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Effective optimal pharmacotherapy requires a comprehensive understanding of the drug’s pharmacokinetic properties. Chronic kidney disease (CKD) influences medication pharmacokinetics. However, whether sex differences exist in the pharmacokinetics of drugs for children with CKD is unknown. The primary aim of this article was to evaluate the effect of sex on pharmacokinetics of drugs commonly used for CKD treatment in children. Secondary outcome was to address the impact of sex in CKD disease progression. Electronic databases, PubMed, EMBASE, Google Scholar, and Web of Science were searched from inception, using Mesh terms in English for sex differences in the pharmacokinetics of drugs in children with CKD. No studies have documented sex-related differences in the pharmacokinetics of drugs for the treatment of CKD in children. As a consequence, it is difficult to predict the effect of sex on pharmacokinetics by extrapolating data from adult studies to children. Evidence to date suggests that girls generally have a higher prevalence and disease progression of CKD when compared to boys regardless of age. Understanding the pharmacokinetics and pharmacodynamics of drugs provides practical consideration for dosing optimal medication regimens. Future kinetic studies are needed evaluating the effect of sex on the pharmacokinetics and pharmacodynamics of drugs in children with CKD.Effective optimal pharmacotherapy requires a comprehensive understanding of the drug’s pharmacokinetic properties. Chronic kidney disease (CKD) influences medication pharmacokinetics. However, whether sex differences exist in the pharmacokinetics of drugs for children with CKD is unknown. The primary aim of this article was to evaluate the effect of sex on pharmacokinetics of drugs commonly used for CKD treatment in children. Secondary outcome was to address the impact of sex in CKD disease progression. Electronic databases, PubMed, EMBASE, Google Scholar, and Web of Science were searched from inception, using Mesh terms in English for sex differences in the pharmacokinetics of drugs in children with CKD. No studies have documented sex-related differences in the pharmacokinetics of drugs for the treatment of CKD in children. As a consequence, it is difficult to predict the effect of sex on pharmacokinetics by extrapolating data from adult studies to children. Evidence to date suggests that girls generally have a higher prevalence and disease progression of CKD when compared to boys regardless of age. Understanding the pharmacokinetics and pharmacodynamics of drugs provides practical consideration for dosing optimal medication regimens. Future kinetic studies are needed evaluating the effect of sex on the pharmacokinetics and pharmacodynamics of drugs in children with CKD.

Pharmacokinetic and clinical studies recommend applying loading dose of colistin for the treatment of severe infections in the critically ill adults. Pharmacokinetic studies of colistin in children also highlight the need for a loading dose. However, there are no clinical studies evaluating the effectiveness of colistin loading dose in children.

In a randomized trial, children with ventilator-associated pneumonia or central line-associated bloodstream infection (CLABSI) for whom colistin was initiated, were enrolled. Patients were randomized into two groups; loading dose and conventional dose treatment arms. In the conventional treatment arm, colistimethate sodium was initiated with maintenance dose. In the loading dose group, colistimethate sodium was commenced with a loading dose of 150,000 international unit/kg, then on the maintenance dose. Both treatment arms also received meropenem as combination therapy. Primary outcomes were overall efficacy, clinical improvement and microbiological cure. Secondary outcomes were colistin-induced nephrotoxicity and development of resistance.

Thirty children completed this study. There was a significantly higher overall efficacy in the group received loading dose (42.9 vs. 6.3%, P = 0.031). There weren’t any significant differences in the clinical and microbiological endpoints. In the subgroup of children with CLABSI, results illustrated a trend toward (though statistically nonsignificant) better clinical cure for patients receiving loading dose.

This preliminary study suggests that colistin loading dose might have some benefits in critically ill children, specifically in children with CLABSI. Further trials are required to elucidate colistin best dosing strategy in critically ill children with severe infections.

In recent years, low molecular weight heparin use has increased in children. Dose of enoxaparin to achieve target anti-Xa and time to achieve anti-Xa are evolving and efficacy outcome data in terms of laboratory and clinical response rate in children still remains to be elucidated. Thus, in this drug utilization and evaluation study, we assessed patterns of enoxaparin use, its concordance with guidelines and laboratory and clinical outcomes in pediatric patients in a Children’s teaching hospital.  

In a prospective observational study, all pediatric patients with a thrombotic event who underwent treatment with enoxaparin were included. Demographic data, clinical outcome data based on follow-up sonography results, laboratory response based on anti-Xa and concordance with guidelines in terms of initial daily dose, duration of treatment, performing sonography to evaluate response, anti Xa check and time of anti-Xa check were evaluated.

During a 9-month period, 41 pediatric patients suffered a thrombotic event and received enoxaparin. Median age of participants was 18.5 months. The anti-Xa level became therapeutic on mean day 4.7 with a mean enoxaparin dose of 1.24 mg/kg. Among participants 42% achieved therapeutic anti-Xa with initial empirical dosing. Less than 25 % of participants had a follow-up sonography and among them, 77% demonstrated complete thrombosis resolution after 4-6 weeks of enoxaparin therapy. We observed one major bleeding event. Concordance with guidelines was low in the aspects of duration of treatment, performing sonography to evaluate response and anti-Xa check.

With initial empiric dosing, it may take several days before anti-Xa become therapeutic. Among half of the children, a higher than recommended 1 mg/kg dose was required to achieve therapeutic anti-Xa level. Educational processes are mandatory regarding enoxaparin use and monitoring among clinicians to improve concordance with guidelines.

Fluoroquinolones are not routinely used as the first‑line antimicrobial therapy in pediatrics. The American Academy of Pediatrics (AAP) and the United States Food and Drug Administration (FDA) approved fluoroquinolones on certain indications in children. The aim of this study was to evaluate to what extent and how ciprofloxacin is used on approved indication or as off‑label. Besides, dose adequacy and treatment duration were assessed.

In a 10‑month observational study, all children receiving systemic ciprofloxacin were assessed. We classified ciprofloxacin prescription to an AAP/FDA or off‑label indication. The off‑label prescriptions were further categorized to justified and unjustified therapy subgroups. The AAP/FDA category and the justified subgroup constituted the appropriate prescriptions.

During the study period, 32 patients were prescribed ciprofloxacin. In general, 37% (12) of prescriptions determined to be appropriate. Of the appropriate prescriptions, 7 were AAP/ FDA‑approved indications. Children with Crohn’s disease with abdominal abscess and children with infectious bloody diarrhea constituted the off‑label; justified therapy subgroup. Unjustified prescriptions mainly occurred in the presence of a suitable alternative antibiotic for ciprofloxacin. Mean ± SD of ciprofloxacin dose (mg/kg/day) and duration (days) were 21.25 ± 6.35 and 13.56 ± 8.48, respectively. Of the appropriate prescriptions, 41% were underdosed. Underdosing was more encountered in patients with cystic fibrosis. Duration of treatment of the appropriate prescriptions was determined to be appropriate.

The majority of children were receiving ciprofloxacin off‑label and in an inappropriate manner. This issue emphasizes that antimicrobial stewardship program on ciprofloxacin use in pediatric hospitals should be implemented. Further studies evaluating clinical and microbiological outcomes of these programs in children are needed.

One of the main problems facing public health providers and administrators in many countries is ensuring the rational use of high-cost drugs. In this regard, on-going process of medication use evaluation can be considered as a useful tool. In this study, we evaluated certain usage aspects of a highly-cost medication, that is, recombinant growth hormone (GH).

This cross‑sectional study conducted from August 2012 to August 2014. Children receiving GH ± gonadotropin releasing hormone (GnRH) analogs were included in the study. A researcher-designed checklist was developed to evaluate the GH utilization in these patients. Baseline demographic characteristics and background clinical and growth data, as well as any aspects of drug therapy including indications, dosing, monitoring, and discontinuation were collected from the patients’ medical records.

Seventy children receiving GH entered the study, of which 23 patients (32.85%) received GH and GnRH analogs simultaneously. At the baseline, 67 children (95.7%) had GH stimulation test, whereas serum insulin-like growth factor-1 (IGF-1) levels were measured in 63 (90%) patients. Sixty‑seven patients (95.71%) had thyroid function test, whereas bone age was determined in 68 children (97.14%). The mean ± standard deviation of GH dose for idiopathic short stature, GH deficiency, Turner’s syndrome and born small for gestational age in our study was 0.22 ± 0.025 mg/kg/week, 0.23 ± 0.04 mg/kg/week, 0.22 ± 0.015 mg/kg/week, and 0.23 ± 0.02 mg/kg/week, respectively. Height and weight of all patients were followed every 3–6 months, regularly. Thirty patients were treated with GH for at least 1 year, of which thyroid hormones and IGF‑1 levels were measured annually in 25 (83.33%) and 26 (86.66%) patients, respectively; while bone age was evaluated in 13 (43.33%) children, annually. GH treatment was discontinued in 15 patients (21.42%), while financial problem was the major reason.

Diagnostic tests and monitoring of height, weight, IGF-1 level and thyroid function was properly performed in this setting. However, a number of patients with ISS and Turner’s syndrome were under-dosed.

Adverse drug reactions (ADRs) are known as a cause of hospital admission. We have carried out a prospective study to characterize and assess the frequency, probability, preventability, and severity of ADRs, which lead to hospital admission in children.

In a prospective observational study, a cohort of children admitted to a tertiary pediatric hospital was randomly screened to assess ADR as the cause of admission from June 2014 to January 2015. ADRs causing admissions were detected based on patients’ records, interviewing their parents, and confirmation by medical team. The probability of the ADRs was assessed based on WHO criteria and Naranjo tool. The preventability assessment was performed using Schumock and Thornton questionnaire.

Of the 658 evaluated emergency admissions, 27 were caused by an ADR giving an incidence of 4.1%. Among ADRs, 37.1% were estimated to be preventable. Antibiotics were the most common medication class which caused hospital admission.

Pediatric pharmacotherapy still needs evidence‑based strategies to improve child care including education, monitoring, planning for medications after ADR occurrence, and implementing preventive measures when applicable.

The aim of the current study was to determine various aspects of methylphenidate adverse reactions in children with attention deficit‑hyperactivity disorder (ADHD) in Iran.

During the 6 months period, all children under methylphenidate treatment alone or along with other agents attending a university‑affiliated psychology clinic were screened regarding all subjective and objective adverse drug reactions (ADRs) of methylphenidate. Causality and seriousness of detected ADRs were assessed by relevant World Health Organization definitions. The Schumock and Thornton questionnaire was used to determine preventability of ADRs.

Seventy‑one patients including 25 girls and 46 boys with ADHD under methylphenidate treatment were enrolled within the study period. All (100%) ADHD children under methylphenidate treatment developed at least one ADR. Anorexia (74.3%), irritability (57.1%), and insomnia (47.2%) were the most frequent methylphenidate‑related adverse reactions. Except for one, all other detected ADRs were determined to be mild. In addition, no ADR was considered to be preventable and serious.

Our data suggested that although methylphenidate related adverse reactions were common in children with ADHD, but they were mainly mild and nonserious.

Oral azithromycin is recommended as anti-inflammatory therapy for patients with cystic fibrosis (CF) 6 years of age and older to improve lung function and reduce exacerbations.

We evaluated the short-term efficacy and safety of nebulized azithromycin as anti-inflammatory therapy in children with CF chronically infected with Pseudomonas aeruginosa.

In a randomized prospective study, children aged 8 - 18 years with clinically stable CF and FEV1 25% - 75% predicted with no recent use of oral, intravenous or inhaled antipseudomonal antibiotics and azithromycin were randomized to receive either nebulized azithromycin (70 mg daily) or oral azithromycin 3 times per week for 28 days. Primary endpoint was changes in pulmonary function (FEV1). Secondary outcomes included changes in Pseudomonas aeruginosa (PA) colonization characteristics (count, phenotype), quality of life and weight.

A total of 280 patients were screened, of whom 60 were found eligible. Forty five patients (25 in the nebulized group) and 20 in the oral group) completed the study. After 28 days of treatment, nebulized azithromycin was significantly associated with improvements in FEV1 % predicted, quality of life measure and weight. Also PA count was significantly decreased. Importantly, improvements of FEV1 % predicted, quality of life, weight and the decline in PA count were statistically significantly greater with nebulized azithromycin compared with oral azithromycin. No significant difference was observed in PA phenotype in either treatment arms.

Nebulized azithromycin is associated with a significant improvement in lung function, PA count, quality of life and weight in clinically stable CF children with chronic PA infection. The improvements observed were greater compared with oral azithromycin. Nebulized azithromycin could be suggested as a new therapeutic strategy for this life-limiting disease. Further clinical trials with novel nebulizer formulation of azithromycin and large number of participants are needed to further assess the efficacy, safety and sustained effect of this new therapeutic approach in children with CF.

Stenotrophomonas maltophilia, a multidrug-resistant gram-negative bacillus is an opportunistic organism. Infections caused by this pathogens needs to be treated promptly and is life-threatening in neonates (1,2). The most common clinical presentations are pneumonia and bacteremia. Treatment includes limited number of antimicrobials with defined MIC cutoffs by US Clinical and Laboratory Standards Institute (CSLI). These include trimethoprim-sulfamethoxazole (TMP-SMX), levofloxacin, ticarcillin-clavulanate, minocycline, ceftazidime and chloramphenicol (1). Treatment of choice is TMP-SMX based on reliable in-vitro activity and favorable clinical outcomes (1, 2). Levofloxacin is a potential alternative to TMP-SMX (1). Usually we encounter high resistant rates to ceftazidime (3). Ticarcillin-clavulanate is not readily available in Iran. Also it is shown to be less active than TMP-SMX in vivo (2). One of the concerns with sulfa antibiotics in neonates is the potential risk of hyperbilirubinemia and kernicterus (2,4-6). The landmark study was in 1956 in which Andersen et al elucidated that premature infants receiving a penicillin/sulfisoxazole combination had a significantly higher rate of mortality and kernicterus compared with oxytetracycline (4). In the study by Thyagarajan et al, suggested that the concept of kernicterus and TMP-SMX remains a theory and needs to be further illuminated in trials. Based on their experience, who prescribed TMP-SMX for treatment of sepsis and pneumonia in newborns and infants in rural and tribal areas in India in a home-based neonatal care setting, no adverse effects, including any signs of central nervous system (CNS) toxicity was noted (6). There are also no dosing recommendations for TMP-SMX in neonates (2) and if used when facing stenotrophomonas maltophilia infection, it is used in an off-label manner. So when we encounter stenotrophomonas maltophilia infection in neonates (term and preterm) with TMP-SMX being the first treatment choice, how could the risk-benefit assessment be judged? When reviewing the literature there are case reports of treatment of neonatal stenotrophomonas maltophilia pneumonia with TMP-SMX with no report of kernicterus (2,7). One of the concerns with fluoroquinolones in children is the risk of arthropathy (8,9). Bradley et al demonstrated that musculoskeletal toxicity 5 years after therapy with levofloxacin appear to be uncommon, clinically undetectable or are reversible in children (10). So the challenge is selecting between TMP-SMX with risk of kernicterus and levofloxacin with risk of arthropathy when treating stenotrophomonas maltophilia pneumonia or sepsis in neonates when it is susceptible to both agents. Since the concern on kernicterus still remains, one conservative approach may be selecting levofloxacin over TMP-SMX in neonates. A recent systematic review and meta-analysis has shown comparable efficacy of fluoroquinolones on mortality to TMP-SMX (11). Other approach may use combination therapy of TMP-SMX with levofloxacin because of high morbidity and mortality associated with this pathogen (2,7). Studies reporting experience regarding successful treatment of this pathogen in meningitis, sepsis, pneumonia or urinary tract infections in neonates are highly needed.

Metabolic and cardiovascular side effects have been noted with the use of second generation antipsychotics (SGAs) and mood stabilizers. Since Omega-3 fatty acids have been known to prevent some cardiovascular risks, this preliminary study was designed to evaluate the cardiovascular benefits of omega-3 when added to the combinations of olanzapine with mood stabilizers. This study was a randomized, double-blind, placebo-controlled, within-subject trial in adult psychiatric patients who were receiving olanzapine combined with lithium (Li) or valproate sodium (VPA). Omega-3 as fish oil with less than 1 g/day of EPA/DHA or its placebo was added to patients’ olanzapine and mood stabilizer regimens for 6 weeks. Metabolic parameters including anthropometric variables, lipid profile, metabolic syndrome indices, C-reactive protein, fibrinogen and lipoprotein (a) [(Lp) (a)] were assessed for participants. Forty one participants completed this study; 20 patients received omega-3 and 21 patients received placebo, added to their regimen of SGA and mood stabilizer. Omega-3 addition did not modulate anthropometric, metabolic syndrome and lipid parameter changes in 6 weeks. However, fibrinogen levels significantly decreased, Lp (a) did not increase and non-high-density lipoprotein cholesterol (non-HDL-C) did not go beyond its target level after omega-3 supplementation. Additionally, a significant inter-group effect was noted for Lp(a). This study suggests that use of short-term omega-3 supplementation added to a combined regimen of olanzapine and mood stabilizer may have a small modulating effect on some cardiovascular risk factors. Trials in longer periods of time and with larger number of patients are needed to further evaluate the effects of omega-3 supplements on preventing cardiovascular risk factors. This trial is registered at irct.ir and its Identifier is as following: IRCT138712231764N1

To compare the effects of topiramate versus valproate sodium as an add-on therapy to a combination of lithium and risperidone (Li+Ris) on body weight and serum lipid profile in children and adolescents with bipolar disorder. In a single-blind randomized clinical trial, thirty children and adolescents with bipolar disorder type I in the manic or mixed phase, treated with the combination of Li+Ris at therapeutic doses for at least 4 weeks who had the indication of add-on therapy due to a recurrent episode; a partial response or non response in the current episode or relapse were included. Participants were randomly assigned to receive either topiramate or sodium valproate as the third drug add-on therapy for a total of 6 weeks. Weight, height and serum lipid profiles were determined at baseline and at the end of week 6. Differences in the mean levels of lipid profiles at baseline and after week 6 evaluation were not significant in both treatment groups. BMI z-score increased in both treatment groups, being significant only in the Li+Ris/Valproate group, increasing from (mean ±SD) 0.38 ±0.55 to 0.72 ±1.23 (p<0.05). Between group changes in BMI z-score was not significant.Among the BMI percentile categories, participants in the normal weight subgroup showed a significant increase in BMI z-score during the 6 week trial, compared to overweight/obese subgroup, in both Li+Ris/Valproate and Li+Ris/Topiramate treatment groups. Elevated mean serum level of triglyceride and a high proportion of participants with elevated total cholesterol (≥ 170 mg/dl), triglyceride (≥ 110 mg/dl), and BMI percentile 85-<95 at baseline (before randomization) and at the end of 6 week study were noted. When topiramate and valproate sodium are used for six weeks as adjunctive treatment to a combination of Li+Ris, they act alike on lipid milieu of children and adolescents with bipolar disorder. Both Li+Ris/Valproate and Li+Ris/Topiramate therapies can lead to an increase in BMI z-score. This increase is statistically significant with Li+Ris/Valproate therapy. This suggests that topiramate could attenuate the ongoing weight gain from lithium and risperidone. In this study, the majority of participants who gained weight were those with BMI less than 85th percentile. This suggests that normal weight patients may have greater weight gain potential than overweight/obese patients.High proportion of metabolic abnormalities among the patients at baseline, which remained elevated throughout the trial, warrants cardiometabolic monitoring in this population.

Metabolic side effects of the second generation (atypical) antipsychotics have been a forefront of attention since their availability. One common concern is the development of hyperglycemia and insulin resistance. The aim of this study was to evaluate the effect of early initiation of omega-3 fatty acids supplementation on glucose-insulin homeostasis in a group of psychiatric patients under treatment with olanzapine and sodium valproate or lithium combination. In a double-blind design, eligible participants with schizophrenia, bipolar I, and schizoaffective disorders who were initiated on olanzapine combination with sodium valproate or lithium were randomly assigned to receive omega-3 or identical placebo capsules for 6 weeks. Fasting blood sugar (FBS), insulin and HbA1c were measured at the baseline and at the end of the 6th week. Homeostatic model assessment of insulin resistance (HOMA-IR), as a measure of insulin resistance, was also determined at the same times. At the end of the study, no significant difference was observed between the two arms in terms of FBS, fasting insulin, HbA1c and HOMA-IR. However, trends toward decreasing both fasting insulin levels (p= 0.06) and HOMA-IR (p= 0.07) were noted in the group receiving omega-3. No significant changes in the outcome variables were observed from the baseline to the final measurements in both groups. This study noted that adding omega-3 fatty acids at the commencement of olanzapine combination therapy with valproate or lithium could not favorably influence glucose-insulin homeostasis. However, trends toward a decrease in insulin levels (p= 0.06) and HOMA-IR (p= 0.07) observed in patients receiving omega-3 suggest a possible beneficial role of this supplement in this population and, therefore, warrant further evaluation.

In this study the effect of topiramate as adjunctive therapy to lithium on mood disorder in adolescents is compared to that of sodium valproate. In a randomized clinical trial, 30 adolescents with bipolar mood disorder in the manic or mixed phase were treated with either topiramate or sodium valproate. All participants had either not responded adequately to a 4 to 6 week period of treatment with lithium carbonate, or had relapsed after a period of remission and needed additional mood-stabilizing drug. Responses were evaluated using Young Mania Rating Scale, Clinical Global Impression Scale and Children Global Assessment Scale. Many of the demographic properties of both groups were similar. In each group the mean of the decrease in symptoms and degree of remission were significant (p<0.001), but the comparison between the two groups did not yield a statistically significant difference. Both topiramate and sodium valproate can be effective in the treatment of adolescent bipolar mood disorder and there is probably no difference in their efficacy.