Acetaminophen administration in pediatric age: an observational prospective cross-sectional study

Fever phobia is a phenomenon seem among parents who think fever is a health danger instead of an important physiological response and mechanism of defense against infection. Because of this parents tend to increase self medication which results in inappropriate use of antipyretics, and most commonly acetaminophen. The issue also comes from the fact that acetaminophen is dosed in children according to weight and not age, so the wrong measurement or guess of a child’s weight leads misdosing. The appropriate dosage is 10-15 mg/kg/dose every 4-6 hours, and higher or more frequent doses can cause hepatotoxicity which is why correct dosing is so important.

For six months, from November 2012 to April 2013, an observational cross-sectional study was performed to evaluate the dosage of acetaminophen administered to children with fever as mg/kg/dose and as a total daily quantity in mg/kg/day and to identify factors that may influences the accuracy of dosing. The clinical records of 1,397 children who had an outpatient visit due to fever between the ages of 1 month to 16 years old were examined. 74% of those children were given acetaminophen and had a body temperature below 38.4°C (or 101.12°F) which is justified because of the attempt to reduce the discomfort of the fever. Dosages up to 15 mg/kg/dose and a daily quantity of <90 mg/kg/day was considered normal and not potentially dangerous. And dosages of >15 mg/kg/dose and >90 mg/kg/day was considered supratherapuetic and potentially dangerous.

The results of the study were that in 1,060 cases, <90 mg/kg/day dose of acetaminophen was administered, and in 337 cases, >90 mg/kg/day dose of acetaminophen were administered. The researchers discovered that higher daily doses of acetaminophen were administered be caregivers with higher levels of education with 71% having a university degree within the >90 mg/kg/day dosing, in comparison to the <90 mg/kg/day group having 63% of the caregivers having secondary education. In addition acetaminophen doses were significantly higher in those who were given drops or syrups than those who were given tablets or suppositories. And a higher risk of acetaminophen overdose was seen when drops and or syrup formula were used. Moreover, 85.7% of the children had a acetaminophen prescription be a health professional, but even then 9.82% of acetaminophen overdose was found.

Although this study was done overseas in Italy and not in America, this is still a prevalent and important issue for pharmacists to be aware of. If we become aware this is an issues, then whenever parents are coming in to pick up acetaminophen prescriptions we can make sure to double check that the dosing is appropriate for the weight of the children to prevent this issue from occurring and to prevent any chances of hepatotoxicity from happening in children too. Not only that but other health care providers like the doctors play a role too, if we can educate them and make them aware of this issue then the right prescription dosages can be written further preventing acetaminophen overdose.

Lubrano R, Paoli S, Bonci M, et al. Acetaminophen administration in pediatric age: an observational prospective cross-sectional study. Ital J Pediatr. 2016;42:20.

Comparison of Efficacy and Safety of Ciclosporin to Prednisolone in the Treatment of Erythema Nodosum Leprosum: Two Randomised, Double Blind, Controlled Pilot Studies in Ethiopia

Leprosy is a infection caused by Mycobacterium leprae that mainly affects the skin and peripheral nerves. Symptoms include skin lesions, neuropathy manifesting as loss of sensation, weakness, and nerve pain. Erythema Nodosum Leprosum is a complication of leprosy  that affects multiple organs causing “uveitis, neuritis, arthritis, dactylitis, lymphadenitis and orchitis”. It is normally treated with high dose steroids, but because it reoccurs it leads to prolongs used of steroids and the associated side effects. For those patients that become steroid resistant or have steroid side effects, there’s little evidence as to the effectiveness of alternative treatments.  Immunosuppression is needed to treat the symptoms and signs of Erythema Nodosum Leprosum.

Ciclosporin is a potent immuno-suppressant is used to treat psoriasis, and because it has a slow onset of action, prednisolone is started at the same time and then gradually decreased as ciclosporin slowly begins to build up to a therapeutic level. Two double-blind controlled trails were conducts with randomized patients either receive the ciclosporin and prednisolone or the prednisolone only treatment. The trial consisted of 13 patients with new ENL and 20 patients with recurrent or chronic ENL over 16 weeks. 10 patients within the new ENL experienced one or more episodes of ENL recurrence, with 1.29 recurrences per patient for those receiving ciclosporin and prednisolone, and 2.4 recurrences per patient for those receiving only prednisolone. However the researchers noted that the difference is because of less-flare-up occurrences in the drug combination group during the intervention period than the group receiving only prednisolone. And that the number of ENL recurrences per patient was not significantly different between the two treatments. 17 patients with chronic ENL experiences one or more episodes of ENL recurrence, the mean was 2.3 recurrences per patient in the combination drug treatment, and 2.0 recurrences per patient for those receiving only prednisolone. The mean number between the two treatments were not significantly different between the two groups.

27 of 30 patients has ENL recurrence during treatment or post treatment period and for those with acute EN the mean time to first episode of NEL recurrence was 23 weeks in ciclosporin and prednisolone group and 09.2 weeks in the prednisolone group. Those with chronic ENL, the mean time to first episode of ENL recurrence was 7.1 weeks in the ciclosporin and prednisolone group, and 11.25 in the prednisolone group. However the results was not considered statistically significant due to the mall size of the group.  In considering the severity of the ENL recurrence, in the chronic ENL group those that received ciclosporin and prednisolone had twice as many flare ups in the intervention period. And that was considered statically significant.

The researchers concluded that most available immunosuppressants can control acute symptoms of ENL, but to prevent ENL recurrence is much harder. Ciclosporin and prednisolone used in conjunction seems to show promising results in managing acute ENL in this small study. This study is relevant to pharmacists because this is a problem that affects many people in third world countries but because of that fact not as much is being doing to resolve the issue. As there’s not a need for this in America or funding for this because it’s not a prevalent issue in our society. But those of us going into research for new drugs can be aware that ENL is a issue in other countries and maybe in the future someone will get the funding and discover a solution to this problem.

Lambert SM, Nigusse SD, Alembo DT, ect al. Comparison of Efficacy and Safety of Ciclosporin to Prednisolone in the Treatment of Erythema Nodosum Leprosum: Two Randomised, Double Blind, Controlled Pilot Studies in Ethiopia. PLoS Negl Trop Dis. 2016;10:2.

Is Routine Iron Supplementation Necessary in Pregnant Women With High Hemoglobin?

Iron supplementation during pregnancy is an important component in prenatal care to prevent anemia. During pregnancy increased plasma volume exceeded increase in red cell volume which causes dilution, and reduction in the concentration of hemoglobin. It has been found that hemoglobin levels can fall from the average of 12.5-13.0 g/dL to about 11.0-11.5 g/dL. According to the WHO, more than 40% of pregnant women suffer from anemia that is caused by iron deficiency about half the time, thus 30-60 mg of elemental iron supplementation is recommended for pregnant women. However, extremely high iron levels in pregnant women can adversely affect the birth outcome. Because of this it seems logical to say that iron supplementation is unnecessary in women who have high hemoglobin levels. This study examined the effects of iron supplementation on iron status markers in pregnant women with high hemoglobin.

The trial was randomized, double-blind, and placebo controlled. The population contained 86 pregnant women with Hemoglobin > 13.2 g/dL and ferritin > 15 μg/l in the 16th – 20th week of pregnancy. From their 20th week of pregnancy to the end, the experimental group were given 1 ferrous sulfate tablet with 50 mg of elemental iron daily, and the control group received a placebo. Hemoglobin and ferritin levels were evaluated at 37 to 39 weeks of pregnancy and after delivery the baby’s birth weight was measured. However 22 women ended up dropping out of the trial due to various reasons, so the date for 64 women were used in conclusions.

The mean hemoglobin concentration was 12.05 g/dL in the experimental group, and 11.94 g/dL in the placebo group which meant a significant difference in hemoglobin levels between the two groups. Though in comparing the birth weight of the babies, there was no significant difference between the two groups. By the end of pregnancy four women in both groups were anemic, however none had a hemoglobin level of less than 10 g/dL and the difference wasn’t significant between the supplement and placebo group. The researchers concluded that since not using iron supplementation didnt cause of anemia in women with hemoglobin concentrations greater than 13.2 g/dL during pregnancy the current recommendations made by WHO for women regarding iron supplementation during pregnancy should be followed. 

The researchers had the right idea in approach this study since it was very logical to think that since high iron levels affect birth outcomes negatively it made sense not to supply those women in their third trimester of pregnancy with high hemoglobin levels with additional iron supplements. There might be more evidence had the population of the overall study been larger, but given what it was those women who were given a placebo did end up having their hemoglobin levels drop to an average of 11.94 g/dL so maybe for those women who have high hemoglobin levels during pregnancy they should take iron supplements, but either towards the lower dosage end or just not take the supplements daily

Alizadeh L, Salehi L. Is Routine Iron Supplementation Necessary in Pregnant Women with High Hemoglobin? Iran Red Crescent Med J.  doi: 10.5812/ircmj.22761 (published 27 January 2016)

Use of a Vaginal Ring Containing Dapivirine for HIV-1 Prevention in Women

More than half of the 35 million persons currently living with HIV-1 infection are women, and a majority live in the sub-Sahara Africa region. Antiretroviral medications used as pre-exposure prophylaxis have been proven to be effective in preventing contracting the HIV-1 virus. However in a few other trials, it was shown that adherence to the tenofovir-containing pills and vaginal gels was low which means that there needs to be more options out there for women so that they can be more compliant and adherent to the drug and prevent the spread of HIV-1 infections. In this trial the researchers decided that since vaginal rings provide sustained and controlled release of medication, it would be a good idea to test out as an antiretroviral-containing form of protection. Since it could provide long-acting HIV-1 protection and reduce overexposure of the active ingredient and deliver the agent right at the site of the viral transmission.

The trial lasted from August 2012 to June 201 with a population of 2,629 healthy, sexually active, nonpregnant, HIV-1–seronegative women between the ages of 18 and 45 years at 15 research sites. Women were randomly assigned with a ratio of 1:1 to either receive either a silicone elastomer vaginal matrix ring containing 25 mg of dapivirine or a placebo vaginal ring. It ended up being 1313 in the dapivirine group and 1316 in the placebo group. Each ring is inserted for 4 weeks and then replaced with a new one, and the women were counseled how to insert/remove the ring and to wear it for the month. They also returned for monthly follow-up visits to test and monitor for HIV and were also give additional adherence counseling.

The results concluded that, the median age of the population was 26 years old, 41% were married, 99.5% reported having a primary sexual partner during the 3 month before trial enrollment, 57% reported use of a condom, and 64% reported their partner knew they would be using a vaginal ring for a research trial. The medium follow up time was 1.6 years, and the longest was 2.6 years. Pregnancy occured at an incident of 3.9/100 person-years in dapivirine and 4.0/100 person-years in placebo group. Across all the sites a total of 168 incident HIV-1 infections occurred during the use period, 71 in dapivirine group and 97 in the placebo group. Incidents of HIV-1 infection in the dapivirine group was lowered by 27% than placebo group. The effectiveness was significant bit not high. The efficacy of HIV-1 protection differed significantly with different age groups, an efficacy of 61% for women 25 or older, and 10% for women under 25. Adherence was also lower in women 18-21  than those older than 21, this emphasizes a greater need for prevention strategies for women of this age group to better help them from contracting HIV-1 infections.

Baeten JM, Palanee-Phillips T, Brown ER, ect al. Use of a Vaginal Ring Containing Dapivirine for HIV-1 Prevention in Women. N Engl J Med. doi: 10.1056/NEJMoa1506110 (published 22 Feburary 2003)

Concord grape juice, cognitive function, and driving performance: a 12-wk, placebo-controlled, randomized crossover trial in mothers of preteen children.

According to the article: “Daily consumption of Concord grape juice (CGJ) over 3-4 mo has been shown to improve memory function in adults with mild cognitive impairment and reduce blood pressure in hypertensive adults.” most likely due to a high concentration of polyphenyols within the grapes. The study chose mothers of pre-teens because they have more stressful lifestyles and “Increased stress can impair cognitive function and elevate blood pressure.” The study included 25 mothers of pre-teens who were also employed for 30 or more hours per week. They were given either 12 oz of the concord grape juice or an energy, taste, and appearance matched placebo daily for 12 weeks and included a 4 week washout. Seven tests were given to test for verbal memory, non verbal spacial memory, executive functioning, psychomotor skill, executive functioning, longitudinal tracking, and lateral tracking. In addition, blood pressure and mood were tested at baseline and at six and then 12 weeks. And then 17 of the 25 also performed a 25 driving test during which they were asked to match the speed and direction of another car.

The researchers discovered from the results of the test that those given concord grape juice did significantly better in verbal recall, spatial recall, psychomotor skill, executive functioning, longitudinal tracking, lateral tracking. They concluded that the juice was associated with better immediate spacial memory and the longitudinal and lateral tracking aspects of the car test. They also noted that this is the first study to test the juice on middle-aged adults whereas previous studies were on older adults with mild cognitive impairment which shows that the benefits are not exclusive to adults exhibiting cognitive decline or neurodegenerative disease. And because this study also included a washout period, it showed that the juice had enduring effects in improving verbally recall, executive functioning, and lateral tracking which mean that polyphenols cause  cause relatively stable physiologic effects that do not disappear quickly after stopping its consumption.

This article was very interesting to read as pharmacists are typically so involved with actual medicine, it almost seems strange to hear about an alternative treatment that seems to work well in improving memory. At the same time its good to keep up with literature about alternative medicine so that when there is a patient who comes in who need help and doesn’t want to take medicine we can help refer them to studies like these and suggest an alternative method to treat their symptoms. Plus unlike herbal medication or other OTCs this is a completely safe treatment since it’s just drinking concord grape juice daily.

Lamport DJ, Lawton CL, Merat NL, et al. Concord grape juice, cognitive function, and driving performance: a 12-wk, placebo-controlled, randomized crossover trial in mothers of preteen children. J Nutr. doi: 10.3945/ajcn.115.114553 (published 10 February 2016).



Effect of Behavioral Interventions on Inappropriate Antibiotic Prescribing Among Primary Care Practices

Inappropriate antibiotic prescribing is a prevalent issue in the healthcare world as over prescribing can lead to antibiotic resistance which means at at a later point when an antibiotic can actually have an affect in reducing symptoms of a disease state it may not be effective. In addition according to the CDC, as of 2013, there has been no new antibiotics made for over 10 years 1. This mean that antibiotics are a precious resources in combating bacterial infections and diseases and if there’s nothing done to prevent over prescribing then antibiotic resistance becomes a more likely and a bigger issue for everyone.

A clinical trial included 248 clinicians among 47 primary care practices in Boston and LA were randomized to receive 0-3 interventions for a period of 18 months from November 2011 to October 2012. Upon enrollment into the study all the clinicians received education on antibiotic prescribing guidelines, and follow up for the trial ended April 2014.  The three interventions were as follow: “suggested alternatives presented electronic order sets suggesting nonantibiotic treatments; accountable justificationprompted clinicians to enter free-text justifications for prescribing antibiotics into patients’ electronic health records; peer comparison sent emails to clinicians that compared their antibiotic prescribing rates with those of “top performers” (those with the lowest inappropriate prescribing rates)”. The interventions were given either alone or in combination.

In total there were 31,712 visits (14,753 during baseline period and 16,959 during intervention period) that qualified for evaluation. The mean prescribing rates decreased from 24.1% at the start of the interventions to 13.1% at the end for controlled practice (-11.0% absolute difference). For suggestive alternatives the percentage went from 22.1% to 6.1% (-16.0% absolute difference); for accountable justification, percentages went from 23.3% to 5.2% (-18.1% absolute difference); and for peer comparison percentages dropped from 19.9% to 3.7% (16.3% absolute difference).  The researchers concluded that  with primary care practices, accountable justification and peer comparison as interventions results in lower rates of inappropriate antibiotic prescribing for acute respiratory tract infections. What would have made any of the interventions more effective? Is there a better way to prevent inappropriate antibiotic prescribing? Why do you think there has not been any new antibiotics invented in so long?

(1)  “Combating Resistance: Getting Smart About Antibiotics.” Centers for Disease Control and Prevention. Centers for Disease Control and Prevention, 26 Nov. 2013. Web.

Meeker D, Linder JA, Fox CR, et al. Effect of Behavioral Interventions on Inappropriate Antibiotic Prescribing Among Primary Care Practices: A Randomized Clinical Trial. JAMA. 2016;315(6):562-570. doi:10.1001/jama.2016.0275.

Zinc Supplementation May Boost Immunity in Elderly

One-third of nursing home patients have lower serum zinc levels which increases their risk for pneumonia and morbidity. In this study, 30 mg zinc supplements for 3 months in nursing home patients to see if it can improve their serum zinc concentrations. 53 nursing home patients aged 65 or older participated in the study, 58% had lower serum zinc concentrations of less than 70 μg/dL. The patients were either given the zinc supplement of 30mg Zn/d or a placebo of 5mg Zn/d. The effects on serum zinc concentration and immune response were examined.

The researchers concluded that zinc supplements were effective at improving serum zinc concentrations the patients and in turn this improvements increased anti-CD3/CD28 and phytohemagglutinin-stimulated T cell proliferation and the number of peripheral T cells. However once results were adjusted, the zinc-induced enhancement to T cell proliferation seemed to be mainly because of an increase in the number of T cells. Withing the population of patients that received the treatment, 16% had an increase in serum zinc concentrations and within the placebo group there was only a 0.7% rate increase. Supplementation of those patient with less than 60 μg serum Zn/dL didn’t increase their serum zinc to greater than or equal to 70 μg serum Zn/dL. The authors concluded that if elderly patients take zinc supplements appropriately, there can be significant impacts on incidents and morbidity from infection.

More research can be done to determine more precisely how long it takes for the supplements to start showing effects, how long of a period of time the supplements should be taken for, the dosage and amount of supplement needed for certain people. This will help aid the elderly population to reach the adequate concentration. One question the study proposes is did taking the zinc supplement help increase the number of T cells or what affected that chance? Since the authors had concluded that “the increase in serum zinc concentration was associated with the enhancement of T cell function mainly because of an increase in the number of T cells.”

Barnett JB, Dao MC, Hamer, DH, et al. Effectiveness of zinc supplementation of serum zinc concentration and T cell proliferation in nursing home elderly: a randomized, double-blind, placebo-controlled trial. Am J Clin Nutr. 2016;103(3):942-5

HIV drugs give couples ‘ray of hope’

There are many couples in Kenya where one is HIV positive and the other negative, but they still want to have children which leads to 44% of new HIV infections. PrEP is a new way to use anti-HIV drugs that are normally given to HIV positive people, that could mean couples can try and have children risk-free. The study took over 4,700 couples and the HIV negative person took the PrEP course over 36% and found that having the drug in their system reduced rate of transmission my over 90% and if the HIV positive person took antiretroviral drugs as well then the risk reduces to zero to close to zero.

Once HIV is in the body it hides in hard to access places and make reservoirs making it hard to flush out. However, if the PrEP drugs are in the system of an HIV negative person, when the virus enters, it gets killed. This means HIV doesn’t get the chance to find those reservoirs to hide in and be hard to flush out and ultimately infect the person.

This allows couples to resolve some conflicts that come with finding out that your partner is HIV positive and allows them to have a more normal relationship. It also helps greatly reduced the number of new HIV infections. Not mentioned in this is how this affects the children of HIV positive women. Whether this course also prevents transmission of HIV to the fetus and allow for uninfected children in unknown. Children who are born HIV positive due to their mother contributes to the population of new HIV infections as well and is another issue to be addressed.

Pitt, C. HIV drug gives couples ‘ray of hope’. BBC. 2016.

Carroll JJ, Ngure K, H Renee, ect at. Gendered differences in perceived risks and benefits of oral PrEP among HIV-serodiscordant couples in Kenya. AIDS Care. doi: 10.1080/09540121.2015.1131972 (published 11 January 2016)