Interaction Between Corticosteroids and Muscarinic Antagonists in Human Airways

There is currently clinical evidence for combining long-acting anti-muscarinic agents with inhaled corticosteroids for treatment of asthma. The interaction of these two medications, however, has not been researched. This study looked at beclomethasone, an inhaled corticosteroid, and glycopyrronium, a long-acting anti-muscarinic agent on human airway smooth muscle tone. To obtain the human airway smooth muscle, portions of lungs undergoing lobectomy for lung cancer were cooled, dissected, and stored. The human airway smooth muscle was tested with beclomethasone alone and also in combination with glycopyrronium. The bronchorelaxant effect of the medications was measured on the tissues.

The results of this study showed that the administration of beclomethasone and glycopyrronium caused significant relaxation of bronchi and bronchioles when the tissue was sensitized (pre-contracted with histamine). The effect was dependent by the activation of a G-protein and subsequent kinase cascade. In non-sensitized bronchi, however, the effects of the medications were not synergistic. Therefore, it was concluded that synergistic interaction occurred with an increase of cAMP concentrations involved with the kinase cascade.

The research of this study not only provides information on the interaction of two medications, but also on the efficacy of utilizing them together to treat asthma. This study is interesting to me because the researchers decided to delve deeper into the pharmacologic reason for using the two types of medications together. By understanding how these medications work together, pharmacists and other healthcare practitioners can better dose these medications and use them to effectively treat asthma and similar conditions.

Cazzola M, Calzetta L, Rogliani P, et al. Interaction between corticosteroids and muscarinic antagonists in human airways. Pulm Pharmacol Ther. 2016;36:1-9.

https://www.clinicalkey.com/#!/content/journal/1-s2.0-S1094553915300158

Deprescribing Potentially Inappropriate Preventive Cardiovascular Medication

It is recommended for patients with low cardiovascular disease (CVD) risk that lifestyle changes be made so as not to require antihypertensive or hyperlipidemia treatment. It can be inappropriate for low CVD risk patients to be prescribed such medications because the risks outweigh the benefits. This study evaluated the barriers and enablers with patients and practitioners when discussing deprescribing cardiovascular medications. The study looked at 9 general practices that had upcoming deprescribing consultations. Conversations between patient and physician were recorded and themes present in the conversations were classified into 6 categories of barriers and enablers: appropriateness, fear, process, influences, dislike, and other.

Out of the 49 consultations studied, 42 resulted in deprescribing of the cardiovascular medication. The results showed that barriers were more frequently brought up by patients in the consultations. Patients and practitioners cited the same amount of enablers. In many of the consultations, the practitioner mentioned an enabler after a patient would mention a barrier. Overall, the study found that patients felt positively about deprescribing medications and felt safe as long as follow-up care was reassured.

This is an interesting study because it focused on how an interaction between a patient and a healthcare provider can affect the outcome of the consultation. Patients may not realize at first that their medications are not necessary because they trust past medical opinions they have been given. However by using “enablers” a practitioner can eliminate the fears of discontinuing medications. This study supports a patient-centered interaction because the barriers and enablers that the patient brings up are just as important as those brought up by the practitioner. I think a learning point from this study is to listen to what concerns a patient has and respond to them in order to take the appropriate action in a patient consultation.

Luymes CH, van der Kleij RM, Poortvliet RKE, et al. Deprescribing potentially inappropriate preventive cardiovascular medication: barriers and enablers for patients and general practitioners. Ann Pharmacother. doi:10.1177/1060028016637181 (published 3 March 2016).

http://aop.sagepub.com/content/early/2016/03/02/1060028016637181.full

Association of Statin Therapy and Risks of Cholethiasis Biliary Tract Diseases, and Gallbladder Procedures: Retrospective Cohort Analysis of a US Population

Cholelithiasis, or gallstones, is a condition that can lead to morbidity. About 80-90% of cholethiasis cases are classified as cholesterol stones. This means that they are the result of bile that is highly concentrated with cholesterol. Because statins decrease cholesterol biosynthesis, they can decrease cholesterol concentration in bile. In order to study cholethiasis in stain users versus nonusers, a retrospective cohort study was conducted using data from the San Antonio Tricare health system from 2003 until 2012. The participants ranged from 30 to 85 years old and were studied longitudinally.  The outcome measures consisted of development of cholethiasis, biliary tract disease, or gallbladder procedures.

The results of the first analysis in this study found no significant association between statin use and gallbladder disorders, specifically cholethiasis. The secondary analysis of the study found a small reduction of cholethiasis among stating users. However, this may have resulted from confounding variables in the secondary analysis.

When I first started reading this article, it made a lot of sense to me that a cholesterol medication would help with gallstones that were caused by high levels of cholesterol. However, the results of this study completely opposed this hypothesis. The authors note that further studies should be conducted that look at statin subtypes rather than just the broad class of statins. We learned from the ACC/AHA 2013 Cholesterol Guidelines that there are high, moderate, and low intensity statin therapies. Do you think it is possible that high-intensity statin therapy may have a significant effect on gallstones in comparison to low intensity statin therapies? Considering this study evaluated all statins broadly, I would hypothesize that there would still not be a significant effect if high intensity statins were directly studied. It would be interesting though to see the results of such research.

Martin D, Schmidt R, Mortensen EM, Mansi I. Association of statin therapy and risks of cholelithiasis, biliary tract diseases, and gallbladder procedures: restrospective cohort analysis of a US population. Ann Pharmacother. 2016;50:161-71.

http://aop.sagepub.com/content/50/3/161.full

Ketamine Continuous Infusions in Critically Ill Infants and Children

Ketamine is an NMDA receptor antagonist that has been used in single doses for sedation and adjunct treatment for bronchospasm in children. Though it has been proven effective for these indications, ketamine has only been evaluated in single doses. This review focuses on the use of ketamine in a continuous infusion for pediatric intensive care units and emergency departments. Not only can it be used for the above reasons but it can in addition be used to treat opioid withdrawal because of its antagonism of glutamate at the NMDA receptor.

For this literature review, articles were pulled from MEDLINE, EMBASE, and International Pharmaceutical Abstracts. Overall, 11 case reports and studies of children receiving a continuous infusion of ketamine either in an emergency department or pediatric intensive care unit were used. The results of the review showed that for bronchospasm, continuous infusions can be used for additional treatment for status asthmaticus that has failed other therapies. Such therapy could avoid mechanical ventilation. The results show that it can also be used as adjunct therapy for sedation and opioid withdrawal. Some limitations exist in this study due to the nature of a literature review. One is the use of case studies that show results that are very patient specific and not comparative. More studies should be conducted to compare continuous infusion of ketamine to other alternatives for the indications of interest.

The research in this article is interesting to me because rather it being a direct study, the authors conducted a literature review much like what we do for our drug information questions in POP. This review opened doors for further research by showing the prospect of administering ketamine in a new way. The authors of this study recommended certain doses and titrations for ketamine. Do you think it is appropriate to recommend such dosing with only a literature review? I believe more pharmacokinetic testing and comparative studies need to be conducted before dosing of continuous infusions be established.

Golding CL, Miller JL, Gessouroun MR, Johnson PN. Ketamine continuous infusions in critically ill infants and children. Ann Pharmacother. 2016;50:234-41.

http://aop.sagepub.com/content/50/3/234.full

Cyproheptadine for the Prevention of Postoperative Delirium: A Pilot Study

A common issue after major surgeries is postoperative delirium that manifests as altered levels of consciousness, disruption in cognition, and disruption in perception. As of yet, there is not a set standard prevention of postoperative delirium. This study focused on testing cyproheptadine as a prevention of postoperative delirium. Cyproheptadine is a histamine H1 antagonist and a serotonin antagonist. It is approved for allergic reactions but is used off-label for migraine prophylaxis and serotonin syndrome.

In this randomized, double-blind, placebo-controlled trial, 40 adults who were admitted to an intensive care unit were studied.  After treatment, the Richmond Agitation-Sedation Scale was used to determine level of consciousness. The delirium was measured using the Confusion Assessment Method scale. The results showed that 4 mg tablet of cyproheptadine given every 8 hours lowered the incidence of delirium in comparison to the placebo. Sedation levels were not significantly affected. Severity of delirium was also not decreased by cyproheptadine use. The overall study was limited by small sample size and only measuring the participant’s delirium once daily.

I found this very interesting because it was a novel approach to a common problem. It is surprising to me that nothing has been found for prevention of such a common result of surgery. Since this is just a pilot study, more information needs to still be collected to determine effectiveness of cyproheptadine and its mechanism of action with regards to delirium. As more studies are conducted, cyproheptadine may be more commonly used to prevent postoperative delirium. It is important as future pharmacists to be aware of pilot studies such as this one, as they may develop into significant drug therapy choices.

Mohammadi M, Ahmadi M, Khalili H, et al. Cyproheptadine for the prevention of postoperative delirium: a pilot study. Ann Pharmacother. 2016;50:180-7.

http://aop.sagepub.com/content/50/3/180.full

Innovative New Drugs for Serious Nonlethal Diseases: The Cost to Develop and the Cost to Buy

As research and medicine progresses, many new drugs have been developed to treat a variety of diseases. However, a pressing issue is the cost of the new drugs being produced. Cost of development has been increasing and was noted in the article to be approximately $2.6 billion. This cost is taking a toll on drug development as the number of drugs approved per billion dollars has halved about every 9 years.

In order to decrease the cost of drug development, some changes can be made to the development process. Specifically, using biomarkers instead of clinical end points to determine efficacy in clinical trials would decrease the time and cost of drug development. The FDA has allowed biomarkers (surrogate endpoints) to be used to expedite the process of drug development which has increased the number of drugs for cancer treatment. While this is effective for lowering costs, it is best to be cautious with this approach because biomarkers do not directly translate to clinical end points. It is recommended that multiple biomarkers be used to test multiple effects of a new drug. Other actions can be taken to lower drug cost once it comes to market such as asking caregivers not to endorse certain drugs to lower the prices. The focus, however, is on decreasing cost while trials are still being conducted. This has shown to help with cancer drug development, but if these concepts are applied to other drugs, we may be able to produce more drugs for nonlethal diseases as well.

This article is extremely relevant to what we are currently learning in Drug Development 1 right now. The cost of drug trials is taking a toll on our “companies” and we have been making deals with investors to gain more money for our phase 2 trials. It is interesting to see how solutions in the real world have been recognized to combat these costs. By speeding up the trials through using surrogate end points, a drug can be brought to market faster and with less costs. A thought I had on this subject was that faster may not always be better. If corners are cut to get a drug to market faster, is it the safest option for the public? The risk of producing a less safe drug may actually incur more costs down the road if a drug needs to be pulled from the market.

Eaglstein, WH. Innovative new drugs for serious nonlethal diseases: the cost to develop and the cost to buy. JAMA Dermatol. 2016:152(2):139-40.

http://archderm.jamanetwork.com/article.aspx?articleid=2471626

Early Intervention for Psychotic Disorders: Building Population Health Systems

Treatment of psychotic disorders is known to be very complex. In order to improve treatments of disorders like schizophrenia, many studies have been conducted that prove early intervention is better, because early treatments will lead to greater reductions in disability later on. The authors of this article note that the necessity for early intervention has been understood nationally and funds for these therapies were set aside in the Consolidated Appropriations Act of 2014.

Because psychotic disorders are complex issues, Vinod and colleagues offer a model for addressing treatment of these disorders. Rather than just looking at a health system as a group of healthcare organizations, they propose integrating multiple community members as part of a greater system with a patient-centered focus. Integrating the community is important because it allows for evaluation of what resources are already available. When gaps in resources are missing, everyone can work together to advocate for the gaps. When applied to psychotic disorders, this approach makes early intervention treatment an issue of population health. By creating “population health systems” as defined in the article, a network of people can come together to improve the health of the population of people suffering from schizophrenia and other similar disorders.

I found this article to be very inspirational in its goals for the future of healthcare. The authors of the article clearly utilize the ideas of a medical home that integrates many healthcare professionals and even builds upon this. Overall, they are calling for the greater community to recognize the initiative to support early intervention for psychotic disorders. As part of the medical home and the community, pharmacists can contribute to this idea of building population health systems. We can do our part by advocating for the health of certain populations and working for the objective goals of these populations. In the case of psychotic disorders, pharmacists can counsel patients on the availability of medication therapies and also refer patients to other early intervention services. What other interventions do you think a pharmacist could make within a population health system?

 

Vinod HS, Anant J, Muir G. Early intervention for psychotic disorders: building population health systems. JAMA Psychiatry. 2016;73(2):101-2

http://archpsyc.jamanetwork.com.pitt.idm.oclc.org/article.aspx?articleid=2480952

Efficacy, Acceptability, and Tolerability of Antipsychotics in Treatment-Resistant Schizophrenia

For schizophrenia that is treatment resistant, clozapine is the standard drug therapy. The high use of clozapine for this condition is largely based on one study conducted by Kane and colleagues that demonstrated its effectiveness. However, since then many clinical trials have been conducted for other second generation antipsychotics. In addition to this fact, clozapine is also noted to have many side effects. Thus, the researchers of this study found it necessary to conduct a meta-analysis to evaluate if clozapine is still the most effective treatment available for treatment-resistant schizophrenia. In order to conduct the meta-analysis, the researchers studied 40 single and double blind randomized clinical trials of adults with treatment-resistant schizoaffective disorder, schizophreniform disorder, or schizophrenia. The drugs involved in the studies were clozapine, haloperidol, olanzapine, and risperidone.

The results of the pairwise meta-analysis showed that olanzapine, clozapine and risperidone were significantly effective as therapies for treatment-resistant schizophrenia. Clozapine, however, was not the most effective of all the drugs. The data showed some inconsistencies due to sampling bias found in the trials. In addition, many of the clinical trials that the researchers would have liked to include in the study were unblinded and thus excluded. Therefore, it can be concluded that evidence for which antipsychotic medication is best for patients with treatment-resistant schizophrenia is limited. More research needs to be conducted to compare clozapine with second generation antipsychotics.

I found this article to be interesting because the researchers conducting this study took it upon themselves to question standard practices. I think it is important to continue studying treatments that are considered “standard” because it allows for continuous improvement in prescribing. If we never questioned ourselves, therapies would never be improved. In this case, clozapine had been shown to be more effective than first generation antipsychotics. However, its effectiveness was not proven over second generation antipsychotics. With the emergence of these newer drugs, I think it is important to reevaluate the situation and compare therapies. With this in mind, as future pharmacists we should try to always stay up to date on such research so that we are able to advise prescribers and patients on the most effective drug available for the indication being treated.

Samara M, Dold M, Gianatsi M, et al. Efficacy, Acceptability, and Tolerability of Antipsychotics in Treatment-Resistant Schizophrenia. Jama Psychiatry. 2016; published ahead of print.

http://archpsyc.jamanetwork.com.pitt.idm.oclc.org/article.aspx?articleid=2488040

Monthly High-Dose Vitamin D Treatment for the Prevention of Functional Decline

A major health concern for older populations is increased risk for falls. This is partly caused by reduced lower extremity function, prevention of which could save many injuries from occurring in older adults. Vitamin D has been thought to aid in lower extremity function and is especially believed to help with muscle weakness. To evaluate this, the researchers of this study conducted a double blind clinical trial to evaluate the effects of high-dose vitamin D in older adults. The study looked at 200 men and women with a low-trauma fall in the past year who were also 70 years and older. These 200 participants were separated into three study groups: one receiving 24,000 IU of vitamin D3 per month (normal dose), one receiving 60,000 IU of vitamin D3 per month, and one receiving 24,000 IU of vitamin D3 plus calcifediol per month. At the end of the study, the increase in 25-hydroxyvitamin D levels was evaluated for each group.

The results for the first group receiving 24,000 IU showed that the 25-hydroxyvitamin D levels increased by 11.7 ng/mL after 12 months. The second group receiving 60,000 IU increased its levels by 19.2 ng/mL. Finally, the third group receiving both the 24,000 IU and the calcifediol increased its 25-hydroxyvitamin D levels by 25.8 ng/mL after 12 months. The participants were also tested using the Short Physical Performance Battery (SPPB). This test assessed lower extremity function by evaluating walking speed, balance, and successive chair stands. When looking at the change in SPPB scores, it can be noted that there was no significant difference between the treatment groups. Further data collected from the study also evaluated the incidence of falls in the subjects. During the 12 month period of the study, 121 of the participants fell. The 60,000 IU group and the 24,000 IU group with calcifediol had significantly higher percentages of falls compared with the treatment group that only received the 24,000 IU of vitamin D3.

It was concluded that higher doses of vitamin D monthly do not provide benefit for the decline in lower extremity function. This was shown through the SPPB scores and the lack of improvement with higher doses. Also, high doses were shown to increase the number of falls in participants and, therefore, may be considered unsafe in older adults who have already experienced a fall.

I found this study to be interesting because we are often told how over the counter vitamins and herbals do not have much research behind them. I therefore chose to read this article to learn more information about vitamins. The study actually proved to me how little we seem to know about these supplements. The consensus on vitamin D that was used as the basis for this study was that it can improve muscle function. However, high doses of it actually seem to have done more harm than good. As a pharmacist, it is important to know this information when evaluating the medication regimen of an older adult. Doses of vitamin D should be monitored closely with someone who experiences falls, especially if they are taking other medications that may also contribute to more frequent falls.

Citation:

Bischoff-Ferrari H, Dawson-Hughes B, Orav J, et al. Monthly high-dose vitamin D treatment for the prevention of functional decline: a randomized clinical trial. JAMA Intern Med. 2016; 176(2): 175-183.

http://archinte.jamanetwork.com/article.aspx?articleid=2478897

Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease

This study looks at the effects of proton pump inhibitors (PPIs) on disease states, as it is one of the most commonly prescribed drug classes. Furthermore, only 25-70% of PPIs have an appropriate indication. Thus, these therapies may be overused. This study focuses on the relationship between PPI use and the development of chronic kidney disease (CKD). Of the risk factors currently known, the prevalence of the disease cannot be fully explained. Thus, iatrogenic risk factors must be observed to help explain the rates of both CKD and acute kidney injury.

In this study, Lazarus and colleagues looked at 10,482 participants of the Atherosclerosis Risk in Communities study. Results were replicated in a study of the Geisinger Health System consisting of 248,751 patients. In the population of participants from the ARIC study, it was found after adjusting for other factors that participants using PPIs had 1.45 times the risk for incident chronic kidney disease. Participants using PPIs were 1.72 times more likely than nonusers to develop an acute kidney injury. The results of the Geisinger Health System analysis confirmed the results and supported the findings through use of direct laboratory measurements. Overall, PPI use was found to be an independent risk factor for both acute kidney injury and chronic kidney disease. The association of PPI use and kidney disease does not necessarily indicate that PPIs directly cause kidney damage. Further investigation into this is needed.

I found the information presented in this study to be very interesting considering that PPIs are so commonly prescribed. I know personally at the pharmacy I work at that multiple omeprazole prescriptions are counted on a daily basis. As future pharmacists, maybe we should consider showing caution to extensive PPI use. In our role, we could counsel patients on the risk factors presented here along with recommending PPIs over the counter less frequently for patients who may be at risk. As stated above, 25-70% of PPIs are not even appropriately indicated in the patients who are using them. A question for my colleagues: do you think a direct cause and effect relationship should be established before limiting PPI use? Or, rather, do you find the information presented here to be significant for limiting the prevalence of PPI use?

Citation:

Lazarus B, Chen Y, Wilson F, et al. Proton pump inhibitor use and the risk of chronic kidney disease. JAMA Intern Med. 2016; 176(2): 238-246.

http://archinte.jamanetwork.com/article.aspx?articleid=2481157