Ranolazine for T2DM and Angina

Greiner and colleagues did a literature review to examine the effects of ranolazine in glycemic control of patients with type II diabetes. Ranolazine is a cardiovascular agent used for the treatment of chronic angina and additionally has been show to reduce A1C levels. This becomes an important drug therapy because it could afford a means of treating type II diabetes and reduce the cardiovascular complications or events associated with type II diabetes.

Clinical studies examined in the trial have shown that ranolazine decrease A1C levels without resulting in hypoglycemia and as a dose-dependent affect on A1C. The authors note that the most common adverse effects related to the administration of ranolazine was nausea, constipation, headache, and dizziness. The authors additionally referenced an animal study that suggested that ranolazine’s ability to reduce A1C levels could be related to preserving the function of beta pacreatic cells. As a conclusion, the authors state that the first line of treatment for patients with type II diabetes should be lifestyle modifications and that metformin should still be considered as the first pharmacological intervention. They state that because of ranolazine’s ability to reduce A1C, it could be considered a new therapeutic agent for individuals with type II diabetes.

I found this study to be very interesting because it is the first time I have become aware of a drug that could be used to treat both type II diabetes and chronic angina related to cardiovascular disease. Because type II diabetes and cardiovascular disease are so closely related, the idea of having a single drug that can help treat both chronic conditions it an exciting prospect. It could reduce the number of adverse events related to drug-drug interactions and it could be an easier treatment option for the patient.

Greiner L, Hurren K, Brenner M. Ranolazine and Its Effects on Hemoglobin A1C. Ann Pharmacother. 2016 Feb 25.

http://aop.sagepub.com.pitt.idm.oclc.org/content/early/2016/02/24/1060028016631757.full.pdf+html

Ivabradine and Cardiovascular Health Outcomes

Weeda and colleagues published a reviews article about the use of ivabradine, a cardiovascular agent FDA-approved for the treatment of chronic heart failure, for the treatment of myocardial ischemia and heart failure with reduced ejection fraction (HFrEF). Ivabradine, as a drug, slows the heart’s pacemaker activity by acting as an f-channel blocker and therefore can be used to slow the heart rate. As a second measure, the authors examined the role of heart rate in these cardiovascular conditions.

The authors found studies that examined the use of ivabradine in patients with ischemic heart disease for the reduction of angina during exercise. In some studies, ivabradine was compared to other cardiovascular agents such as atenolol or diltiazem and was not found to be more effective. Additionally, some studies looked at ivabradine’s effect on the health outcomes related to cardiovascular disease. Again, ivabradine was not shown to be more effective at reducing nonfatal myocardial infarction or cardiovascular-related mortality when compared to the placebo, despite having shown a reduction in patient heart rate, Studies also showed that the health outcomes (hospitalizations, MI, or cardiovascular related mortality) of patients with HRrEF was also not significantly different in patients receiving ivabradine compared to placebo despite ivabradine patients have a lowered heart rate.

Authors concluded that ivabradine was not shown to be an effective treatment for chronic stable angina patients with coronary artery disease. They also found that ivabradine was not a valid substitute for more traditional therapies such as beta-blockers, ACE inhibitors, ARBs, or aldosterone receptor antagonist. Ivabradine is likely most useful as an adjunct therapy for patients that cannot tolerate beta-blocker dosing or as a means of reducing heart rate.

I found this article interesting because I think it touches on a topic that occurs a lot in drug development. Oftentimes, researchers invest so much money and time into a medication that can do exactly what it is supposed to do without changing health outcomes. In this case, ivabradine was shown to reduce patient heart rate but without concomitant therapy with a more traditional cardiovascular agent was not able to reduce negative health outcomes. I think that while research is an essential into drug therapies are an essential part of the pharmacy profession more work needs to be done regarding more basic physiology. For instance, what does preclinical or other clinical research suggest the effect of slowing heart rate have on cardiovascular events? Is there a correlation between those two factors? If so, why doesn’t ivabradine’s ability to slow heart rate affect cardiovascular health outcomes?

Weeda ER, Nguyen E, White CM. The Role of Ivabradine in the Treatment of Patients With Cardiovascular Disease. Ann Pharmacother. 2016 Feb 25

http://aop.sagepub.com.pitt.idm.oclc.org/content/early/2016/02/24/1060028016631571.full.pdf+html

Review of the Treatment of Severe Alcohol Withdrawal

Schmidt and colleagues published a review article in The Annals of Pharmacotherapy looking at the different treatment options for sever alcohol withdrawal. Severe alcohol withdrawal is characterized by seizures and delirium and cannot be treated with the normal dosing of benzodiazepines. Most patients that experience alcohol withdrawal have only minor side effects that, while they affect daily life, do not require aggressive treatments plans. In about 5% of patients, however, the withdrawal symptoms are severe and as of now the best treatment for these patients is not well known. Additionally, the main treatment goal for alcohol withdrawal syndrome is to minimize the side effects and to prevent progression of the symptoms. Some treatment plans involve supportive treatment and replenishment of fluids, vitamins, and electrolytes to prevent further health problems.

The most common pharmacological therapy for alcohol withdrawal syndrome is benzodiazepines though as noted by the authors, some cases of severe alcohol withdrawal syndrome do not respond to benzodiazepine treatment. Another pharmacotherapy that can be uses is phenobarbital but the evidence supporting this treatment protocol is very limited due to a lack of evidence regarding efficacy. Propofol is the most common form of treatment in benzodiazepine-refractory alcohol withdrawal syndrome cases. One final treatment available is dexmedetomidine, an alpha-2 receptor antagonist. But without affecting GABA transmission that is affected by excessive alcohol use and related to withdrawal symptoms, this medication cannot be used to treatment the seizures that can be associated with severe alcohol withdrawal.

I found this study to be very interesting because it reviews the available options that can be used to treatment individuals experiencing alcohol withdrawal syndrome. There can be a tendency for stigmatization in situations like this but it is always important to understand and acknowledge the physical and chemical changes that occur as a result of excessive alcohol consumption. The treatment of withdrawal symptoms is important for successful recovery and is an important tool to helping patients get back on their feet.

 

Schmidt KJ, Doshi MR, Holzhausen JM, et al. A Review of the Treatment of Severe Alcohol Withdrawal. Ann Pharmacother. 2016 Feb 9.

http://aop.sagepub.com.pitt.idm.oclc.org/content/early/2016/02/08/1060028016629161.full.pdf+html

Pharmacotherapy Options for Obesity

A recent article published in The Annals of Pharmacotherapy did a comparison of the available pharmacotherapy options for patients struggling with obesity. Specifically, Nuffer and colleagues looked at phase 3 clinical trial data from 4 new drug therapies that have been approved for the weight management and obesity. Because obesity is closely related to a wide variety and large number of health problems and disease states, it is important to look into potential pharmacotherapies that could be helpful and effective. The drugs studied in this trial are lorcaserin, naltrexone/bupropion SR, phentermine/topiramate ER, and liraglutide. According to the research in this article, the phase 3 clinical trial data shows that each of these four medications contribute to long-term weight loss. Additionally, each of the four drugs can also lead to GI-related adverse events, such as nausea, vomiting, and constipation. One important note about all of the medications is that they are all pregnant category X drugs.

The authors conclude by explaining that the introduction of these 4 medications approved for the management of obesity advance a physician’s ability to effectively help their patients. These authors examined the data from each of these medications but there have not been any direct comparisons performed between them to tease out which would be the most effective. All of the medications show promise at achieving long-term weight loss. The suggestion offered by the authors is that because there is not a single drug that stands out as being better than the others, physicians need to decide on medications in a patient-specific manner. Other factors such as lifestyle, other disease states, and other medications could impact the decision of which medication to use.

Overall the article was meant to summarize the benefits and problems associated with 4 medications recently approved for weight management and obesity. As noted by the authors, the lack of a direct comparison between the medications means that there is not yet an objective means of determining which of the drugs if any would be safer or more effective. Obesity is a serious problem that is affecting people around the globe and is directly associated with many negative outcomes. As of yet, there is not a truly good means of maintaining long-term weight loss so I am looking forward to following these medications to see if we can finally provide patients with the help they need to lose weight.

Nuffer W, Trujillo JM, Megyeri J. A Comparison of New Pharmacological Agents for the Treatment of Obesity. Ann Pharmacother. 2016 Feb 17.

http://aop.sagepub.com.pitt.idm.oclc.org/content/early/2016/02/16/1060028016634351.full

Prasugrel Treatment in Children with Sickle Cell Disease

In a recent, multinational Heeney and colleagues looked into oral prasugrel, an antiplatelet agent, for the treatment of sickle cell anemia. Individuals with sickle cell anemia often suffer from what is referred to as vaso-occlusive crisis. This means that the sickled red blood cells block blood vessels leading to a common complaint of pain from the patient and in severe circumstances organ damage. In this study, 341 patients ranging from 2 to 17 years of age with a sickle cell anemia were divided into two groups: the placebo group and the prasugrel group. Primary research determinant was the rate of vaso-occlusive events. The secondary outcomes of the trial were amount and duration of pain symptoms associated with sickle cell disease. The treatment period of the trial lasted between 9 and 24 months.

The results of the study found that the use of prasugrel slightly lowered the occurrence rate of vaso-occlusive events but was not statistically significant. Prasugrel did not significantly affect the rate of hospitalization due to vaso-occlusive events nor did it affect the duration of the hospital stay. The authors of this journal indicated that prasugrel is not an effective treatment for vaso-occlusive crisis in patients with sickle cell anemia. They also suggested that due to the complex nature of sickle cell anemia that prasugrel could still be considered for use in a multidrug therapeutic approach to treating sickle cell anemia in these children.

Overall the study was well designed and organized and previously published articles supported the results of the trial. Sickle cell anemia is still a disorder that affects millions of people around the world and requires a multifaceted approach to treatment. This study was attempting to determine whether prasugrel could be used to reduce pain in children with sickle cell anemia. This type of treatment is important to prevent overuse of pain medications and improving the quality of life for sickle cell patients. Further research should be done to determine whether any antiplatelet drugs could be used to reduce these complications of this complex disease.

Heeney MM, Hoppe CC, Abboud MR, et al. A Multinational Trial of Prasugrel for Sickle Cell Vaso-Occlusive Events. N Engl J Med. 2016 Feb 18;374(7):625-35

http://www.nejm.org.pitt.idm.oclc.org/doi/full/10.1056/NEJMoa1512021#t=article

Glycemic Control Therapy Following Liver Transplant

In this study, Linder and colleagues were looking into the treatment of post-transplant diabetes mellitus (PTDM) in liver transplants patients. Following liver transplants, about 70% of patients develop impaired glucose regulation and this impairment can lead to transplant rejection and patient fatality. The development of PTDM can lead to infection, prolonged hospital stays, transplant failure, and rejection. This study looked into whether the administration of insulin to treat post-transplant hyperglycemia affected the development of PTDM.

The study found that acute rejection diagnosed through biopsy was higher in patients who exhibited PTDM. The study also found that graft failure and rejection rates were no different between the PTDM and PTDM-free group. Daily insulin use and daily average blood glucose levels were not shown to be positive predictors for the development of PTDM. The study did find, however, that individuals with higher blood glucose levels while on the medical floors were more likely to develop PTDM. These findings could suggest that effective management of blood glucose levels post-transplant.

This study was a univariate and retrospective study. Because of this, the data found may not be particularly relevant in the clinic. Some of the findings found as a result of this study were not seen in larger, multivariate studies. Additionally, because the study was retrospective, there was no variable control nor could specific criteria for the diagnosis of diabetes be upheld. Additionally, the study looked at the effects of immunosuppressant that were taken by transplant patients, but did not account for any other medications.

I found this research to be interesting but only as a small-scale study. For instance, a larger more controlled study found that more immediate insulin therapy decreased liver transplant patient’s risk for developing diabetes. This larger study could be used to implement hospital policies that would increase the number of patients receiving glycemic-control medications following transplants and decrease the adverse events associated with PTDM. I would be interested to see the next level of this study to see if something as simple as insulin therapy could in fact decrease rates of graft failure, rejection, and patient fatalities.

 

 

Linder KE, Baker WL, Rochon C, et al. Evaluation of Posttransplantation Diabetes Mellitus After Liver Transplantation: Assessment of Insulin Administration as a Risk Factor. Ann Pharmacother. 2016 Feb 4.

http://aop.sagepub.com.pitt.idm.oclc.org/content/early/2016/02/03/1060028015627662.full

Amoxicillin for Uncomplicated Severe Acute Malnutrition in Children

One of the biggest issues facing global health is the severe malnutrition affecting millions of children around the world. The malnutrition in these children is so severe that medical intervention is necessary. Severe malnutrition cases can be further complicated by bacterial infections and broad-spectrum antibiotics were prescribed for treatment of those infections. The treatment of infections is coupled with nutritional recovery, generally in complicated cases. This study conducted by Isanaka and colleagues studied the use of amoxicillin in the treatment of bacterial infections in children with uncomplicated severe malnutrition. In 2007, the World Health Organization supported the use of community-based treatment of severe malnutrition with the goal that they were identify and treatment more malnourished children. This previous publication, however, did not examine the effectiveness of the drug therapy protocol.

During this study, the children were randomly assigned to two groups: the amoxicillin group and the placebo group. Both groups of participants were also provided with the Ready to Use Therapeutic Food (RUTF), which is meant to provide them with all of their basic nutritional needs to aid in nutritional recovery. Follow-up appointments were scheduled at 4, 8, and 12 weeks form the start of the study. During these visits, stool, urine, and blood samples were obtained and tested for signs of bacterial infection. The primary outcome of the study was nutritional recovery at 8 weeks, based on increased measurement of the upper arm, a lack of edema, and a weight-for-height z score of -2 or higher. Secondary outcomes were nonresponse or no changes at 8 weeks, death from any cause, or transfer to inpatient.

Overall, the study found no significant difference in the likelihood of nutritional recovery between the amoxicillin and placebo groups. Despite this, the time to nutritional recovery as significantly reduced in the amoxicillin group. The amoxicillin group also had a significantly decreased overall risk of transfer to inpatient facilities but did not affect the mean time to transfer to inpatient. Amoxicillin increased early increases in weight and mid-upper-arm circumference and decreased the frequency of diarrhea. Despite all of these findings the researchers concluded that routine amoxicillin use in this population does not significantly effects nutritional recovery.

This study provided an interesting insight into the routine use of antibiotics and questioned their efficacy and necessity. This study produced some interesting results but the improvement in weight gain and the slight decreases in adverse events were observed in the short-term. This study did not look at the long-term effects of this type of therapy and because of this cannot say that this improvement in weight gain lasts for any extended period of time. The ultimate goal of this treatment is long-term nutritional stability and the nature of this study cannot speak to this outcome. Additionally, as suggested in the paper, it may be unclear whether the amoxicillin is actually affecting nutritional recovery or serving as a protective agent while the RUTF actively impacts nutritional status. All of these confounding factors make it unclear whether amoxicillin is beneficial under these circumstances and further research will be required to assess the necessity of antibiotic use in this population.

 

Isanaka S, Langendorf C, Berthé F, et al. Routine Amoxicillin for Uncomplicated Severe Acute Malnutrition in Children. N Engl J Med. 2016 Feb 4;374(5):444-53.

http://www.nejm.org/doi/pdf/10.1056/NEJMoa1507024

Prophylactic Metformin in Obese Pregnant Women without Diabetes

In a recent study published in the New England Journal of Medicine, Syngelaki and colleagues studied the effect of metformin use in obese pregnant women without diabetes. Obesity in pregnant women can increase adverse events for both the mother and the baby and lifestyle changes do not seem to have a strong impact on the likelihood of these events. In this study, the patients in the study were given either metformin or a placebo pill. During the follow-up visits, the researchers obtained vitals such as weight, blood pressure, and urinanlysis for proteins and ketones. They were also interviewed to monitor adherence and episodes of nonadherence were documented. The primary outcome measured in this study was the difference between the infant’s expected birth weight given gestational age and the actual birth weight, also known as the median neonatal birth-weight z score. One of the secondary outcomes measured in the study was gestational weight gain.

The data obtained from the study showed no significant difference in the median neonatal birth-weight z score. There was also not difference in the number of “large-for-gestational-age neonates” or the number of adverse events for the mother or the fetus. In fact, the metformin group had the same number of adverse events and a larger number of side effects. Overall, the study used information from previous publication that suggest that higher pregnancy BMI and increase weight gain during pregnancy increase the prevalence of complications such as preeclampsia. Results from this study suggest that prophylactic 3 mg dose of metformin during the second trimester of pregnancy decreased gestational weight gain but did not have an effect on the median neonatal birth weight.

I found this study to be very interesting because the obesity rates in the United States are high relative to other countries and this obesity rate impacts many different health determinants. This study to me was particularly interesting because it was looking at obese women without diabetes, who also can develop adverse complications during pregnancy. The study was well-designed, using an ethnically diverse population and sampling from three different hospitals. The results were supported by other previously published literature and it was an important topic of research given that lifestyle and diet modifications do not reduce obesity-related complications during pregnancy.

 

 

Syngelaki A1, Nicolaides KH, Balani J, et al. Metformin versus Placebo in Obese Pregnant Women without Diabetes Mellitus. N Engl J Med 2016; 374:434-443 (published February 4, 2016)

http://www.nejm.org.pitt.idm.oclc.org/doi/full/10.1056/NEJMoa1509819#t=article