Benzodiazepine use and risk of incident dementia or cognitive decline

Benzodiazepines are commonly prescribed for the treatment of insomnia and anxiety. Approximately 9-12% of older adults in the United States report to be using benzodiazepines. These medications are associated with deleterious effects such as falls, fractures, and delirium. Furthermore, previous single dose studies have shown that benzodiazepines impair aspects of cognition, such as memory and attention. Some studies suggest that long term use of benzodiazepines do not increase the risk of cognitive decline, but the results are conflicting. Thus,the objective of this research study is to determine whether higher use of benzodiazepines is associated with a higher risk of dementia or more rapid cognitive decline.

The cognitive abilities screening instrument (CASI) was administered every two years to screen for dementia and was used to examine cognitive trajectory. In addition, every two years the  cognitive function, collect demographic characteristics, health behaviors, and health status of patients are examined. Incident dementia and alzheimer’s disease were determined. At the end of the study, 797 participants  (23.2%) developed dementia, and 637 of them developed alzheimer’s disease. The risk of dementia was only slightly higher in people with minimal exposure to benzodiazepines but not with the highest level of exposure. The low risk observed may represent treatment of prodromal symptoms. Overall, this pattern does not support a causal relationship between benzodiazepine use and risk of dementia.

This study was particularly interesting because there has already been several research articles that have found a relationship between benzodiazepines and dementia. Despite that, these researchers still pursued this topic because they observed conflicting results in multiple studies. With this knowledge, patients may feel relieved to find out that benzodiazepines will not cause a decline in cognitive function. Do you think it is important to develop research projects that focus on topics that were addressed in the past? Why or why not?
Gray SL, Dublin S, Yu O, et al. Benzodiazepine use and risk of incident dementia or cognitive decline: a prospective population based study. BMJ. 2016;352:i90

Routine Amoxicillin for Uncomplicated Severe Acute Malnutrition in Children

Approximately 19 million children under the age of 5 worldwide suffer from severe acute malnutrition. This condition contributes greatly to mortality and disease burden among children. In order to reduce the risk of death from severe acute malnutrition, nutritional and medical intervention is required. Furthermore, bacterial infection can complicate cases of severe acute malnutrition, since the risk of infection is high. For this reason, in 1999 the World Health Organization (WHO) recommended the routine use of broad spectrum antibiotics for the management of severe acute malnutrition. More recent statistics show that malnutrition is 4 to 5 times as high as the number before the introduction of standards of treatment. Despite the recent developments, there has been no strong evidence about whether the use of the same medical protocol for community based regimens should be used. Thus, researchers conducted a randomized, double-blind, placebo-controlled trial in Niger to examine the effect of routine amoxicillin use on nutritional recovery in children with severe acute malnutrition.

Overall, 64% of the children enrolled in the study recovered from severe acute malnutrition. However, these results did not significantly indicate that routine provision of amoxicillin was superior to placebo for nutritional recovery in children with uncomplicated severe acute malnutrition. First, Amoxicillin reduced the risk of hospitalization when compared to placebo, but about 53% of children transferred to inpatient care were admitted to the hospital for malnutrition. Next, among hospitalized children, there was no significant differences in mean of stay between the placebo group and intervention group, but both groups recovered at the same times. Despite these findings, researchers were able to conclude that amoxicillin reduced the risk of transfers to inpatient care due to complicated gastroenteritis and showed benefits over short-term weight gain.

From this study, it seems that overall Amoxicillin did not show superiority to placebo treatment. These findings challenge the view that routine antibiotic therapy is always necessary or beneficial for the treatment of severe acute malnutrition. Eliminating the use of Amoxicillin could help simplify the treatment regimen, which would result in increased cost savings associated with drugs, staff, and systems for delivery. In addition, there are multiple factors that can be costly to treat, such infections that result from resistance to antibiotic regimens. I believe that it’s good that these researchers decided to check the treatment guidelines for using amoxicillin, because determining the true value of the regimen and be greatly beneficial for the future treatment of severe acute malnutrition. Do you believe it is important to routinely research established treatment guidelines? Why or why not? Are you aware of any treatment guidelines that have been updated in the past few years?

Isanaka S, Langendorf C, Berthe F et al. Routine Amoxicillin for Uncomplicated Severe Acute Malnutrition in Children. N Engl J Med. 2016; 374:444-453

Effects of Prescription Drug Reduction on Quality of Life in Community Dwelling Patients with Dementia

Due to the rapid aging of Japanese society, community-dwelling medical care has become a social necessity. In this study, researchers focused on patients over 65 years of age with dementia. Approximately 4.62 million Japanese elders over the age of 65 suffer from dementia, and the morbidity rate associated with dementia is 15%. The goal of these researchers is to find methods that allow elderly people, including dementia patients to lead high-quality lives.

Community-dwelling medical care consists primarily of drug therapy. Thus, problems associated with polypharmacy are expected to increase. The use of multiple drugs and diminished cognitive function may cause the elderly to experience problems using drugs appropriately. Patients with six or more drugs have been reported to show a higher incidence of adverse drug reactions than other patients. Japanese researchers decided to study whether drug reduction in community-dwelling dementia patients would change the quality of life and the activities of daily living three to six months after the drug reduction.

Researchers studied 50 community-dwelling patients ages 65 or older, and the number of prescription drugs taken by each patient was reduced by an average of 2.6. In the intervention group with reduction in medications, researchers found that the scores associated with quality of life remained stable and scores related with activities of daily living slightly increased. There were also significant increases in items related to activities of daily living, such as transferring to bed, walking, and bladder control. However, there were worsened scores for anxiety/depression questions. This may have been due to the reduction of use of benzodiazepines.

Since there were results that were associated with an increase in activities of daily life, I believe that it would be a good idea to conduct more research on drug reduction. It would be interesting to see if other studies had stronger evidence about the benefits of drug reduction. In addition, I think it would be a good idea to learn about when drug reduction may be appropriate in a clinical setting. What is your opinion about drug reduction? Do you believe that this is an important topic that must be researched?

Sakakibara M, Igarashi A, Yoshimasa T et al. Effects of Prescription Drug Reduction on Quality of Life in Community-Dwelling Patients with Dementia. J Pharm Pharm Sci. 2016;18(5): 705-712

Intervention of Inflammation and Cancer by Active Ingredients of Traditional Chinese Medicine

There has been a large amount of evidence showing that inflammation and cancer are strongly related. As a result, anti-inflammatory agents have been investigated for cancer prevention and treatment, including non-steroidal anti-inflammatory drugs (NSAIDs) and traditional Chinese medicine. Traditional Chinese medicine contains a wide range of biologically active substances, such as alkaloid, polysaccharides, quinones, and more. Several active ingredients in this medicine have been reported to inhibit inflammation, activate inflammatory immune response, and/or inhibit cancer cell proliferation and tumor growth.

Researchers from the College of Pharmacy in Ji Nan University examined the main components of traditional Chinese medicine. Multiple mechanisms of pathways of active ingredients in Chinese medicine were studied. The researchers reported thirteen active ingredients that showed anti-inflammatory and anti-tumor effects, and identified seven classes of ingredients that possibly have anti-inflammatory and anticancer mechanisms. Many ingredients have exhibited effects in suppressing inflammation, preventing tumorigenesis, and controlling tumor growth. However, the target inflammatory factors and the appropriate dosing for control inflammation and strengthen immune surveillance are still unclear.

The research on anti-inflammatory and anti-tumor functions of traditional Chinese medicine compounds is limited to only individual chemical constituents. However, traditional medicine has a combination of many active ingredients that can have synergistic effects. Therefore, researchers believe that future studies should examine whether and how synergistic, additive, and antagonistic effects of multiple ingredients of traditional medicine contribute to the anti-inflammatory and anti-tumor functions.

Since I have limited knowledge about traditional Chinese medicine, I find it fascinating that there are multiple active ingredients that can have anti-inflammatory and anti-tumor functions. I have personally used traditional Chinese medication when I was experiencing a common cold, and it helped relieve my symptoms. Thus, I think it is a great idea to study how these traditional medications work, because there are many benefits associated with these medicines. Many Chinese people rely on these traditional medicines, but in the United States it is uncommon to see traditional Chinese medicine sold.

Do you think it is important to research natural medications? Why or why not? Also, if the use of traditional Chinese medicines became more well-known, do you think this treatment will have a large impact in the United States?

Huang YH, Cai TG, Xia X et al. Research Advances in the Intervention of Inflammation and Cancer by Active Ingredients of Traditional Chinese Medicine. J Pharm Pharm Sci. 2016;19(1):114 – 126

Use of Erythropoietin and Darbepoetin in Improving Brain Development in Premature Infants

Infants born with an extremely low birth rate have the potential to develop neurodevelopmental disabilities, such as cerebral palsy (CP), mental disabilities, and learning and attention deficits during school age. As of today, successful neuroprotective interventions have yet to be developed, but a group of scientists have found that two drugs, erythropoietin and darbepoetin, have a strong potential to have neuroprotective effects in infants.

Erythropoietin and darbepoetin are in a class of drugs called erythropoiesis stimulating agents (ESAs), which have been used clinically over 20 years to help stimulate red cell production. Erythropoietin stimulates red blood cell production in adults who have anemia attributable to end-stage renal disease or cancer. Darbepoetin is a biologically modified long-acting ESA that allows dosing every 1 to  4 weeks due to the increased half-life of the drug. Darbepoetin is also used for adults with anemia attributable to end-stage renal disease or cancer. In addition, darbepoetin was shown to have a similar half-life in infants. Premature infants also lack the ability to make new red blood cells so they often need frequent blood transfusions to replace blood taken for lab tests. However, use of erythropoiesis stimulating agents are shown to decrease the number of blood transfusions in premature infants.

In this research study, scientists performed a randomized, masked, and multicenter study comparing erythropoietin, darbepoetin, and placebo given through 35 weeks post conceptual age, with transfusions administered according to protocol. The surviving infants were evaluated at 3.5 and 4 years of age, and the primary outcome was the infant’s composite cognitive score. Assessments of full-scale IQ, general language, and overall measure of executive function, on the basis of tests evaluating inhibitory control and spatial working memory, were conducted.

Rather gathering data, scientists would that the infants randomized to receive the ESAs had better cognitive outcomes compared with placebo recipients at 3.5 and 4 years of age. Specifically, they scored about 12 points higher on average on IQ tests than the untreated infants, but about 10 points lower than the normal weight infants. Furthermore, on tests measuring memory and impulsive behavior, the treated infants had similar results as the infants born at normal weight.

This study mostly examined white and hispanic infants, so larger studies that include more diverse patient populations are needed to determine whether ESAs can help a broader range of infants. Thus, it is still too soon to recommend the medicines for treating developmental delays. However, treatment for medical problems and developmental delays due to prematurity has not kept pace, so this particular finding was significant.

I am glad to see that there are steps being taken to study the developmental delays in premature infants. Possibly in the future, parents can be relieved that their premature infants will be able to avoid potential developmental issues. However, in the future, I hope that there will be more research focusing on other developmental issues associated with premature birth. Do you believe that this finding will have a large impact in the future? What other areas of study related to premature birth do you think researchers should focus on in the future?

Source:

Ohls, R. K., Cannon, D. C., Phillips, J., et al. Preschool Assessment of Preterm Infants Treated With Darbepoetin and Erythropoietin. Pediatrics. 2016

Drug Dosing and Pharmacokinetics in Children With Obesity

A sixth of children in the United States are affected by obesity. When a person is obese, their body composition and physiology is altered, which results in a change in effects associated with drug dosing and pharmacokinetics. Thus, the effect of  drug disposition on obesity can possibly lead to therapeutic failure or toxic side effects. Although this fact is well known, there is little information known about the effect of childhood obesity of drug pharmacokinetics. Currently, there is no comprehensive, evidence based understanding of the effect of childhood obesity of drug pharmacokinetics. Thus, researchers conducted a systematic review to find studies in the last 40 years that provided evidence of the effect of obesity on drug disposition in children. They searched literature databases to find if any studies contained data on drug clearance, volume of distribution, or drug concentration in obese children.

Researchers were able to discover 20 studies in the last 40 years that met the inclusion criteria and contained pharmacokinetic data for 21 drugs. Out of these studies, 11 out of 17 drugs had clinically significant pharmacokinetic alterations observed in children with obesity. In addition, for 5 out of 13 drugs studies showed that pharmacokinetic alterations resulted in substantial differences in exposure between children with and without obesity. Overall, studies indicated important obesity-related changes in drug pharmacokinetics. However, there were many limitations associated with these studies. For example, the majority of studies included small numbers of children. Furthermore, many drugs that were studies are not commonly prescribed drugs. There was no data for several important drug classes where obesity-related toxic overdosing or subtherapeutic underdosing may have been previously observed in adults, such as in acute care, cardiovascular, and anesthesia.

After reviewing these articles, researchers concluded that the relative information available about the drug pharmacokinetics of children who are obese is concerning, because it is so limited. To account for physiological and pharmacologic factors, some physicians adjust weight-based dosing using various metrics of body size, such as ideal body weight. However, this dosing strategy is largely based on theory or extrapolated data from studies in adults. Some analyses have identified that these dosing strategies may give false predictions of clearance and other pharmacokinetic values. To address this issue, researchers are currently collaborating with the National Institute of Child Health and Human Development in a systematic review of acute care and commonly used drugs to develop a pharmacokinetic database for obese children. As a result, data generated from this review will be utilized to make appropriate dosing recommendations for obese children. For future studies about pharmacokinetics in obese children, researchers hope to focus on including drugs if different therapeutic drug classes, based on drug use, medical need, and expected pharmacokinetic alterations in obesity (based on adult studies).

After reviewing this article, I was surprised to find that there were very few studies published about the pharmacokinetic factors of drugs in obese children. Since there are many children who are obese in the United States, I believe it is important to discover the pharmacokinetic parameters of drugs in obese children. With more information available, pharmacists and physicians will be able to better treat these children. Did you find this article surprising? Why or why not? Do you have any thoughts on why there have not been many studies published about childhood obesity and drug pharmacokinetics?

 

Harskamp-van Ginkel MW, Hill KD, Becker KC, et al. Drug Dosing and Pharmacokinetics in Children With Obesity: A Systematic Review. JAMA Pediatr. 2015;169(7):678-685.

 

Use of Ketamine for the Treatment of Severe Depression

Traditional antidepressants and mood stabilizers available on the market often take weeks or months to work. Thus, since 2006 researchers have been studying how ketamine can reverse the type of severe depression that traditional antidepressants are unable to treat. Ketamine is a staple anesthetic in the emergency rooms that are regularly used for children with broken bones or dislocated shoulders. This drug is also used in burn centers and veterinary medicine. In popular culture, ketamine known as a date-rape drug that can quickly numb and render someone immobile.

There are several uses of ketamine, and researchers are finding that it produces a rapid and robust antidepressant effect that can be a quick end to suicidal thinking. For this reason, experts are calling this discovery the “most significant advance in mental health in more than half a century”. A study in the Journal of American Medical Association reported that drugs in a leading class of antidepressants were no better than placebos for most depression. However, with ketamine, one physician reported a 75% effective response rate for treating patients with depression. Ketamine has worked for patients who have spent years switching between antidepressants, mood stabilizers, and other therapies. A significant number of people who do not respond to antidepressants may try cognitive behavior therapy, electroshock therapy, and transcranial stimulation. Instead of going through with these alternative treatments, researchers are hoping that use of ketamine will benefit these patients more.

Currently, patients who seek out ketamine treatment go through six IV drips over a two week period. The dose is about a 10th of the amount used in anesthesia, and the drug takes effect within minutes or hours. So far, there are no signs of addiction involved with this treatment. However, there are several concerns involved with the use of ketamine for the treatment of depression. The relief involved with ketamine is only temporary. Studies have shown that relapse usually occurs a week after an infusion, which is causing patients to seek booster infusions. Low doses of ketamine have also been reported to cause intense hallucinations. Researchers are also concerned about the many unknowns, such as the effect on heart rate and blood pressure and the long-term benefits of the usage of ketamine. In addition there is currently no registry for tracking the number of patients being treated with ketamine for depression, the frequency of treatments, dosage levels, follow up care, and adverse effects. Thus, more standardization is needed for this treatment. Finally, patients who are currently receiving ketamine treatment usually go to anesthesiologists, who are not primarily responsible for treating mental health, which is the field of expertise of psychiatrists. If ketamine treatment becomes more widespread, the relationship between anesthesiologists and psychiatrists may change.

I believe that researching the use of ketamine treatment will be beneficial in the future, because the effectiveness of current treatments for depression are not as effective. However, based on the current information, I agree that there needs to be more research done on ketamine use for depression, especially since the relief is only temporary with ketamine. If Ketamine is becoming more well known as a treatment for depression, there must be more standardization involved. Do you think there any other possible risks of the usage of ketamine for severe depression? Furthermore, if IV administration for ketamine will still continue in the future, how do you think this will affect the role and relationship of anesthesiologists and psychiatrists?

Way, M. L. Ketamine Infusion for the Treatment of Depression. Am J Psychiatry. 2015;10:6-8. 

The Needle-free Administration of Anesthesia

Approximately 5-8% of people in the United States are afraid of dentists. This may be due to the fact that dental procedures such as root canals, cavity fillings, and teeth pulling are painful and invasive. In order to alleviate this pain, dentists administer anesthesia through needles before they begin a procedure. Although, many patients also fear these injections, causing them to cancel appointments or avoid dental care.

A team at the University of Sao Paulo is Brazil wanted to investigate an alternative method of administering anesthetics into the body more effectively, instead of relying on the needle administration of anesthesia. During the experiments, the anesthetic hydrogels prilocaine hydrochloride (PCL) and lidocaine hydrochloride (LCL) were combined. These anesthetic hydrogels were applied on the mouth lining of a pig. Then, the researchers found that applying a tiny electric current (a process called iontophoresis) made the anesthetics more effective. With the addition of the electric current, the PCL entered the body more effectively, and the permeation of anesthetic through the mouth increased 12-fold. This significant finding has lead researchers to develop an iontophoretic device to use specifically in the mouth. They plan to use this device to conduct preclinical trials.

Although this study was focused on dentistry anesthesia, the findings can also apply to other areas of care, such as cancer treatment. The same research group has been working on developing a method to deliver drugs for the treatment of skin and eye diseases. It is difficult to deliver drugs to the eyes and skin, but with this recent discovery these scientists can study whether iontophoretic devices may be able to improve drug delivery.

I believe that delivering anesthesia without the use of the needle is a fascinating discovery. An estimated 1 in 5 people have trypanophobia (the fear of needles). Having this fear prevents patients from recieving care, because they avoid procedures involving needles, such has dental appointments or vaccinations. If this concept of delivering anesthesia via iontophoretic device is successful with other drugs, then patients with trypanophobia will be more willing to come to appointments and receive treatment. This novel route of administration will give patients access to effective and safe dental treatments. Going with needle-free administration can also decrease costs and decrease the risks of intoxication and contamination associated with needles. Since there are multiple benefits that can come from this innovative research, I think it’s a great idea that scientists are pursuing this idea.

Do you think using iontophoresis in drug delivery could have a great impact on future medical procedures?

Camila Cubayachi et al. Needle-free buccal anesthesia using iontophoresis and amino amide salts combined in a mucoadhesive formulation. Colloids Surf B Biointerfaces 2015; 136:1193-1201