Nalbuphine Potentiates Reversal of Fentanyl Overdose by Naloxone.

Developing an effective antidote for fentanyl-induced overdose to achieve timely reversal is an unmet public health need. Previously, we found that naloxone derivative NX90 with mild κ-opioid agonistic properties was three-fold more effective than the parent naloxone in reversing a fentanyl overdose in rats. To investigate whether κ-agonistic properties could indeed augment the robustness of overdose reversal, we evaluated a κ-agonist/µ-antagonist nalbuphine (NB) as well as its combinations with naloxone (NX) in a fentanyl overdose model in rodents. An administration of either NB or NX as single agents at 0.1 mg/kg doses produced a full recovery in 90 ± 9.9 min and 11.4 ± 2.7 min, respectively. A higher dose of NX at 0.2 mg/kg reversed an overdose within 4.8 ± 1.0 min. In contrast to that, the coadministration of NB and NX at 0.1 mg/kg each produced a synergistic effect, with overdose reversal in 3.4 ± 0.2 min. The coadministration of NX and NB at sub-therapeutic doses of 0.05 mg/kg each was also 1.2-fold more effective than NX at 0.2 mg/kg. We further found that co-administration of NB at different doses (0.025, 0.05, 0.1 mg/kg) and ratios (1:4 and 1:1) with NX had differential effects on overdose reversal, cardiorespiratory liabilities, and analgesia.

Modifying naloxone to reverse fentanyl-induced overdose.

Developing an effective antidote for fentanyl-induced overdose (OD) is an unmet medical need that requires both lipophilicity comparable to fentanyl and fast onset of overdose reversal. We synthesized and evaluated a bioreversible derivative of naloxone (NX-90) in silico, in vitro and in vivo to yield a robust reversal of fentanyl-induced OD in rats. All monitored reflexes along with the heart rate (HR) and respiratory rate (RR) were fully restored faster in the NX-90 groups than in naloxone groups on equimolar bases when given intranasally. In NX-90 treated rats RR over the time of observation (RR AUC) was significantly higher at all respective doses with no re-narcotization observed. Apart from the enhanced pharmacodynamics profile, NX-90 was found to have lower circulating levels of naloxone, clean profile in in vitro selectivity panels, as well as Ames and CYP450 counter screens. Finally, we demonstrated a robust release of the parent naloxone in brain matrix, as well as lower peripheral naloxone levels after NX-90 iv administration. With the demonstrated pharmacological profile superior yet congruent to naloxone we nominated NX-90 for preclinical development as an effective intranasal fentanyl antidote.

Natural Endotoxemia in Dogs-A Hidden Condition That Can Be Treated with a Potential Probiotic Containing Bacillus subtilis, Bacillus licheniformis and Pediococcus acidilactici: A Study Model.

Spore-based Bacillus spp. products are considered to have a higher probiotic potential compared to products containing only lactic acid bacteria because their viability in the gastrointestinal (GI) tract is higher, even when GI environmental conditions are unfavorable. The aim of this study was to assess the effect of a Bacillus subtilis, Bacillus licheniformis and Pediococcus acidilactici spore-based potential probiotic on the natural levels of postprandial endotoxemia. A total of 11 dogs completed the study: group 1-healthy dogs: n = 5; group 2-dogs with apparent dysbiosis: n = 6. For 30 days, the dogs were fed the probiotic product; clinical examinations and blood sampling were done before and after completion of the probiotic treatment. Endotoxin levels were assessed pre-meal, 6 h and 12 h post-meal, before initiation and after completion of the treatment. The results showed a decrease in endotoxin levels after treatment, especially 12 h post-meal (group 1: 20.60%; group 2: 44.93%). This study reports new information with regard to natural endotoxemia levels in dogs and suggests that a multi-strain formula (spore-based) consisting of B. subtilis, B. licheniformis and P. acidilactici is able to diminish endotoxin values.

Subconjunctival ocular filariasis -Case report.

We are presenting the case of a patient who was clinically diagnosed with subconjunctival ocular dirofilariasis, confirmed by the parasitological examination. The treatment consisted in the surgical extraction of the parasite, a local treatment with antibiotics and steroidal anti-inflammatory mydriatic and general treatment with antihelminthic, antibiotic, analgesic, and anti-inflammatory drugs. The intraoperative and postoperative evolution of the case was favorable.

Multiple congenital cardiovascular defects including type IV persistent truncus arteriosus in a Shetland pony - Short communication.

This case report describes the pathological findings of multiple congenital cardiac defects in a 2-year-old female Shetland pony with clinical signs of chronic respiratory distress. Persistent truncus arteriosus (PTA) type IV, interventricular septal defect, overriding aorta, pulmonary trunk agenesis, pulmonary arteries arising from the descending aorta, and compensatory right ventricular hypertrophy were observed.

Screening for anthelmintic resistance in equid strongyles (Nematoda) in Romania.

Resistance to anthelmintic medication of equid strongyles is a worldwide phenomenon and for this reason systematic investigations of resistant parasite populations are necessary. The purpose of the present study was to investigate the presence and distribution of equid strongyles resistant to the anthelmintics used in Romania, as well as the pre-treatment and post-treatment prevalence of species of strongylid nematodes. The Faecal Egg Count Reduction Test was performed between 2010 and 2013 on a total number of 588 horses and 23 donkeys from 26 locations (subgroups). Animals of the first group (I) consisting of subgroups no. 1-11 were treated with Albendazole (ABZ), those of the second group (II) consisting of subgroups no. 12-23 with Fenbendazole (FBZ), while Ivermectin (IVM) was used on animals of the third group (III) consisting of subgroups no. 24-26. Resistant strongyles have been found in 82% (average lower limit of the 95% confidence interval, LCL95%, was 65) of the total equids from the group treated with ABZ. In the group of horses treated with FBZ, resistant strongyles were identified in 75% of the subgroups (LCL95% = 44). No resistant strongyles have been identified in IVM-treated horse groups (LCL95% = 98). The pre-treatment prevalence of the species of the Strongylinae Müller, 1780 was 22%, whereas that with nematodes of the subfamily Cyathostominae Molin, 1861 78%. Post-treatment reduction of strongyline nematodes was observed (5%), which demonstrates the sensitivity of large strongyles to common anthelmintics. The post-treatment prevalence of cyathostomes was of 95%, which proves their resistance, especially to ABZ- and FBZ-based anthelmintics.

Phytotherapeutic activity of Euphorbia cyparissias extracts on Ixodidae (Acari) female ticks.

BACKGROUND: Given its numerous biologically active components, Euphorbiaceae has been found to be a large plant family and polyvalent with quite interesting therapeutic activity that can be studied. MATERIALS AND METHODS: The ixodicidal activity of Euphorbia cyparissias extracts was studied in vitro and in vivo. Tested concentrations were 10, 5, 2, 1, 0.5 and 0.25%. RESULTS: For the in vitro study, conducted on field-collected female specimens of Dermacentor marginatus and Haemaphysalis punctata, the efficacy results showed that the ticks died after exposure in the case of 10, 5, and 2% tincture concentrations. The effects appeared after 30 minutes and became more visible 120 minutes after each exposure. The statistical differences regarding the used concentrations were found to be: F = 6.51, df = 5, P < 0.001. The in vivo study of the efficacy of E. cyparissias concentrations was performed on 35 naturally infested sheep and on 30 bovines parasitized with Ixodes ricinus, sprayed with tincture and glycerinate dilutions (bovines) on days 0 and 7. The results revealed detrimental effects on the survivability of female ticks, the most prominent being the reduction of their movement capacity. In sheep in vivo efficiency observed within 24 hrs varied, between 1 and 23% for D. marginatus and between 7 and 27% for H. punctata and respectively between 2 and 53% after 24 hrs, for I. ricinus, comparable effects being also found 72 hrs after the second administration of Euphorbia extracts. CONCLUSION: Extracts from E. cyparissias may be used, with results, as an ecologic alternative tick control management method, being a cheap solution, with a sizeable role in reducing the use of synthetic and/or other harming and resistance source ixodicidal conditionings.