilous adventure. This particular scene shows an Assiniboine First Nations guide rescuing one of the group's horses, Bucephalus, from drowning. The other horse was not so fortunate. Bucephalus, incidentally, had been carrying Cheadle's diary and drawings at the time of the rescue.
Gallery Hours
- Tuesday 11am-5pm
- Wednesday 11am-5pm
- Thursday 11am-5pm
- Friday 11am-9pm
- Saturday 11am-5pm
- Sunday 11am-5pm
- Closed Monday


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½ C butter
½ C flour
4 C whole milk
2 T Dijon mustard
8 oz Aged Cheddar, shredded
8 oz Gruyere, shredded
4 oz parmesan, grated
1 tsp salt
cracked pepper to taste
2 T cognac, optional
1 lb elbow macaroni
Your favorite hot dogs
Hot dog buns
Optional garnish: crispy shallots or roughly ground potato chips for crunch
In a large pot of boiling salted water, cook the macaroni. Drain the noodles.
Meanwhile, heat the milk in a small saucepan, but don't boil it. Melt butter in a large (4-quart) pot and add the flour. Cook over low heat for 2-3 minutes, stirring with a whisk until it turns light brown. While whisking, add the hot milk and cook until thickened and smooth. Stir in the Dijon mustard. Turn off the heat, add the Gruyere, Cheddar, Parmesan, salt and pepper. (add cognac if using)
Add the cooked macaroni and stir well.
Top your favorite hot dog with mac n cheese and crispy onions or chips.


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Hilarious is the only way to describe how my Saturday mornings have been of late.
Three weeks ago, my oldest son, Beckett, began his first organized "sporting" activity, Little Kickers, and it's been quite enjoyable for the entire family.
By its name, the obvious deduction is it's a soccer program. However, as those parents whose kids have participated already know well, it has little to do with soccer. Actually, what I have found is the soccer balls are simply there for the parents to kick around while their kids run like maniacs for an hour.
In the rare instance that my son actually kicks a ball, accidentally or not, I act like it's the greatest feat ever. During last Saturday's session, I think he successfully connected with a ball three times and I'm not sure either was intentional. It's more like a necessity to move the ball out of his way so he can easily get from point to another.
When a ball does capture his attention, Beckett seems to prefer to pick it up, hold it, lick it, maybe kiss it, say 'ball' and then it toss it aside like an empty sippie cup.
Rather than get too involved with the balls, he favors some friendly taps on the head of a fellow participant, like he does his 12-week-old brother or his dogs. Sometimes, he even likes to stick his pointer finger in a fellow participant's ear, nose or eye before laughing and running off in another direction haphazardly. To that, of course, I apologize, while fighting off my immature side's instinct to laugh along with him. I realize I need to let him know that's not okay, but the issue is I need to catch up to him first. That's not always an easy feat.
Although there's no soccer being taught, and that's wise because it would be a waste of time, the program is great for kids my son's age. There are six kids in his time slot and age group (18 to 24 months).
The thing I most enjoy is how different each kid seems to be. Since Beckett tends to the rambunctious side more often than not, I am constantly amazed at how some kids are incredibly mellow. There was one boy that simply sat wide-eyed and observed most of the time. Even when he did run around and get excited, he was careful not to get too far away from his parents. I was in awe because on the opposite extreme is Beckett, who runs around the place and is constantly trying to climb the divider to join in with the bigger kids on the adjacent field.
Here's some other highlights of this new adventure:
— One of my favorite memories came on the first day of the program. Dispersed throughout the field are these little circular markers where the kids are supposed to sit while the instructor talks. After spotting them, Beckett immediately ran over, pushing aside the soccer balls on his way, and began stacking them one by one. Since nobody else was around, I just let him go at it. A minute later, all 10 were stacked and he gave himself a standing ovation. He loves stacking blocks and cups and will try to stack just about anything. He even tried to stack a few soccer balls atop each other on the first day. He quickly learned that was not possible, but for some reason still tries each session.
— As to be expected, minor injuries are inevitable with a group of toddlers playing. Last Saturday, while the parents held up a parachute so the kids could run underneath, Beckett came running over to me crying. I did not immediately know what had happened and encouraged him to continue running around and having fun. He was having none of it so I picked him up to settle him down. A grandmother quickly informed me that he had bumped heads with another boy, pointing to her grandson who was sitting in the middle of the field sporting a nickel-sized bruise on his forehead. The funny thing was Beckett had no visible injuries and was wailing, while the other boy was just sitting down rubbing his forehead but not crying. Later, I apologized to his parents and I wondered if he had seen the collision. The dad proudly reported that he had the head bump on tape and offered to show it to me. I took his word for it.
— In the first session, Beckett became familiar with "green light-red light". It was a nightmare at first with kids running randomly all over the place, while the parents tried to corral and coax them into staying near them. Fortunately, everyone is improving a little bit and it's not quite as hectic, but there are still a few independent souls unwilling to stop when the "red light" is called. I find Beckett, whose attention span can be difficult to contain, in that lot often, but he's showing signs of improvement.
— Another aspect of the program calls for the kids to jump in place for a while. Most of the kids have not mastered that yet. In Beckett's case, for some reason, he equates marching to jumping. It seems to be the lazy man's way to jump. Either way, we are working on it. In the meantime, I simply pick him up off the ground a couple inches and put him back down to try and teach him. The only problem with that is he laughs hysterically and really enjoys it. I may have to rethink that approach because he thinks that's a fun game in and of itself.
Overall, the primary ambitions of the Little Kickers program seems to be to teach the kids how to listen, allow them socialize with others their age and to tire them out. All that sounds good, and I particularly love the burning off energy part.
Last week, on the way home, Beckett fell asleep in the car. Apparently, it did the trick. As most parents know well, an exhausted kid can be a wonderful thing.


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- WiFi
- Car park
- Air conditioning
- Pets admitted
- Accessible
- Gym
- Business
Choose your room
When you stay at West Hartford Inn in West Hartford, you'll be in the historical district and minutes from The Children's Museum and The Center & The Square. This hotel is within close proximity of American School for Deaf and Playhouse on Park. Enjoy the recreation opportunities such as a fitness center or make use of other amenities including complimentary wireless Internet access. Featured amenities include a computer station, express check-out, and complimentary newspapers in the lobby. Free self parking is available onsite. Make yourself at home in one of the 52 air-conditioned guestrooms. Complimentary wireless Internet access keeps you connected, and cable programming is available for your entertainment. Private bathrooms with shower/tub combinations feature complimentary toiletries and hair dryers. Conveniences include coffee/tea makers and irons/ironing boards, as well as phones with free local calls.


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Studying Paolo's brains
ESA astronaut Paolo Nespoli, now working as a flight engineer on the International Space Station, is busy with a range of scientific experiments. The latest is peering inside his head to help understand how the human brain works.
Our brains are changing all the time – nerves are rearranging themselves and the connections between the nerve cells are reforming as the brain memorises new information, stores the old and continuously adapts to new situations.
New experiences, learning, physiological changes, sleep disturbance and fatigue are among the most influential factors.
Sometimes, especially after an accident or a cerebral stroke, the recover power of brain tissue is simply mind-boggling: the remaining healthy tissue can take over the functions of damaged areas.
Space is a stress factor
The weightlessness in orbit is also a big change for brains. Not only are there changes in blood circulation and other physical conditions, but the way that cognitive functions of daily life are managed also alter dramatically.
Adapting to the multitudinous effects that gravity has on the human body and the way the brain deals with them is perhaps the greatest demand that the nervous system has to face in space. The increased load on the cognitive capacity is accompanied by a multitude of stresses on the brain.
On 21 December, his second full working day on the Station, Paolo set up the Neurospat experiment with assistance from crewmate Cady Coleman.
Neurospat aims to detect the brain's mechanisms involved in the altered behaviour in weightlessness and to locate the crucial parts of the cerebral cortex.
Helping life on Earth
Neurospat uses a laptop computer with a special program, a visor to focus on the computer without external visual distractions and an electroencephalograph to record brain activity.
By recording this activity, European scientists are probing the activity that underlies cognitive processes involved in four different tasks: visual-motor tracking, perception of how the body is oriented, 3D navigation and discriminating the orientation of objects.


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Discussions about how companies handle privacy are metadiscussions, because data use policies provide information about information, namely, how platforms collect, use and share it. It's easy to come up with platitudes when operating in such an abstract realm. People like the catchy norm of "transparency." It suggests that our dignitary ills are cured when we know how companies such as Facebook use the information about us that they hoard.
But transparency as a norm suffers from a hobbling flaw when put into practice — it is antithetical to the proprietary interests companies hold dear and which the law protects. At a fundamental level, the exploitation of big datasets is how most online social platforms make money. Granular knowledge about the user equals more targetedness of the ad. Targeted-er ads can be sold at a premium. The fact that a platform can collect so much information about a user is one thing. The method for the information's use is another. It's the face of the latter aspect into which transparency flies.
No company that has invested substantially in developing effective methods for utilizing its collected data is going to have an authentic incentive to lift the hood on its data-utilizing methods. The protection of the law of trade secrets would evaporate in any instance where a company were to do that.
Any reluctance to transparency on the part of the platform betrays this misalignment of incetives between platform and user. Calling on transparency as the norm will only exacerbate the misalignment. What people are actually looking for when they call for transparency are reasons to trust. The metadiscussion needs a new pathway to get to trust, because the path that transparency affords is, ironically, blocked.
Photo credit: motoyen


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This crazy incredible hunk of solid sterling evil bling is now available to purchase through Käärme for $340. And I should note that there are only 2 remaining, not including my own. Which you would have to pry from my cold, lifeless fingers. Note my my sick BÖC t-shirt I got at Muskelrock.
Also, we now have a blog. Peace! &hearts


text: URMC / Encyclopedia / Content Search Encyclopedia Coenzyme Q-10 Other name(s): Co Q-10, Q-10, ubiquinone, ubiquinol General description Coenzyme Q-10 is a fat-soluble type of substance called a quinone. It's similar to vitamins E and K. Since it was first found 40 years ago, research has been ongoing. It may have benefits for the heart. Coenzyme Q-10 is made by cells throughout the body. It acts as a catalyst in the respiratory chain. This chain makes energy from carbohydrates. It's abundant in cell membranes, especially in the mitochondria. Coenzyme Q-10 is a powerful antioxidant by itself. It's also powerful when used with vitamin E. Levels of coenzyme Q-10 decrease with age. They're also low in people with heart disease. The amount of coenzyme Q-10 in the body peaks around age 20 and then decreases. Intense exercise also makes coenzyme Q-10 turn over faster. This lowers its levels. Organ meats are good sources of coenzyme Q-10. These include the heart, lung, kidney, spleen, liver, pancreas, and adrenals. Medically valid uses Coenzyme Q-10 has been studied for its role in congestive heart failure (CHF). It's also been studied to see how it impacts heart disease. . Unsubstantiated claims There may be benefits that have not yet been proven through research. Coenzyme Q-10 is claimed to help prevent LDL oxidation. This reduces the risk of atherosclerosis and re-perfusion injury after open-heart surgery. It also lowers the risk of liver injury from cholesterol-lowering medicines such as statins. Coenzyme Q-10 has also been used to boost exercise tolerance and athletic performance. It may also help blood sugar control in people with diabetes. It may also boost the immune system to fight disease when used alone or with vitamin B-6. It may also help increase fat metabolism. Some claims say that coenzyme Q-10 may also treat periodontal diseases and gingivitis. It may also aid in breast cancer, chronic stable angina, mitral valve prolapse, heart rate issues. It may also help with high blood pressure (hypertension), Parkinson's disease, and muscular dystrophy. Dosing format Supplements range from 10–300 mg. There is no set dose. However, doses of 30–100 mg per day have been suggested. Higher doses may be used in some cases. You should take this supplement with a meal that contains fat. This helps your body absorb it better. Coenzyme Q-10 isn't absorbed well from the gastrointestinal tract. Women who are pregnant or breastfeeding should talk to their healthcare providers before taking any supplements. Side effects, toxicity, and interactions Doses of up to 600 mg per day for every kg of body weight do not show toxicity. In some cases, minor side effects can happen. These can include: Burning feeling in your mouth Loss of appetite Nausea Diarrhea Trouble falling or staying asleep (insomnia) Rashes Dizziness Irritability Fatigue Heartburn Headache Light sensitivity Stomach pain If you're taking certain cholesterol medicines such as statins, you should take 100 mg per day of coenzyme Q-10. . These medicines block your body from making coenzyme Q-10. Medical Reviewers: Diane Horowitz MD Raymond Kent Turley BSN MSN RN Rita Sather RN


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What our clients say…
"Bob, thank you so much. Apollo loves you and is always happy when she is with you. It is such a pleasure to know you are there for our pet."
Roger and Cathy Maggio, Apollo's owners
Roger and Cathy Maggio, Apollo's owners
Contact UsE-mail
Canine Companions
[email protected]
Phone Us
(866) 438-8759
+1 (973) 875-5016
Via the Web Site


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IRVINE, Calif., Oct. 9, 2012 /PRNewswire/ -- AtheroNova Inc. (OTCBB: AHRO) ("AtheroNova"), a biotech company focused on the research and development of compounds to regress atherosclerotic plaque announced today that the Company is supporting an additional preclinical study to expand the uses of compounds under the company's pending patents. The study is being conducted at UCLA's The David Geffen School of Medicine on a contract basis.
"We are pleased to commence this significant study," stated Thomas W. Gardner, CEO of AtheroNova. "This is a significant achievement for the Company as we work towards our goal of developing innovative new treatments for lipid related diseases."
About AtheroNova
AtheroNova Inc., through its wholly-owned subsidiary, AtheroNova Operations, Inc., is a development-stage biotechnology company targeting novel compounds to dissolve or regress atherosclerotic plaque deposits—a thickening of the arteries due to buildup of fat, cholesterol, and other substances. These plaque deposits, which progressively narrow and block the arteries, are the main underlying cause of cardiovascular disease, including heart attack, stroke, and peripheral artery disease (PAD). The Company's most advanced candidate, AHRO-001, works to significantly reduce the incidence and severity of plaque by employing a bile salt to dissolve existing atherosclerotic plaque deposits as well as prevent the formation of new ones. For more information, please visit www.AtheroNova.com.
Forward-Looking Statements
Except for historical information contained herein, the statements in this release are forward-looking and made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Forward-looking statements are inherently unreliable and actual results may differ materially. Examples of forward looking statements in this news release include statements regarding the preclinical studies being conducted for the Company by UCLA and the development of applications for AtheroNova's compounds and the development of applications for AtheroNova's technology. Factors which could cause actual results to differ materially from these forward-looking statements include such factors as significant fluctuations in expenses associated with clinical trials, failure to secure additional financing, the inability to complete regulatory filings with the Food and Drug Administration, the introduction of competing products, or management's ability to attract and maintain qualified personnel necessary for the development and commercialization of its planned products, and other information that may be detailed from time to time in AtheroNova's filings with the United States Securities and Exchange Commission. AtheroNova undertakes no obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.
SOURCE AtheroNova Inc.


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Foot Cozy Heated Slippers
Luxurious, microwavable slippers relieve achy arches.
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Foot Cozy Heated Slippers provide relief from tired, cold, or sore feet. Simply toss these one-size-fits-all slippers into the microwave and enjoy the comfort of an enveloping warmth combined with an aromatherapy blend of cinnamon, clove, and eucalyptus.
Foot Cozy Heated Slippers contain a removable, scented grain insert that absorbs the heat from the microwave and then slowly releases it to warm your feet. Foot Cozys can also be put into the freezer for cold therapy. They are also machine washable. So, sit back, kick your feet up and relax while these heated slippers transform your tired, achy soles into soft, supple feet.
Features & specs
- Toss in the microwave to heat
- Aromatherapy insert is a blend of cinnamon, clove, and eucalyptus
- Freezer-safe for cool therapy
- Machine washable
- Fits women's sizes: 6 - 11
- Fits men's sizes: 5 - 10
- Comes in an attractive carrying case / gift box
Sole Therapy (get it?)
Normally, we give ourselves a little pat on the back when we come up with a clever pun. Unfortunately, "sole therapy" really isn't that clever unless we were a massage store that only offered foot massages. Then, we'd think we were being above-average clever.
OK, on to the sales pitch! As the manufacturer states, Foot Cozys Heated Slippers weren't made for walkin'. These microwave slippers are made for sitting, lounging, relaxing, unwinding, resting, chilling, snoozing, but definitely not for working, slaving, laboring, or toiling. When you return home from a long day of work, toss your Foot Cozy Heated Slippers into the microwave and kick back and relax on your couch. You'll enjoy a combination of soothing warmth and an aromatherapy blend of cinnamon, clove, and eucalyptus (it smells really good, trust us).
Easy to heat using your microwave
To enjoy the radiating heat of the Foot Cozy Slippers, simply put them into the microwave for about twenty seconds. Obviously, don't overheat them, and be sure to test the temperature before putting the heated slippers on your feet.
Aromatherapy insert will calm and relax you
In the bottom of each Foot Cozy Heated Slipper is a grain-filled pouch that includes a blend of cinnamon, clove and eucalyptus. The pouch absorbs and then slowly releases most of the heat generated by the microwave.
Hassle-free maintenance as Foot Cozys are machine washable
There's nothing more annoying than forgetting an item is "hand wash only", accidently throwing it into the washing machine, and subsequently ruining it. That won't happen with your Foot Cozys. Simply remove the grain insert (that's the aromatherapy thing that makes these slippers smell so wonderful) and toss them into the machine. Of course, slippers shouldn't require frequent washing, but it's nice to know it'll be simple and easy should you ever need to wash them.
One size fits all (or most)
The Foot Cozy Heated Slippers fit women's sizes ranging from 6-11 and men's sizes from 5-10. If your shoe size does not fit into that range, you'll probably find the Foot Cozy to be uncomfortable.
Makes a fantastic gift
We realize that any product given to the right person can be a fantastic gift. For instance, a sledgehammer given to your favorite house thief. However, most sledge hammers don't have attractive gift packaging. Fortunately for you gift givers, Foot Cozy Heated Slippers are packaged in a lovely box with magnetic clasps and handle.
This product has been discontinued. Frown face!
Burning Questions: You Ask, We Answer
Want to ask your own Burning Question?
Unfortunately, this product is not currently available for purchase. Therefore, we cannot accept any new burning questions. Sorry!