Pidotimod increases inflammation in wounded zebrafish embryos.

Pidotimod (PDT) is a synthetic dipeptide molecule which can improve immune responses in mice and humans, protecting hosts from infection. However, the exact mechanism of protection remains ill-defined. The effect of pidotimod has not yet been investigated in the inflammatory response of zebrafish. In this study, we used tail wound and infection models of zebrafish to study the effect of PDT on inflammation. We found that zebrafish larvae were sensitive to PDT immersion causing toxicity at doses above 50 µg/mL. The tail wound assay showed that PDT increased the recruitment of neutrophils and macrophages to the wound site and promoted the transcription of the pro-inflammatory cytokine il1b. However, we did not observe protection of uropathogenic Escherichia coli or Mycobacterium marinum infected zebrafish larvae following PDT treatment. This study provides a new platform for PDT research, which is worthy of further research to identify further effects of PDT therapy.

Whether Immunostimulants Are Effective in Susceptible Children Suffering From Recurrent Respiratory Tract Infections: A Modeling Analysis Based on Literature Aggregate Data.

Immunostimulants are gradually being used in the prevention and treatment of recurrent respiratory tract infections in susceptible children, but their drug effects have not been quantified. The purpose of this study was to confirm the efficacy of immunostimulants in the prevention and treatment of recurrent respiratory tract infections in susceptible children. A model-based meta-analysis was used to describe the time course of placebo and immunostimulants in the prevention of respiratory tract infections in children. The cumulative number of respiratory tract infections was used as an indicator of efficacy. A meta-analysis was used to analyze the incidence of drug-related adverse events. Fourteen articles with 2400 pediatric subjects were finally included in the analysis. The results showed that the cumulative number of respiratory tract infections increased linearly with time, with the incidence of respiratory tract infections in the placebo group being 0.65 (95% confidence interval [CI], 0.55-0.75) per month. OM-85 BV and pidotimod reduced the incidence of respiratory tract infections by 0.21 (95%CI, 0.16-0.26) and 0.19 (95%CI, 0.17-0.21) compared to placebo per month, respectively. Pidotimod and OM-85 BV can effectively reduce the incidence of respiratory tract infections in susceptible children, with no significant increase in the incidence of drug-related adverse events when compared with placebo (risk ratio values were 1.07 [95%CI, 0.66-1.71] and 1.31 [95%CI, 0.54-3.19], respectively). This study provides quantitative support for the application of immunostimulants for the prevention of recurrent respiratory tract infections in children.

Pirometaxine™ (Narlisim™) in pediatric nasal congestion: a retrospective study.

BACKGROUND: Nasal congestion represents a troublesome health issue which is especially and invalidating in children. Effective nasal drugs, such as sympathomimetic drugs, are usually forbidden in children under 12 years of age because of their potential systemic adverse effects. Hypertonic nasal physiological solutions have recently been successfully used to decongest nasal mucosa in children: its mechanical activity has been universally recognized as safe and effective and it represents a well-established, useful treatment in children. METHODS: We have retrospectively analyzed a case series of 40 children treated for 4 days (96 hours) with a new class 1s medical device nasal hypertonic spray containing Pirometaxine™ (Narlisim™) in outpatient affected by nasal congestion due to common cold. Every child was evaluated on a 3-point symptom assessment scale (0: no symptom; 1: mild symptom; 2: moderate symptom; 3: severe symptom) at the beginning of the trial (T0) and after 48 (T1) and 96 hours (T2). The symptoms assessed were nasal obstruction, nasal secretion, headache, flash of cold, pharyngodynia, cough, and sneeze. RESULTS: The results, in terms of short-term efficacy to control nasal obstruction (T1 vs. T0: P<0.0001; T2 vs. T0: P<0.0001), nasal secretion (T1 vs. T0: P<0.0001; T2 vs. T0: P<0.0001) and all the symptoms related to common cold have supported the efficacy of this hypertonic nasal solution. No adverse events have been pointed out during the trial supporting the safety of this new nasal hypertonic approach. CONCLUSIONS: The absence of adverse events after 48-96 hours along with the short-term effectiveness of this new treatment seems to represent a new, safe option to treat children affected by nasal congestion secondary to common cold. Considering the current lack of safe treatments for children under 12 years of age, Narlisim™ can be considered as a useful short-term option to control nasal congestion in children.

Effects of a dragonfly (Anax i.) homeopathic remedy on learning, memory and cell morphology in mice.

BACKGROUND: Homeopathy is a form of alternative medicine in which uses highly diluted preparations that are believed to cause healthy people to exhibit symptoms similar to those exhibited by patients. The aim of this study was to investigate the effects of dragonfly (Anax imperator, Anax i.) on learning and memory in naive mice using the Morris water maze (MWM) test; moreover, the effects of dragonfly on MK-801-induced cognitive dysfunction were evaluated. METHODS: Male balb-c mice were treated with dragonfly (30C and 200C) or MK-801 (0.2 mg/kg) alone or concurrently (n = 10). Dragonfly (D) and MK-801 were administered subchronically for 6 days intraperitoneally 60 min and 30 min, respectively, before the daily performance of the MWM test. RESULTS: This study revealed that in the familiarization session and first session of the MWM test, Anax i. D30 significantly decreased escape latency compared to the control group, although MK-801, D30 and D200 significantly increased escape latency at the end of five acquisition sessions. Anax i. combined with dizocilpine maleate (MK-801) also significantly decreased escape latency in the familiarization session and first session of the MWM test, although this combination increased escape latency compared to the MK-801 alone group at the end of the test. Time spent in escape platform's quadrant in the probe trial significantly decreased while mean distance to platform significantly increased in MK-801, D30 and D200 groups. In the MWM test, Anax i. combined with MK-801 significantly decreased speed of the animals compared to the MK-801 alone group. General cell morphology was disturbed in the MK-801 group while D30 and D200 seemed to improve cell damage in the MK-801 group. CONCLUSIONS: These results suggest that the homeopathic Anax i. can impair learning acquisition and reference memory, and it has beneficial effects on disturbed cell morphology.

Synthesis and evaluation of dual antiplatelet activity of bispidine derivatives of N-substituted pyroglutamic acids.

N-aralkylpyroglutamides of substituted bispidine were prepared and evaluated for their ability to inhibit collagen induced platelet aggregation, both in vivo and in vitro. Some compounds showed high anti-platelet efficacy (in vitro) of which six inhibited both collagen as well as U46619 induced platelet aggregation with concentration dependent anti-platelet efficacy through dual mechanism. In particular, the compound 4j offered significant protection against collagen epinephrine induced pulmonary thromboembolism as well as ferric chloride induced arterial thrombosis, without affecting bleeding tendency in mice. Therefore, the present study suggests that the compound 4j displays a remarkable antithrombotic efficacy much better than aspirin and clopidogrel.

Pidotimod for the prevention of acute respiratory infections in healthy children entering into daycare: A double blind randomized placebo-controlled study.

Acute respiratory tract infections (ARTIs) are very common in pediatric age and reach a peak in the first 4 years of life, especially in children attending daycare. Pidotimod, a synthetic immunostimulant, may reduce the incidence of ARTIs in children with predisposing risk factors. Nevertheless studies on healthy children are presently lacking. We performed a double-blinded randomized placebo-controlled trial study to assess the efficacy of Pidotimod in a population of 3-year-old healthy children who just entered kindergarten. The main outcome was the incidence of respiratory infections in this population and the secondary outcome was the prescription of antibiotics. The study group consisted of healthy 3-year-old children who had not yet attended day-care centers. Patients were enrolled by a convenience sample of 17 family pediatricians (FP). Children were randomized to receive either Pidotimod 400 mg per os or placebo twice daily for the last 10 days of each month from October 2013 to April 2014. Any time a child presented to his/her FP with fever and ARTI was diagnosed, clinical and therapeutic data were collected. A total of 800 children were pre-screened, 733 did not meet the inclusion criteria and 10 refused to participate. Of the 67 eligible subjects, 57 were successfully enrolled within the study recruitment period and randomized to receive Pidotimod (n = 29) or placebo (n = 28). Eight children were lost to follow-up. In the final analysis were thus included 24 children who received Pidotimod and 25 who received placebo. The incidence rate ratio for respiratory infections was 0.78 (95%CI 0.53 to 1.15, p = 0.211) for Pidotimod vs. placebo. The corresponding risk ratio for antibiotic usage was 0.56 (95%CI 0.27 to 1.16, p = 0.120). In our trial, Pidotimod did not prove to be statistically superior to placebo for the prevention of ARTI in a population of healthy children who entered kindergarten. However, Pidotimod showed some potential as a means for reducing antibiotic usage in these children.

Metadoxine improves the three- and six-month survival rates in patients with severe alcoholic hepatitis.

AIM: To evaluate the impact of metadoxine (MTD) on the 3- and 6-mo survival of patients with severe alcoholic hepatitis (AH). METHODS: This study was an open-label clinical trial, performed at the "Hospital General de México, Dr. Eduardo Liceaga". We randomized 135 patients who met the criteria for severe AH into the following groups: 35 patients received prednisone (PDN) 40 mg/d, 35 patients received PDN+MTD 500 mg three times daily, 33 patients received pentoxifylline (PTX) 400 mg three times daily, and 32 patients received PTX+MTD 500 mg three times daily. The duration of the treatment for all of the groups was 30 d. RESULTS: In the groups treated with the MTD, the survival rate was higher at 3 mo (PTX+MTD 59.4% vs PTX 33.3%, P = 0.04; PDN+MTD 68.6% vs PDN 20%, P = 0.0001) and at 6 mo (PTX+MTD 50% vs PTX 18.2%, P = 0.01; PDN+MTD 48.6% vs PDN 20%, P = 0.003) than in the groups not treated with MTD. A relapse in alcohol intake was the primary independent factor predicting mortality at 6 mo. The patients receiving MTD maintained greater abstinence than those who did not receive it (74.5% vs 59.4%, P = 0.02). CONCLUSION: MTD improves the 3- and 6-mo survival rates in patients with severe AH. Alcohol abstinence is a key factor for survival in these patients. The patients who received the combination therapy with MTD were more likely to maintain abstinence than those who received monotherapy with either PDN or PTX.

Efficacy and safety of pidotimod in the prevention of recurrent respiratory infections in children: a multicentre study.

Acute respiratory infections (ARI) still represent a big challenge for paediatricians, especially in those children defined as "ailed" as they are more susceptible to such kinds of disease. In this paediatric population, the immune system is still under-developed with an evident alteration in cytokine levels. A clinical study was carried out in 5 sites in Russia with the intention to enroll children particularly susceptible to contract respiratory infections (defined as "ailing"), assigning them to a treatment group with pidotimod in comparison with a control group, treating them for 30 days and observing the reduction in the number of ARI episodes throughout the follow-up period (6 months). Moreover, changes in serum immunological markers were evaluated at baseline and 30 days after treatment discontinuation. One hundred and fifty-seven ailing children were enrolled and assigned to two arms: a main pidotimod treatment group or a control group. The percentage of incidence of ARIs in the observation period at three different time points was statistically significant (p < 0.05). At the end of the follow-up period (after 6 months), ARIs had developed in 72 children (92.3%) in the main group and in 79 patients (100%) in the control group. Concerning changes of the immunological markers, the treatment group showed a better profile of normalization compared to the control group. The 30-day pidotimod therapy course led to improvement/reduction in the rate of acute respiratory infection recurrence in ailing children within a 3-month period, with a quick elimination of symptoms and signs of infection and, as a result, a faster recovery. The normalisation of the content of the pro-inflammatory cytokine interleukin-8 confirmed the immune-modulatory effect of the investigational drug, underlying its prophylactic effect.

Attention benefits after a single dose of metadoxine extended release in adults with predominantly inattentive ADHD.

OBJECTIVE: To assess the first-dose effectiveness and tolerability of metadoxine extended release (MDX) in adults with predominantly inattentive attention-deficit/hyperactivity disorder (ADHD-PI). METHODS: In this double-blind, placebo-controlled, crossover study, adults with ADHD-PI were randomized 1:1:1 to receive a single dose of MDX 1400 mg, MDX 700 mg, and placebo (ClinicalTrials.gov identifier: NCT01685281). The primary efficacy end point was the mean change in the Test of Variables of Attention (TOVA) ADHD score from baseline to 3 to 5 hours after drug administration. Secondary assessments included TOVA subscores, TOVA response rates (defined as an increase of 0.8 points in the TOVA ADHD score), and the Cambridge Neuropsychological Automated Test Battery. Safety assessments included adverse events and vital signs. RESULTS: The intention-to-treat population included 36 patients (52.8% men; mean age, 32 years). The efficacy of MDX 1400 mg was demonstrated by a statistically significant difference in the mean (± SD) change in the TOVA ADHD score at baseline to 3 to 5 hours after drug administration compared with placebo (2.0 [4.2]; P = 0.009). The TOVA response time variability subscore was significantly different between MDX 1400 mg and placebo (mean difference, 7.9 [19.2] points; P = 0.022). Significantly more adults responded to single-dose MDX 1400 mg versus placebo (97.1% vs 71.4%, P = 0.006). There were no statistically significant differences between MDX 700 mg and placebo on any measures. Exploratory analyses of the Cambridge Neuropsychological Automated Test Battery did not yield significant findings. Fatigue and headache were the 2 most frequently reported adverse events. There were no clinically significant abnormalities in laboratory values, vital signs measurements, Columbia-Suicide Severity Rating Scale scores, or electrocardiographic parameters. CONCLUSIONS: Single-dose MDX 1400 mg significantly improved sustained and selective attention in adults with ADHD-PI as measured by the TOVA ADHD score 3 to 5 hours after drug administration. Single doses of MDX 700 and 1400 mg were well tolerated.

Pyroglutamic acid-induced metabolic acidosis: a case report.

High anion gap metabolic acidosis due to pyroglutamic acid (5-oxoproline) is a rare complication of acetaminophen treatment (which depletes glutathione stores) and is often associated with clinically moderate to severe encephalopathy. Acquired 5-oxoprolinase deficiency (penicillins) or the presence of other risk factors of glutathione depletion such as malnutrition or sepsis seems to be necessary for symptoms development. We report the case of a 55-year-old women who developed a symptomatic overproduction of 5-oxoproline during flucloxacillin treatment for severe sepsis while receiving acetaminophen for fever control. Hemodialysis accelerated the clearance of the accumulated organic acid, and was followed by a sustained clinical improvement.

In-vivo antitumour effect of daunorubicin-GnRH-III derivative conjugates on colon carcinoma-bearing mice.

Targeted cancer chemotherapy is a novel approach developed for the specific delivery of anticancer drugs. Tumour targeting can be achieved by combining a chemotherapeutic agent with a targeting moiety that recognizes tumour-specific or highly expressed receptors on cancer cells. We used the gonadotropin-releasing hormone-III (GnRH-III) as a targeting moiety to which the chemotherapeutic agent daunorubicin (Dau) was attached through an oxime bond either directly or by inserting a GFLG tetrapeptide spacer. The in-vivo toxicity of Dau-GnRH-III derivative conjugates was evaluated on healthy BDF-1 female mice, and their tumour growth inhibitory effect was determined on C26 murine and HT-29 human colon carcinoma-bearing mice. Both oxime bond-containing conjugates were well tolerated and exerted significant antitumour activity on C26 colon carcinoma-bearing mice at a dose of 30 mg Dau content in conjugate/kg body weight. Furthermore, the conjugates inhibited the tumour growth more than the free drug at a dose that was still not toxic. Similar tumour growth inhibitory effects were obtained on HT-29 human colon carcinoma-bearing mice using three treatments with 15 mg Dau content in conjugate/kg. The tumour growth inhibitions according to the tumour volume and the tumour weight were 44/41% and 58/50%, respectively. Considering the results, both of the investigated Dau-GnRH-III derivative conjugates were well tolerated and had significant antitumour effect on colon carcinoma-bearing mice.

A randomized, double-blind, placebo-controlled, multicenter study evaluating the efficacy, safety, and tolerability of extended-release metadoxine in adults with attention-deficit/hyperactivity disorder.

OBJECTIVE: To evaluate the efficacy, safety, and tolerability of an oral extended-release (ER) formulation of the nonstimulant metadoxine in the treatment of adult attention-deficit/hyperactivity disorder (ADHD). METHOD: This was a 1:1 randomized, double-blind, placebo-controlled, parallel-design, phase 2 study of metadoxine ER 1,400 mg/d treatment for 6 weeks, following a 2-week baseline/screening period, involving 120 adults with DSM-IV-defined ADHD. A follow-up assessment occurred 2 weeks after the trial was completed. Efficacy measures included changes in Conners' Adult ADHD Rating Scale-Investigator Rated (CAARS-INV) total ADHD symptoms score with adult ADHD prompts (primary measure), response rates (≥ 25% or 40% improvement in CAARS-INV total ADHD symptom score), Test of Variables of Attention (TOVA) performance, and Adult ADHD Quality of Life (AAQoL) total score. The study was conducted from March 15, 2011, to August 21, 2011. RESULTS: Intent-to-treat analysis revealed that subjects receiving metadoxine ER showed statistically significant improvement in CAARS-INV total ADHD symptoms score (P = .02), higher rate of response (≥ 25% [P = .03] or ≥ 40% [P = .04] improvement) on the CAARS-INV total ADHD symptoms score, and improvement in TOVA score (P = .02) and AAQoL score (P = .01) compared with the placebo group. Improvements in ADHD symptoms (scored by CAARS-INV) were significantly different in subjects treated with metadoxine ER versus placebo as early as 2 weeks following treatment initiation. Metadoxine ER was generally well tolerated, with nausea (17% [10/58] vs 0% [0/59]), fatigue (31% [18/58] vs 27% [16/59]), and headaches (29% [17/58] vs 39% [23/59]) being the most frequently reported adverse effects for the metadoxine ER and placebo groups, respectively. CONCLUSIONS: Findings suggest that metadoxine ER is a well-tolerated and effective treatment for adults with ADHD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01243242.

Pidotimod: a reappraisal.

Pidotimod (Polimod ) is a synthetic dipeptide molecule with biological and immunological activity on both the adaptive and the innate immune responses. In vitro studies, both from animal and human specimens, have documented a good activity on innate and adaptive immune responses and have been confirmed by in vivo studies. These activities have been applied in clinical studies demonstrating the efficacy of pidotimod in reducing the rate of recurrent infections of the upper respiratory and urinary tracts in children. The same results were obtained in recurrent respiratory tract infections in adults. Interestingly, these effects are more evident in the setting of immune defects such as senescence, Downs syndrome, and cancer.

New therapeutic approach to Tourette Syndrome in children based on a randomized placebo-controlled double-blind phase IV study of the effectiveness and safety of magnesium and vitamin B6.

BACKGROUND: Tourette Syndrome (TS) is a neurological condition presenting chronic motor and phonic tics, and important degree of comorbidity. Considered an uncommon illness, it first becomes apparent during childhood. Current standard treatment only achieves partial control of the condition, and provokes frequent, and sometimes severe, side effects. METHODS AND DESIGN: Main aim: To show that, with respect to placebo treatment, the combination of 0.5 mEq/Kg magnesium and 2 mg/Kg vitamin B6 reduces motor and phonic tics and incapacity in cases of exacerbated TS among children aged 7-14 years, as measured on the Yale Global Tic Severity Scale (YGTSS). Secondary aims: Assess the safety of the treatment. Describe metabolic changes revealed by PET. Measure the impact of the experimental treatment on family life. METHODOLOGY: Randomized, blinded clinical trials. Phase IV study (new proposal for treatment with magnesium and vitamin B6). SCOPE: children in the geographic area of the study group. Recruitment of subjects: to include patients diagnosed with TS, in accordance with DSM-IV criteria (307.23), during a period of exacerbation, and provided none of the exclusion criteria are met. INSTRUMENTATION: clinical data and the YGTSS score will be obtained at the outset of a period of exacerbation (t0). The examinations will be made after 15 (t1), 30 (t2), 60 (t3) and 90 days (t4). PET will be performed at the t0 and t4. We evaluated decrease in the overall score (t0, t1, t2, t3, t4), PET variations, and impact made by the treatment on the patient's life (Psychological General Well-Being Index). DISCUSSION: Few clinical trials have been carried out on children with TS, but they are necessary, as current treatment possibilities are insufficient and often provoke side effects. The difficulty of dealing with an uncommon illness makes designing such a study all the more complicated. The present study seeks to overcome possible methodological problems by implementing a prior, phase II study, in order to calculate the relevant statistical parameters and to determine the safety of the proposed treatment. Providing a collateral treatment with magnesium and vitamin B6 could improve control of the illness and help reduce side effects. This protocol was approved by the Andalusian Government Committee for Clinical Trials (Spain). This study was funded by the Health Department of the Andalusian Regional Government and by the Healthcare Research Fund of the Carlos III Healthcare Institute (Spanish Ministry of Health). TRIAL REGISTRATION: Current Controlled Trials ISRCTN41082378.

5-Oxoproline as a cause of high anion gap metabolic acidosis: an uncommon cause with common risk factors.

High anion gap metabolic acidosis might be caused by 5-oxoproline (pyroglutamic acid). As it is very easy to treat, it might be worth drawing attention to this uncommon and probably often overlooked diagnosis. We present three cases of high anion gap metabolic acidosis due to 5-oxoproline seen within a period of six months.

Phase I study of magnesium pidolate in combination with hydroxycarbamide for children with sickle cell anaemia.

In sickle cell anaemia, red cell dehydration increases intracellular HbS concentration and promotes sickling. Higher erythrocyte magnesium reduces water loss through negative regulation of membrane transporters. Hydroxycarbamide (also known as hydroxyurea) reduces sickling partly by increasing intracellular HbF. Combining drugs with distinct mechanisms could offer additive effects. A phase I trial combining oral magnesium pidolate and hydroxycarbamide was performed to estimate the maximum tolerated dose (MTD) and toxicity of magnesium. Cohorts of three children with HbSS, who were on a stable dose of hydroxycarbamide (median 28.5 mg/kg/d), received magnesium pidolate for 6 months beginning at 83 mg/kg/d. The dose was escalated by 50% for subsequent cohorts. Laboratory evaluations were performed at 0, 3, 6 and 9 months. Sixteen children (aged 4-12 years) participated. All four dose-limiting toxicities (grade III diarrhoea and abdominal pain) occurred within the first month of starting magnesium. Additionally, diarrhoea grades I (n = 1) and II (n = 3), and abdominal pain grade II (n = 3) occurred. Hydroxycarbamide dose reduction or interruption was not required. The MTD for magnesium pidolate used in combination with hydroxycarbamide was 125 mg/kg/d. KCl co-transporter activity declined after 3 months of magnesium pidolate (P = 0.02). A phase II study is needed to investigate the efficacy of this drug combination.

Urticaria due to calcium pidolate.

Calcium salts are often prescribed in the prevention and treatment of osteoporosis. Adverse reactions have been described, mostly concerning to the gastrointestinal tract, parathyroid glands and bone resorption. We report the case of a 52-year-old woman who started treatment with 500 mg per day of calcium-pidolate. 90 minutes after the intake of the second dose, she experienced an itchy maculopapular eruption. Skin Prick Tests were carried out with the implicated drug and calcium-carbonate and they both were negatives. An oral-challenge-test with 500 mg of calcium-pidolate was ruled out. 60 minutes later, the patient responded positively when she experienced a similar reaction with erythematous and itchy papulae on the trunk and the neck. Finally, an oral-challenge-test with 500 mg calcium-carbonate was performed with good tolerance. To the best of our knowledge, this is the first documented case of allergy to calcium-pidolate with tolerance to other calcium salt.