Current Drug Safety - Volume 8, Issue 4, 2013

Inflammatory neuropathies are treatable immune-mediated disorders of the peripheral nerves, the prevalence of which is higher than previously believed. Although there are now established treatments of proven benefit for acute and chronic inflammatory neuropathies consisting of intravenous immunoglobulins, corticosteroids and plasma exchanges, there are patients who fail to respond to these therapies. Immunosuppressants have been used in these refractory patients and also to lower the requirements of therapies of established efficacy due to their cost (e.g. immunoglobulins) or sideeffects (e.g., corticosteroids). These drugs include “conventional” immunosuppressants like azathioprine, cyclophosphamide etc. and also newer drugs like Rituximab. Other immunomodulatory drugs like interferon beta have also been trialled in some patients. Currently the role of newer drugs like Fingolimod in inflammatory neuropathies is being studied. In this article, the issue of treating inflammatory neuropathies with immunomodulatory and immunosuppressive agents in the context of their potential adverse effects, is reviewed and discussed. The published evidence on these drugs is reviewed, rationale behind the use of such drugs is analyzed and benefit to risk ratio highlighted.

Background: Fluid resuscitation is widely practiced in intensive care units for the treatment of sepsis. A comparison of the evidence base of different fluids may inform therapeutic choice. Methods: The risks of mortality and morbidity (the need for renal replacement therapies (RRT)) were assessed in patients with severe sepsis. A network meta-analysis compared trials for crystalloids, albumin and hydroxyethyl starch (HES). A literature search of human randomized clinical trials was conducted in databases, the bibliographies of other recent relevant systematic reviews and data reported at recent conferences. Mortality outcomes and RRT data with the longest follow up period were compared. A Bayesian network meta-analysis assessed the risk of mortality and a pair-wise metaanalysis assessed RRT using crystalloids as the reference treatment. Results: 13 studies were identified. A fixed-effects meta-analysis of mortality data in the trials demonstrated an odds-ratio (OR) of 0.90 between crystalloids and albumin, 1.25 between crystalloids and HES and 1.40 between albumin and HES. The probability that albumin is associated with the highest survival was 96.4% followed by crystalloid at 3.6%, with a negligible probability for HES. Sub-group analyses demonstrated the robustness of this result to variations in fluid composition, study source and origin of septic shock. A random-effects pairwise comparison for the risk of RRT provided an OR of 1.52 favoring crystalloid over HES. Conclusion: Fluid therapy with albumin was associated with the highest survival benefit. The higher morbidity with HES may affect mortality and requires consideration by prescribers.

Objectives: The objective of this study was to evaluate the pharmacotherapy of bipolar II disorder during pregnancy and the postpartum period. Methods: The use of psychotropic drugs and recurrence risk during and after pregnancy was studied in a prospective, observational study of 37 women with bipolar II disorder. Results: During pregnancy the majority of participants (54.0%) were not on any psychotropic medication, approximately one third (32%) received monotherapy, and the rest were on combination therapy. In comparison, during the postpartum period only 14% of participants were not on any psychotropic medication, approximately 35% received monotherapy, and over 50% were on combination therapy. While only 13.5% of participants were on 3 or more psychotropic drugs during pregnancy, 21.6% required 3 or more psychotropic drugs after childbirth in order to manage their symptoms. During pregnancy, 51 % of women had a mood episode compared to a recurrence rate of 70% in the postpartum period. Limitations: Small sample size, lack of a control group, and absence of random treatment assignment. Conclusions: The findings of this prospective, observational study indicate that the recurrence risk is much higher after childbirth than during pregnancy in spite of higher utilization of psychotropic drugs in the postpartum period.

Objective: The objective of this study was to determine if patients who weigh ≥100 kg are more likely to receive under-dosing of etomidate compared to those who weigh <100 kg for rapid sequence intubation in the emergency department (ED). Methods: This was a retrospective cohort study conducted in an academic ED in the United States. Adult patients who received etomidate for rapid sequence intubation were evaluated and categorized into two groups based on weight: 1) <100 kg or 2) ≥100 kg. The mean dose of etomidate (mg/kg) was compared between the groups using an unpaired Student’s t-test. The percentage of patients who received under-dosing (less than 0.2 mg/kg) was compared between groups using the Chi-squared test. Results: A total of 200 patients were included in the final analyses (100 patients in the <100 kg group and 100 patients in the ≥100 kg group). There were no baseline differences in age, sex, paralytic used, or trauma status between the treatment groups. The mean etomidate dose (mg/kg ± standard deviation) was significantly lower in the ≥100 kg group compared to the <100 kg group (0.18 ± 0.03 vs. 0.28 ± 0.07, respectively; plt;0.001). There were significantly more patients in the ≥100 kg group who received under-dosing of etomidate compared to the <100 kg group (68% vs. 2%, respectively; p<0.001). Conclusions: Patients who weigh ≥100 kg are more likely to receive under-dosing of etomidate compared to those who weigh <100 kg for rapid sequence intubation in the ED.

Background: Lithium is one of the most effective medications in the treatment of mood disorders. The long-term lithium therapy can alter kidney morphology and function. Objective: To evaluate the relation of Magnetic resonance imaging (MRI) of the kidneys and renal function in patients undergoing chronic lithium therapy. Methods: Thirty five consecutive patients with mood disorders who were undergoing lithium therapy for at least two years were evaluated with a 1.5 tesla MR imaging and renal function tests. The relationship between renal size, the presence, number and location of renal microcyst with renal function were evaluated. The partial correlation analysis was performed to assess correlation between variables. Results: The mean size of kidney was 106.0 mm ± 6.0 and 106.0 mm ± 11.0 in right and left kidneys respectively. The mean number of microcysts in both kidneys was 6.2. There was a positive correlation between duration of lithium treatment and number of renal microcyst (P-value=0.03). Correlation between MRI findings and renal function tests was not statistically significant. Conclusion: The present study revealed that longer duration of lithium therapy can increase number of renal microcysts which is well shown with MR imaging. It seems that increasing renal microcysts may not be consistent with renal function impairment especially in earlier treatment phase. Thus the question arises is that MRI may not be as the first line method for clinicians who aim to assess renal function during long term lithium therapy.

Background and Aims: The association between gastrointestinal (GI) bleeding and subsequent detection of GI cancer in patients using antiplatelet/anticoagulant medications is unclear. We investigated the association between the occurrence of GI bleeding and the detection of GI cancer and assessed whether this association differs in patients treated with clopidogrel or warfarin compared to non-treated patients. Methods: A claims analysis was conducted using the Truven Health MarketScan® Research databases. Patients were grouped into the treatment cohort if they received a prescription for clopidogrel or warfarin or into the non-treatment cohort if they did not receive these medications. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for GI cancer diagnosed after GI bleeding. Results: Overall, in the treatment cohort, patients who experienced a GI bleed were 6 times (HR: 5.64, 95% CI, 5.12, 6.21) more likely to be diagnosed with GI cancer compared with those without bleeding. In the non-treatment cohort patients were 13 times (HR: 13.34, 95% CI, 12.21, 14.58) more likely to be diagnosed with GI cancer after GI bleeding. The HRs of GI cancer were higher within 6 months of the first GI bleed and decreased remarkably thereafter. Conclusions: This study suggests that an episode of GI bleeding increased the rates of detection of GI cancers

Forty five crude extracts of nine selected medicinal plants, based on their use in respiratory and other disorders in traditional systems of medicine were analyzed for their potential activity against three pathogenic species of Aspergillus. The presence of phenols, tannins, flavanoids, terpenoid, steroids, alkaloids and saponins in the different extracts was established. The crude extracts were examined for antifungal activity in concentration ranging from 5000.0 to 19.53 µg/ml using microbroth dilution assay in which twenty two extracts exhibited the anti-Aspergilli activity. The petroleum ether extract of Justicia adhatoda and water extract of Commelina bengalensis exhibited the maximum activity against Aspergillus fumigatus, Aspergillus flavus and Aspergillus niger. Their in vitro minimum inhibitory concentrations (MICs) were found to be 156.0-312.0 µg/ml by microbroth dilution and spore germination inhibition assays. In disc diffusion assay, at concentration of 10 µg/disc of some crude extracts showed significant activity against Aspergilli. The toxicity (in vitro and in vivo) of bio-active fractions was evaluated, in which the extracts isolated from J. adhatoda were found to be non-toxic. Gas chromatography-mass spectrometry (GCMS) studies were performed for various extracts (petroleum ether, chloroform and acetone) of J. adhatoda which resulted in the identification of several bioactive compounds. The antifungal activity along with acute toxicity, cyto-toxicity as well as genotoxicity of extract fractions from J. adhatoda justifies the use of such screening in the expedition for new drugs.

Objective: The aim of this study was to evaluate the frequency of metformin-associated lactic acidosis in our metformin-intoxicated patients, the general approach for their management, and determine the frequency of hypoglycemia and outcome in these patients. We also wanted to see if there was a significant difference in the course and outcome of metformin poisoning between our patients and those reported in the literature. Materials and Methods: Files of all patients diagnosed with metformin toxicity were retrospectively evaluated. A purposemade questionnaire containing the patients’ demographic data, vital signs and lab tests on presentation, time of development of hypoglycemia and metabolic acidosis (if any), treatment modalities performed for the patients and their indications, and the patients’ outcomes was filled. The patients were evaluated in total and then assigned into two groups of metformin alone (group 1) and multi-drug toxicity including metformin (group 2) and were compared. Results: A total of 204 patients were reviewed. Fifty-five (26.9%) were in group 1 and 149 (73.1%) were in group 2. Sixteen and 52 patients in groups 1 and 2 had acidosis. Dialysis was performed in only four patients, all of whom belonged to group 1 (P = 0.005). They were all dialyzed only once. Two patients (1%) died both of whom were in group 2. Groups 1 and 2 were insignificantly different in all characteristics except for their aspartate transaminase and creatine phosphokinase. Almost 23% of the patients in group 1 had experienced hypoglycemia sometime during their course of hospitalization. Conclusions: Although lactic acidosis is considered to be a serious condition resulting in high mortality and morbidity rates, it seems that our patients can easily and safely be managed with conservative therapies. Most of them do not need aggressive treatments including hemodialysis. Metformin seems to cause hypoglycemia more than what was previously considered.

Eisenmenger syndrome is associated with irreversible increase in pulmonary vascular resistance causing reduced survival. Bosentan, a non-selective endothelin receptor antagonist is the commonly used specific pulmonary arterial hypertension drug in Eisenmenger syndrome. In this paper, we present a case of recurrent gastrointestinal bleeding in a 23-year-old female with Eisenmenger syndrome who was only under bosentan treatment, which has not been reported previously. Most common adverse effect of bosentan is elevation in the liver enzymes however, bleeding complication is very rare. On the contrary, it was proposed that bosentan might be a potential protector against hyperacidity and mucosal erosion that occur as a consequence of stress. Although the mechanistic relationship of bleeding tendency and role of Eisenmenger syndrome concomitant with bosentan treatment is far from conclusive statement for now, this association warrants and should draw attention of clinicians and researches in this field.

Introduction: Hyperammonemia is one of the rare nevertheless serious side effects associated with valproic acid treatment. Two cases of valproic acid induced hyperammonemia are detailed in this article. Cases: Case one describes an adult male who developed hyperammonemia after acute exposure to valproic acid as a treatment for his bipolar disorder-manic episode. Case two developed a similar pattern of toxicity but after chronic exposure to valproic acid. Both patients were receiving a combination of valproic acid and quetiapine. Discussion: Measurement of the ammonium level should be considered where there is a decreased level of consciousness in patients receiving valproic acid irrespective of the diagnosis and even after a long term exposure. A possible risk of hyperammonemia can result from a combination of valproic acid and quetiapine, however further studies are yet needed to confirm this hypothesis.

Background: Arrhythmia induced by etoposide is exceedingly rare. There are only a very few individual case histories of arrhythmias during etoposide infusion, including atrial fibrillation. Objective: Through this uncommon case, we propose to study the pathophysiology, the diagnosis and the management of this entity. Case Report: We report a case of a 57-year-old man, without cardiac history, followed for endocrine tumor of the pancreas with liver metastases who had presented atrial fibrillation (AF) after etoposide infusion. Conclusion: It is important to consider cardiac monitoring during etoposide infusion in patients with known cardiac disease or at high risk of cardiac complications.