L-Carnitine Ameliorates L-Asparaginase-Induced Acute Liver Toxicity in Steatotic Rat Livers

Acute lymphoblastic leukemia (ALL) is a cancer of leukocytes that is responsible for thousands of deaths in the US each year. Although pediatric patients are the most common developers of ALL, nearly 80% of ALL deaths occur in adult patients. This is at least in part because of differential treatment of ALL in pediatrics and adults. Pediatric bodies are more adaptive, and can often withstand stronger chemotherapy than adult patients. L-asparaginase is a chemotherapeutic which is often used in combination therapy to treat ALL. However, it is largely avoided in adult patients due to its adverse effect profile, which includes hypersensitivity, clotting disorders, pancreatitis, and hepatotoxicity.

L-carnitine is an amino acid derivative which is used for transport of fatty acids across the mitochondrial membrane, where they can then be oxidized for energy. It has been implicated in reducing drug-induced toxicity from a number of other drugs, including HIV medications. A study done in Germany investigated the effects of L-carnitine administration on liver damage in diet-induced liver steatosis in rats treated with asparaginase.

Liver steatosis was induced in rats by providing a carbohydrate enriched and fat free diet, producing mild-to-moderate (30-40%) steatosis in the liver. Rats were then anesthetized and their livers were harvested and reperfused in vitro for 120 minutes. L-asparaginase was the added to the reperfusion. Hepatic effluent was collected at 5, 15, 30, 45, 60, 75, 90, 105, and 120 min post-reperfusion and analyzed for biomarkers of liver toxicity (AST, GLDH, and LDH). On the second day, the perfusion was moved to fresh medium containing various amounts of asparaginase and L-carnitine. Remarkably, biomarkers of liver damage decreased for all tissue treated with L-carnitine.

Adverse effects associated with chemotherapeutics are one of the major limitations of drug-based cancer treatments. As chemotherapeutics are literally designed to kill cells (albeit, hopefully only cancerous ones), reduction in these adverse effects via only modification of the drug may risk losing anti-cancer efficacy. Therefore, pre-treatments are an important option for maintaining optimal chemotherapeutic efficacy while mitigating adverse effects in the treatment of cancer patients. Therefore, identification of compounds which may have the potential to reduce or reverse adverse effects is critical in optimizing cancer therapy. With more evidence, L-carnitine may be able to be used in human clinical trials to rescue hepatotoxic effects from ALL administration.

Do you guys think that using more drugs to rescue the adverse effects of another drug is a viable therapeutic approach? Or rather, should we invest our research in producing de novo drugs with an intrinsic reduction in adverse effects? What are the benefits and limitations of each approach?

Roesmann A, Afify M, Panse J, et al. L-carnitine ameliorates L-asparaginase-induced acute liver toxicity in steatotic rat livers. Chemotherapy. 2013;59(3):167-75.

Pharmacist-led feedback workshops increase appropriate prescribing of antimicrobials

Inappropriate antimicrobial prescribing is a common occurrence in hospitals, and may lead to increased patient morbidity. Not only does this produce deleterious effects for individual patients, but it also contributes to the growing global health problem of anti-microbial resistance. Research has indicated that most inappropriate antimicrobial prescriptions are written by junior doctors in their first 2 years of practice. Therefore, initiatives targeting these junior doctors and educating them on proper antimicrobial use may increase individual health outcomes and help alleviate the problem of antimicrobial resistance.

A European study aimed to reduce inappropriate antimicrobial prescriptions by targeting junior doctors with intervention provided by pharmacists. This was done via data collection on junior doctors’ prescribing habits, followed by feedback workshops aimed at addressing knowledge gaps, discussing social and behavioral aspects of prescribing, and encouraging reflection. 29 doctors were recruited for the study, 14 were randomized to the intervention group and 15 were randomized to the control group. The normalized rate of suboptimal prescribing was significantly lower for the intervention group than the control group. Analysis showed that pharmacist intervention increased junior doctors’ awareness of their prescribing behavior.

This article was a prime example of how pharmacist intervention in drug therapy can improve health outcomes, both on an individual and public health scale. Often, I feel doctors hesitate to consult pharmacists about drug therapy unless the drug being provided is a particularly complex or new drug (such as chemotherapy or psychiatric drugs). Something as commonplace as antimicrobials is not typically seen as being a serious enough drug to warrant pharmacist opinion. However, it is clear that by including pharmacists in the decision-making process on antimicrobial prescriptions and allowing them to educate prescribers, better health outcomes can be achieved. How do you think pharmacists can become more involved in the decision-making process and education for prescribing more commonplace medications, such as antibiotics, antivirals, etc.? Especially in an outpatient setting where pharmacists are often not on-site?

McLellan L, Dornan T, Newton P, et al. Pharmacist-led feedback workshops increase appropriate prescribing of antimicrobials. J Antimicrob Chemother. pii: dkv482. [published 2016 Feb 24]

High-Density Lipoproteins (HDL) – Nature’s Multi-Functional Nanoparticles

HDL, or high-density lipoproteins, is commonly known clinically as “good cholesterol” because of its cardiovascular protective effects through its anti-inflammatory and antioxidant properties. HDL is also involved in transport of endogenous biomolecules, such as proteins, vitamins, hormones, and miRNA, to specific tissues. Because of this, HDL is now a candidate for an endogenous nanoparticle-based drug delivery system.

There are several attributes of HDL which make it a good candidate for drug delivery when compared to other synthetic nanoparticle delivery systems. Specifically, its small size, high tolerability in humans, long half-life, and tissue specificity make it, at least in theory, a very effective drug delivery system.

The major component of HDL is a protein called ApoA1, and recombinant Apo proteins have already been incorporated into HDL in an attempt at specific drug delivery. A number of these recombinant HDL products have advanced to clinical trials. Typical safety concerns include slight liver toxicity and elevation of serum concentrations of liver transaminases (enzymes). This is due to the fact that lipids are largely metabolized in the liver. However, these side effects are typically not major or severe.

Using HDL as drug nanocarriers is particularly intriguing from a clinical perspective because they offer so much specificity in target organ transport. Specifically, HDL may be used in delivery to cardiovascular, hepatic, tumor-containing, and immune organs and tissue. HDL already has an intrinsic ability to target atherosclerotic lesions, giving it high specificity for damaged and diseased CV tissue. Its metabolism in the liver also makes it a good candidate for delivery to damaged hepatic tissue. Because of HDL’s long half-life, it will circulate in the blood and tend to accumulate near tumor cells due to increased angiogenesis, making it a viable delivery system for anti-cancer drugs. Finally, HDL interactions with immune cells make it a good candidate for drug targeting the immune system.

I thoroughly enjoyed reading this review because it was able to merge analytical chemistry (nanotechnology), physiology (HDL function), pharmaceutics (drug delivery), and medicinal chemistry (recombinant HDL complexes) to create a novel drug delivery system. I really enjoy when the elegance of translational science is able to be applied in a clinically relevant way. What do you guys think – is HDL as a nanocarrier a viable option for drug delivery systems? What do you think would be the pros and cons of such a system?

Kuai R, Li D, Chen YE, et al. High-density lipoproteins (HDL) – nature’s multi-functional nanoparticles. ACS Nano. [published 18 Feb 2016]

Are Genetic Tests for Atherosclerosis Ready for Routine Clinical Use?

Pharmacogenetics and personalized medicine is a relatively new field of research, and as of yet has stayed mostly in the realm of pharmaceutical science research, not yet moving into clinical guidelines and practice. In a review done by Brighman and Women’s Hospital of Boston, researchers investigated 3 areas of pharmacogenetics associated with prevention, diagnosis, and treatment of atherosclerosis. They assessed each area on how effective it would be to incorporate genetic information into clinical guidelines and practice, as well as if more research may need to be done to make an effective incorporation.

The 3 areas investigated included: 1) familial hypercholesterolemia (FH), 2) prediction of cardiovascular (CV) risk, and 3) genetic interactions with treatment.

FH is caused by a dominant autosomal genetic defects in low-density lipoprotein (LDL) cholesterol, or bad cholesterol, metabolism which produces unusually high amounts of LDL. Because of this genetic, determining HL status of patients via genetic analysis represents a strong case for incorporating genetic analysis into clinical care.

CV risk presents a slightly less convincing case for pharmacogenetic incorporation into clinical practice, as the risk factors for CV events are numerous, varied, and compound with many comorbidities, and not strongly genetically defined. However, with more research, this may create a stronger case for using pharmacogenetics in clinical practice.

Finally, genetic interactions with treatment has large potential utility to improve efficacy and safety of drug therapy and treatment, both in terms of pharmacodynamics and pharmacokinetics. Factors causing variance are less numerous in treatment than in CV risk, so implementing genetic information to guide clinical prescription and optimization presents an even stronger case than CV risk. It is, however, limited by the necessity to identify candidate genes which vary safety and efficacy of treatment therapies. Additional research to identify these genes will continue to increase the case to use pharmacogenetics in determining optimal treatment options.

I think that this is a good article in that it very clearly makes the connection between the research and clinical components of pharmacogenetic testing. It questions how effective pharmacogenetics would be in actually adjusting clinical practice for a number of areas for this disease state. My question is: which area analyzed by this review do you think will have the biggest impact on the emerging field of personalized medicine, and why do you believe so?

Paynter NP, Ridker PM, Chasman DI. Are genetic tests for atherosclerosis ready for routine clinical use? Circ Res. 2016;118(4):607-19.

Improved Pregnancy Outcomes with Increasing Antiretroviral Coverage in South Africa

Since 2005, many sub Saharan African countries have made it a priority to provide antiretroviral therapy for HIV positive pregnant women with the intent of promoting maternal health and reducing mother-to-child transmission of HIV. These therapies include longer-duration therapy as well as multi-drug combinations. Recently (in 2014), the World Health Organization changed its recommendation to initiating triple-antiretroviral therapy (Tenofovir, Emtricitabine, and Efavirenz) for all HIV positive women, regardless of pregnancy, in order to further improve women’s health as well as ensure therapy commencing from the start of any possible pregnancy. This research group conducted a cross-sectional study analyzing birth data from Durban, South Africa in order to determine the effect of HIV drug regimens on overall pregnancy outcomes.

Researchers compared data collected from 2011 and 2014 in order to determine the effect of the changed WHO recommendation for HIV positive women. Researchers found an overall increase in the percentage of women receiving triple antiretroviral therapy and saw an overall reduction in stillbirths for HIV positive women. They also found, however, that unregistered pregnancy and unregistered HIV positive status remained significant risk factors for stillbirth, preterm birth, and low birth weight.

I think that this article showcases very well that although we are able to implement effective drug therapy treatments which can lead to improved health outcomes, it still remains a challenge to adequately screen and diagnose health conditions. This is especially true in under-served populations, such as sub-Saharan Africa. No matter how good the triple-antiretroviral therapy is, it is useless to treat women who are unregistered as HIV positive.

As pharmacists, however, we don’t have the ability to either diagnose or (in most cases) prescribe medications. I submit that this does not mean that we have no responsibility for ensuring that our patients receive adequate diagnoses and appropriate prescriptions for their disease states and conditions. While we can currently screen for some disease states, such as hypertension, there are still many conditions which are beyond our power to screen for. My question is: what are some disease states that pharmacists could feasibly change community practice in order to screen patients for, and what would we as pharmacists need to do in order to gain the resources and legislation necessary to facilitate these screenings?

Moodley T, Moodley D, Sebitloane M, et al. Improved pregnancy outcomes with increasing antiretroviral coverage in South Africa. BMC Pregnancy Childbirth. 2016;16(1):35.

The IGNITE Network: A Model for Genomic Medicine Implementation

Pharmacogenomics is an up-and-coming field which has a lot of potential to contribute to personalized medicine and optimizing drug therapy outcomes for patients. However, since pharmacogenetics is such a new field, patients, clinicians, and researchers alike are attempting to understand how to gather and use genomic data in order to optimize clinical decision-making, prescribing, and treating.

The National Institutes of Health funded the IGNITE (Implementing GeNomics In pracTicE) Network in 2013 to suport the development and investigation of genomic-based medicine. The goals of IGNITE are to 1) expand genomic medicine implementation efforts, 2) develop collaborative projects in genomic medicine, 3) contribute to evidence-based medicine outcomes using genomic information, and 4) define and share the best practices of genomic medicine. IGNITE consists of 6 members at Duke University, Icahn School of Medicine at Mount Sinai, Indiana University, University of Florida, University of Maryland, and Vanderbilt University, with the Coordinating Center located at University of Pennsylvania. Each center conducts collaborative research on family health history, diabetes, chronic kidney disease, underserved health populations, cancer, and other disease states, all with the goal of determining how genetic libraries and pharmacogenomics can fit into diagnosing, prescribing, and achieving optimal health outcomes.

I am personally very interested in pharmacogenomics and love to see this new field getting national funding which is being participated in by such prestigious universities around the country. However, I wonder if other people feel differently. Do others feel that too much emphasis in modern medicine being placed on the role of pharmacogenomics? Are we pouring too much money into a new field which hasn’t had adequate time to prove its value in informing clinical decision-making? Some people don’t even want to have their genome sequenced (we learned that in Drug Development with Dr. Empey the other week) – are we pouring money into something that most patients won’t even want to participate in? Or do we all believe that sometime in the not-so-distant future we will all have our genomes sequenced for reference at each PCP check-up visit?

Weitzel, KW, Alexander M, Bernhardt BA, et al. The IGNITE network: a model for genomic medicine implementation and research. BMC Med Genomics. 2016;9(1):1.

HIV Interventions in African American Churches

African Americans account for nearly 50% of new HIV cases in America each year. They also tend to experience delayed diagnosis of the infection, meaning that they enter therapy later and are more likely to die from AIDS sooner than white patients. This is because of a higher prevalence of lack of access to health insurance among the African American population, for a variety of reasons. Authors of this article sought to find an appropriate outlet for increasing the availability of HIV education and testing for the African American population, specifically focusing in on the Black Church.

The Black Church has always had a strong influence in promoting social change in African American populations, and it experiences strong and stable attendance from African Americans across the country. Many church leaders support increasing availability of HIV testing for its members, but factors such as lack of HIV training, resources, controversy over condom use, premarital sex, and homosexual relationships, and HIV stigma have largely prevented this from being an effective avenue for intervention and prevention.

This study reports on the half-way point findings of the Taking It to the Pews initiative, a 12 month program aiming to increase HIV testing rates among African American church members and community members through church-planned outreach events. They attempted to do so by (1) stressing the importance of HIV testing, (2) reducing stigma associated with AIDS and HIV testing, and (3) increasing availability and access to testing.

4 churches (2 intervention and 2 control) were assessed in the Kansas City area. The odds of members of the intervention churches reporting receipt of an HIV test at the 6 month follow-up was 2.6 times greater than the control church members. Among the subset of church members who hadn’t received an HIV test within the 6 months before the survey, members of intervention churches were 3.3 times more likely to get tested. 47% of intervention church members versus 28% of control church members had received testing at the 6 month follow-up.

I think this article brings up a lot of great points about our role as pharmacists. Does our role in promoting healthcare stop when we leave the pharmacy at the end of the work day, or do we have a responsibility to start initiatives such as this in our community and other places that we may hold leadership initiatives? What are some appropriate community outlets for us to raise health awareness? Additionally, how can we as pharmacists contribute to removing the stigma that goes along with discussing, educating, and treating diseases such as HIV?

 

Berkeley-Patton J, Bowe-Thompson T, Bradley-Ewing A, et al. Taking it to the pews: a CBPR-guided HIV awareness and screening project with black churches. AIDS Educ Prev. 2010;22(3):218-37.

Pharmacogenomics & A New Target Therapy for Schizophrenia

Schizophrenia is one of the earliest recorded and least understood mental illness that we face today. Schizophrenia is a chronic and severe mental disorder characterized by hallucinations, delusions, movement disorders, and withdrawal from others. The current treatments for schizophrenia are limited, and they tend to treat only the psychotic symptoms of the disease. Targeting the cause of the disease has been – until now – impossible, as much remains unknown about the pathology of schizophrenia. While it has been known that schizophrenic symptoms are associated with excessive synaptic pruning (removal of synapses in the brain during adolescence and young adulthood) – and this correlates to the typical interval of onset of the disease during adolescence and young adulthood – the exact mechanism of how the disease develops has remained a mystery until now.

A collaborative research team from Broad Institute, Harvard Medical School, and Boston Children’s Hospital has recently published results that suggest a genetic basis for the onset of schizophrenia symptoms. Their genetic analysis of almost 65 000 people points to overexpression of the complement component 4 (C4) gene in the expression of Alzheimer’s disease. Complement protein genes can be present in varying alleles, and different alleles (DNA) directly affect the overall expression level (mRNA) of the gene. In other words, the variation of the genetic sequence of the gene directly impacts the amount of protein produced.

Complement proteins have a well-established role in the immune system, where they tag foreign pathogens for destruction by phagocytic immune cells. However, their role in neurology is an entirely novel discovery. Researchers were able to localize the C4 proteins to neural synapses in humans, and proved that in mice they contributed to the synaptic pruning process during postnatal development.

Because of this study, a molecular basis of schizophrenia as a disease is now in the works. By understanding the molecular cause of the disease, researchers will be better able to identify therapeutic targets and develop new pharmaceutics and other treatments which go after the cause and onset of disease, rather than just managing the symptoms.

This article made me think about the emerging role of genetics in healthcare. By understanding the genetic expression associated with schizophrenia, researchers will be better able to pinpoint the molecular basis of the disease and create better therapeutics which target the cause of the disease, instead of just the symptoms. There is a new intersection of basic science (genetics) and therapeutics (pharmacy and medicine) that is entirely new to science and healthcare. This makes me wonder – should we be focusing more on basic science, such as genetics, during our professional curriculum so that we will be able to both understand and contribute to emerging healthcare technologies, such as pharmacogenetics? Or is that role reserved for PhDs?

Additionally, what other types of disease states are there out there for which pharmacogenetic analysis would help us to determine the cause, and can we create better medicines that target the cause rather than just the symptoms? One that I think of are benzodiazepines, which treat only the physical symptoms of anxiety instead of the psycho-cognitive causes.

Sekar A, Bialas AR, de Rivera H, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016;530;177–183.