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FDA issues warning over loperamide heart risks

15 JUN 2016

The US Food and Drug Administration (FDA) has issued a warning that high doses of the antidiarrheal medication loperamide are associated with a risk of heart problems.

The FDA says that healthcare professionals should be aware that higher-than-recommended doses can cause serious cardiac events, including QT interval prolongation, Torsades de Pointes or other ventricular arrhythmias, syncope and cardiac arrest. It also encourages them to consider loperamide, also known by the brand name Imodium, as a possible cause of unexplained cardiac events.

Additionally, the US medicines regulator warns that the risk of serious heart problems can be increased by interactions between loperamide and other drugs, such as some antibiotics and antifungals.

A recent article in the Annals of Emergency Medicine[1] (online, 29 April 2016) highlighted a growing issue of loperamide abuse by people with opioid addiction. The drug, an opioid agonist, has no central nervous system effects at therapeutic doses, but at higher doses might induce euphoria.

The paper outlined two cases where patients had died after using supratherapeutic doses of the drug to manage symptoms of opioid withdrawal. Some people also use loperamide to attempt to self-treat opioid addiction, the authors say.

The FDA says that most reported cases of serious heart problems with loperamide involved doses much higher than the recommended dose. It advises healthcare professionals to counsel patients on the importance of taking only the recommended dose and the risk of cardiac adverse events, as well as potential drug interactions.

Loperamide has been authorised for use in the UK since 1975.

A spokesperson for the Medicines and Healthcare products Regulatory Agency, the UK medicines regulator, says: “We are aware of the safety warning issued by the FDA about the abuse and misuse of loperamide (Imodium). We will consider what implications this may have for UK public health.”

References:

Eggleston W, Clark KH & Marraffa JM. Loperamide abuse associated with cardiac dysrhythmia and death. Annals of Emergency Medicine 2016. doi: 10.1016/j.annemergmed.2016.03.047

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Nephrinuria as potential screening tool for preeclampsia

An elevated level of urinary nephrin (nephrinuria) may be associated with an increased risk of preeclampsia (PE), according to a study, suggesting that a certain cut-off can facilitate identification of women with greater PE risk.

Researchers investigated the feasibility of nephrinuria use to assess the risk of PE by enrolling 89 pregnant women without hypertension or significant proteinuria in pregnancy (SPIP). The number of urine samples obtained was 31 during the first trimester, 125 during the second, and 93 during the third. Outcomes were changes in nephrin:creatinine ratio (NCR) and protein:creatinine ratio (PCR). SPIP was defined as PCR >0.27.

PE occurred in 14 of the women. In this group of women, NCR positively correlated with PCR (correlation coefficient, 0.862; p<0.0001).

However, there were no significant changes in NCR even with marked increases in PCR among 75 women with normotensive pregnancies. This shows that the increase in nephrinuria over the physiological range of proteinuria in pregnancy was small.

The risk of later PE development was greater among asymptomatic women with NCR >122 ng/mg (95th centile value for 75 women with normotensive pregnancies) than among those with NCR ≤122 during both the second trimester (relative risk [RR], 5.93; 95 percent CI, 2.59 to 13.6; 60 vs 10 percent) and third trimester (RR, 13.5; 3.31 to 55; 75 vs 5.5 percent).

Nephrin is a protein that is predominantly found at the glomerular slit diaphragm of podocytes. Previous studies have reported that nephrin expression is reduced in kidney biopsy specimens from women with PE and in autopsy specimens from women who died from PE. The reduced expression may be linked to increased shedding of nephrin from podocytes.

The findings suggest that NCR is unlikely to increase in normal pregnancy despite the gradual increases in PCR, whereas both NCR and PCR increase gradually with advancing gestation in PE pregnancies, researchers said. This indicates that urinary NCR may prove more useful in identifying women who are at higher risk of PE compared with urinary PCR.

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C-section preferable to vaginal delivery in acute fatty liver of pregnancy

11 Aug 2016

Caesarean delivery appears to be linked to better pregnancy outcomes in acute fatty liver of pregnancy (AFLP) compared with vaginal delivery, according to a meta-analysis of 80 studies.

“In cases of AFLP where the condition is identified, the termination of pregnancy is the only treatment available to achieve the most desirable outcomes for both the mother and foetus. However, the guidelines for selecting the delivery mode among women with AFLP are lacking,” the investigators said.

“At present, most doctors prefer to choose caesarean section (C-section) for AFLP patients based on their clinical experience rather than a further assessment of the risks.”

To evaluate the effect of C-section versus vaginal delivery on the maternal and perinatal outcomes, the investigators pooled data from studies involving 1,350 women with AFLP (mean age 25.2 years; mean gestational age 36 weeks; mean AFLP-to-delivery interval 8.14 days). Primary endpoints were maternal, perinatal, and neonatal mortality. Secondary endpoints included liver failure-associated complications, other organ injuries, obstetric haemorrhage, and infection.

C-section was associated with lower maternal and perinatal mortality risks compared with vaginal delivery (relative risk [RR], 0.56; 0.41 to 0.76; and RR, 0.52; 0.38 to 0.71, respectively). Meanwhile, neonatal mortality risk varied between the two delivery methods. [Sci Rep 2016;6:28826]

Complications and injuries—including disseminated intravascular coagulation, hypoglycaemia, ascites, encephalopathy, renal insufficiency, pancreatitis, and multiple organ dysfunction syndrome—as well as obstetric haemorrhage and infection did not differ significantly between C-section and vaginal delivery.

The protective effect of C-section on maternal mortality is multifactorial, the investigators said.

“The reduction in the risk may be associated with the maternal physical features since the differences in body size and pelvic structure will give rise to the different obstetrical indications and results of delivery mode in patients with AFLP. It may also be related to the severity of AFLP, as caesarean section may be more appropriate to terminate pregnancy in more severe cases,” they explained.

They also cited medical factors such as longer interval prior to delivery as a possible contributing factor to the increased mortality risk among women with AFLP.

“[B]ased on current evidence, caesarean section is the safest method of delivery and should be recommended to lower the risk of adverse pregnancy outcomes in AFLP. Nevertheless, additional optimally designed studies that consider the possible confounding factors could eventually provide a better, comprehensive understanding of the association between perinatal mortality and the mode of pregnancy termination in AFLP,” they concluded.

 

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Rivaroxaban outperforms heparin, warfarin; tied to lower hospital visits, healthcare costs

13 Aug 2016

Treatment with rivaroxaban appears to be associated with reduced incidences of hospitalisations and outpatient visits among patients with deep vein thrombosis (DVT) compared with low-molecular-weight heparin (LMWH) and warfarin, according to a study.

Researchers followed adult patients with DVT who initiated treatment with rivaroxaban (n=512) or LMWH/warfarin (n=512) immediately after diagnosis. The number of hospitalisations for all causes and for venous thromboembolism (VTE), healthcare resource utilisation (ER, outpatient, and other visits), as well as healthcare and pharmacy costs were assessed at 1, 2, 3, and 4 weeks after the diagnosis and compared between the two treatment arms.

The rivaroxaban treatment arm showed significantly lower mean all-cause hospitalisation numbers over 1 week (0.012 vs 0.032; p=0.044) and 2 weeks (0.022 vs 0.048; p=0.040) compared with the LMWH/warfarin arm. The mean VTE-related hospitalisation numbers were also significantly lower in the rivaroxaban arm over 1 week (0.008 vs 0.028; p=0.020), 2 weeks (0.016 vs 0.042; p=0.020), and 4 weeks (0.034 vs 0.068; p=0.036).

In terms of all-cause and VTE-related outpatient visits, the mean numbers were markedly lower among patients in the rivaroxaban arm than among those in the LMWH/warfarin arm over 1, 2, 3, and 4 weeks (p<0.001 for all).

Meanwhile, all-cause and VTE-related ER and other visits were comparable between the two treatment groups over the first 4 weeks.

Rivaroxaban users reported lower mean all-cause total healthcare costs than LMWH/warfarin users over the first 2 weeks (week 1: US$2,332 vs $3,428; p<0.001; week 2: $3,108 vs $4,524; p<0.001). Similarly, mean costs associated with all-cause hospitalisations (weeks 1 and 2) and pharmacy (weeks 1 to 4) were significantly lower among rivaroxaban users. Costs related to ER visits (weeks 1 to 4), outpatient visits (weeks 1 to 4), or other visits (with the exception of week 1) did not differ among patients between the two treatment arms.

The findings suggest that rivaroxaban is superior to LMWH/warfarin, with advantages such as simplified care facilitating less healthcare resource utilisation.

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Gallbladder removal tied to increased risk of peptic ulcers

9 Aug 2016

Cholecystectomy potentially increases the risk of subsequent peptic ulcers, according to a population-based study from Taiwan.

Surgical removal of the gallbladder is the gold standard for treating symptomatic gallstones. Despite this, a good number of patients (up to 47 percent) remains dissatisfied after the procedure. The dissatisfaction is frequently attributed to postcholecystectomy syndrome (PCS). Evidence shows that cholecystectomy promotes gastritis, which contributes to PCS.

To investigate the subsequent risk of peptic ulcers after cholecystectomy, the researchers examined the medical records of 5,209 patients who underwent cholecystectomy and received a discharge diagnosis of gallstone in comparison with 15,627 matched controls. Follow-up period was 5 years. Geographic location, hypertension, hyperlipidaemia, diabetes, CHD, obesity, alcohol abuse/alcohol dependence syndrome, and tobacco use disorder were included in the analysis as confounding factors.

Peptic ulcers developed in 9.76 percent of patients overall, with the prevalence being higher in the surgery than the control group (674 [12.94 percent] vs 1,359 [8.7 percent]; p<0.001). The likelihood of subsequent diagnosis of peptic ulcers was 2.34-fold (95 percent CI, 1.98 to 2.77) higher at 1 year, 1.84-fold (1.63 to 2.06) higher at 3 years, and 1.56-fold (1.41 to 1.72) higher at 5 years for patients who underwent cholecystectomy than for patients who did not. [Sci Rep 2016;doi:10.1038/srep30702]

On further analysis, after controlling for confounders and excluding cholecystectomy patients who died during the follow-up, the 5-year risk of developing peptic ulcers was attenuated (hazard ratio [HR], 1.48; 1.34 to 1.64). Patients in the surgery group were 1.70 times (1.44 to 1.99) and 1.71 times (1.36 to 2.15) as likely as controls to develop gastric and duodenal ulcers, respectively. Overall, the risk of peptic ulcers, regardless of the type, was higher in the surgery than in the control group.

“The mechanisms underlying the relationship between a cholecystectomy and peptic ulcers remain unclear. One possible explanation could be that [duodenogastric reflux (DRG)], which damages the gastric mucosa by bile acids and pancreatic phospholipase A2, leads to peptic ulcers. In addition, some animal studies demonstrated that DGR suppresses somatostatin concentrations and increases intragastric gastrin and acid secretion,” researchers explained.

As the previous studies suggested, DGR may play a role in the pathogenesis of gastric and duodenal ulcers, in addition to the altered antroduodenal motility and delayed gastric emptying after a cholecystectomy, researchers said, adding that H. pylori is also considered an important risk factor in peptic ulcers.

The current study is limited by the absence of information on H. pylori in gastric biopsies, as well as relevant records on data for laboratory examination, biochemical examination, or diagnostic imaging. The researchers also mentioned that physicians do not routinely biopsy the gastric mucosa to identify bile reflux gastritis in Taiwan, preventing them from identifying the pathogenesis of cholecystitis.

“Despite the aforementioned limitations, this study demonstrated a relationship between a cholecystectomy and a subsequent diagnosis of peptic ulcers,” they said.

“We suggest that clinicians be alert and suspect peptic ulcers with persistent epigastric pain or dyspepsia in patients with a prior cholecystectomy.”

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Mesoblast cell treatment shows promise for rheumatoid arthritis

11 Aug 2016

Mesoblast Ltd has announced that data from a mid-stage trial for its experimental stem-cell therapy indicated that the therapy significantly alleviated symptoms and disease activity in rheumatoid arthritis (RA) patients who have stopped responding to commercially available biotech drugs. The findings hold numerous implications in the development of new, effective therapeutic approaches to rheumatoid arthritis.

A new method of combating RA

The symptoms and progression of RA are caused by pro-inflammatory white blood cells and activated T cells of the immune system. These trigger multiple pro-inflammatory cytokine pathways; that is, they activate many kinds of small proteins which signal to the cells to become inflamed. In other words, there is more than one way to transmit the message to the cells to get inflamed.

Existing therapies each target one way of transmitting the ‘inflammation message’ by inhibiting one type of protein, but none target more than one at the same time. Mesoblast’s treatment, on the other hand, inhibits multiple types of proteins that cause inflammation. Therefore, the patient experiences significant relief from the symptoms.

Hope for those who stopped responding to conventional drugs

Treatment with the Melbourne-based company involved the intravenous delivery of MPC-300-IV, a tier 1 product candidate consisting of 300 million Mesenchymal Precursor Cells (MPCs). The results of their 48-patient, 12-week Phase 2 trial have deemed the treatment to be well-tolerated with no serious side-effects nor any infusion-related accidents.

ACR is a scale to measure change in symptoms of RA. If patients experience a 20% relief of RA symptoms, the trial is said to have achieved ACR20. In patients who had previously been treated with at least one biologic drug, ACR20 was achieved by 55% of those who had received an infusion of 2 million cells per kilogram of their weight. In patients who had received treatment from at least one biologic drug without the infusion, only 33% achieved ACR20.

There is a term used to refer to a higher degree of improvement, ACR70, when patients report a 70% relief from RA. This was achieved by 36% after a single infusion of the Mesoblast treatment, compared to the placebo group which obviously showed no improvement. The biotechnology company also claims that the cell therapy improved patients’ physical function and reduced overall disease activity.

According to a statement made by Dr Allan Gibofsky, a rheumatologist at the Hospital for Special Surgery, New York, Mesoblast’s cell infusion therapy has ‘the potential to fill the major unmet medical need’ for patients that gain no benefit from popular biological treatments. The effects of new treatment methods for RA must be twofold – alleviating pain from RA and stopping the disease from getting worse simultaneously.

 

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Guidelines on treatment and prevention of UTIs in children

1 Aug 2016

Urinary tract infections (UTIs) occur in 1 percent of boys and 3 percent of girls, with a 30 to 50 percent chance of recurrence, according to the AAUS Guidelines for UTIs in Children presented at the 14th Urological Association for Asia Congress in Singapore.

In addition, UTI is also associated with significant morbidities, including renal scar, hypertension, and chronic kidney disease, said Shang-Jen Chang from the Department of Urology at Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation in Taiwan.

UTIs in children are classified according to site (cystitis and pyelonephritis), episode (first infection and recurrent infection), severity (simple UTI and severe UTI), symptom (asymptomatic bacteriuria and symptomatic bacteriuria), and complicating factor (uncomplicated UTI and complicated UTI).

UTI diagnosis requires both positive urine culture and urinalysis that suggests infection, said Chang.

In treating UTI, the appropriate antibiotics should be given immediately after urine specimen for culture has been obtained; final antibiotic choice should be adjusted to the narrowest spectrum antibiotic when susceptibility result is available; and the choice of empirical antibiotic agents is guided by the pathogen and the local resistance patterns.

“For children with febrile UTI, the total course of antibiotic therapy should be 7 to 14 days,” said Chang, adding that “[p]rompt treatment of a febrile UTI is important to eradicate the acute infection, to prevent bacteraemia, to improve the clinical condition, and … to reduce the likelihood of renal damage.”

He also noted that antibiotics prophylaxis may be considered to prevent recurrent UTI in infants and children with or without vesicoureteral reflux (VUR) after a first UTI, but that its benefits must be weighed against the risk of antimicrobial resistance with future infections.

For children with febrile UTI, renal and bladder ultrasonography (RBUS) should be regularly conducted as soon as possible, said Chang, before adding that top-down or bottom-up approach is recommended for VUR diagnosis.

To prevent UTI in infants and children, Chang recommends breast feeding, as well as the consumption of probiotics, cranberry and related products.

Circumcision

The risk of febrile UTI in males and breakthrough febrile UTI in males with VUR may be diminished by circumcision, according to the guidelines, but that it should only be performed if the practice is accepted by the general population.

“In countries where childhood circumcision is rarely performed, other measures for febrile UTI/VUR should be the preferred choice,” it said.

 

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Opioid use potentially life-threatening for elderly COPD patients

5 Aug 2016

Initiation of opioid use in elderly patients with chronic obstructive pulmonary disease (COPD) more than doubled the risk of death from respiratory-related complications compared with non-opioid users, according to a retrospective population-based cohort study in Canada.

“The fact that incident opioids are frequently initiated in older adults with COPD makes these results particularly worrisome,” the researchers said. “Our findings suggest that a careful, individualized approach needs to be taken when administering opioids to older adults with COPD, given the potential for adverse respiratory outcomes.”

“These data raise concerns regarding the degree and manner with which opioids are used among vulnerable older adults with COPD,” said study authors Dr. Nicholas Vozoris from the Division of Respirology at the Department of Medicine of St. Michael’s Hospital in Ontario, Canada, and Dr. Denis O’Donnell of the Department of Medicine at Queen’s University in Ontario, Canada.

These findings showed that adverse outcomes could also develop in new lower-dose opioid users (≤30 mg morphine equivalents per day) and not limited to higher-dose opioid users as suggested in previous studies, the authors added.

When comparing the subgroup of patients using opioid-only medication with controls, new opioid users had a higher risk of outpatient exacerbations (p<0.0001).

The subgroup of new opioid-only users were also more likely to visit the emergency department or be hospitalized for COPD or pneumonia, or die from COPD or pneumonia or any other cause compared with controls (all p<0.0001).

Opioid-only agents usually contain more potent opioids like codeine and were indicated at a higher dose than opioid/non-opioid combination therapy, which might explain the difference in exacerbation risk in the subgroup analysis, the authors said.

“I almost never use opioids for my COPD patients. I would think that opioid-containing medication may be used to suppress cough or try to relieve the sensation of dyspnoea in these patients [in the study],” said Dr. Ong Kian Chung, a consultant respiratory specialist from the KC Ong Chest & Medical Clinic at Mount Elizabeth Medical Centre, Singapore, who was unaffiliated with the study.

“I would be cautious if the patients are very frail, elderly, already requiring oxygen supplementation and/or non-invasive ventilatory support,” he said.

For such vulnerable groups of patients, antihistamines, mucolytics or dextromethophan can be used to manage cough, while long-acting bronchodilators such as methylxanthines can be used for chronic dyspnoea, and steroids for COPD exacerbation, suggested Ong.

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Overweight/Obesity Up Incidence of Hand, Hip, Knee Osteoarthritis

Aug. 3, 2016

Being overweight or obese increases incidence of OA, especially in the knee.

The incidence of hand, hip, and knee osteoarthritis (OA) increases with overweight and obesity, particularly in the knee, according to a study published in the August issue of Arthritis & Rheumatology.

Carlen Reyes, M.D., Ph.D., from Universitat Autònoma de Barcelona in Spain, and colleagues conducted a population-based cohort study using primary care records for subjects aged ≥40 years who were without a diagnosis of OA on Jan. 1, 2006, and had body mass index (BMI) data available. A total of 1,764,061 subjects were observed for a median follow-up of 4.45 years.

The researchers found that the incidence rates of knee, hip, and hand OA were 3.7, 1.7, and 2.6 per 1,000 person-years, respectively, for subjects in the normal-weight category, and 19.5, 3.8, and 4.0, respectively, for those with grade II obesity. Being overweight or obese versus normal weight increased the risk of OA at all three joint sites, especially at the knee. The risk of knee OA increased two-, 3.1-, and 4.7-fold with a status of overweight, grade I obesity, and grade II obesity, respectively.

“Being overweight or obese increases the risk of hand, hip, and knee OA, with the greatest risk in the knee, and this occurs on a dose-response gradient of increasing BMI,” the authors write.

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Third Dose of MMR Vaccine Can Help Control Mumps Outbreaks

Aug. 3, 2016

CDC advised third dose in recent outbreak with transmission despite high two-dose coverage.

A third dose of measles-mumps-rubella (MMR) vaccine is recommended in cases of mumps outbreak in which transmission is sustained despite high two-dose MMR coverage, according to research published in the July 29 issue of the U.S. Centers for Disease Control and Prevention’s Morbidity and Mortality Weekly Report.

Justin P. Albertson, from the University of Illinois at Urbana-Champaign, and colleagues conducted an investigation into a confirmed mumps outbreak in 2015. They identified 317 cases of mumps during April 2015 to May 2016.

The researchers recommended a third MMR vaccine because of sustained transmission in a population with high two-dose coverage with MMR. The Advisory Committee on Immunization Practices did not formally recommend for or against use of a third dose. However, the CDC provided guidelines for use of a third dose as a control measure during outbreaks in a setting in which transmission is sustained despite high two-dose MMR coverage. The final case in this outbreak occurred in May 2016.

“Although evidence of its effectiveness is needed, a third dose of MMR vaccine may be considered as a control measure during mumps outbreaks occurring in settings in which persons are in close contact with one another, when transmission is sustained despite high two-dose MMR coverage, and when traditional control measures fail to slow transmission,” the authors write.