Effects of a Single Opioid Dose on Gastrointestinal Motility in Rabbits (Oryctolagus cuniculus): Comparisons among Morphine, Butorphanol, and Tramadol

The aim of this study was to evaluate and compare the effects of single doses of butorphanol, morphine, and tramadol on gastrointestinal motility in rabbits (Oryctolagus cuniculus) using non-invasive imaging methods, such as radiographic barium follow through and ultrasonographic contraction counts. Time-lapse radiographic and ultrasound examinations were performed before and after a single intramuscular dose of 5 mg kg−1 butorphanol, 10 mg kg−1 morphine, or 10 mg kg−1 tramadol. Pyloric and duodenal contraction counts by ultrasonography and radiographic repletion scores for the stomach and caecum were analysed using a mixed linear model. No significant effect was noted on ultrasound examinations of pyloric and duodenal contractions after administration of an opioid treatment. Morphine had a significant effect on the stomach and the caecum repletion scores, whereas butorphanol had a significant effect only on the caecum repletion score. Tramadol had no significant effect on the stomach or caecum repletion scores. The present findings suggest that a single dose of 5 mg kg−1 butorphanol or 10 mg kg−1 morphine temporarily slows gastrointestinal transit in healthy rabbits, preventing physiological progression of the alimentary bolus without the induction of ileus. In contrast, a single dose of 10 mg kg−1 tramadol has no such effects.

632. Clinical Experience with a New Fully Liquid Presentation of the MenACWY-CRM Vaccine. Results from Two Multicenter, Randomized, Controlled, Observer-Blind, Phase 2b Studies

Background Currently, licensed MenACWY-CRM conjugate vaccine presentation (Lyo/Liq) consists of two vials (lyophilized MenA, liquid MenCWY) to be reconstituted before injection. A new, fully liquid, single vial formulation has been developed and evaluated in two clinical studies in adolescents and adults aimed at demonstrating immunological non-inferiority of the liquid presentation for MenA. Methods Overall, 1337 subjects, 10 to 40 years of age (y), were exposed to a single 0.5 mL intramuscular dose of MenACWY Liquid and 1332 to MenACWY-CRM(Lyo/Liq). MenACWY-CRM Liquid was aged before administration, to test the vaccine immunogenicity at the end of the intended shelf-life and establish release and end of shelf life specifications. MenACWY-CRM(Lyo/Liq) was used as comparator and was not aged. In study 1 (NCT03652610), the Liquid vaccine underwent an ageing process under controlled conditions to reach ~30% MenA free saccharide (FS). In study 2 (NCT03433482), the Liquid vaccine was naturally aged at 2–8°C for approximately 24 and 30 months. Primary immunogenicity objective in both studies was non-inferiority of MenACWY-CRM liquid to licensed vaccine, as measured by human serum bactericidal assay (hSBA) geometric mean titers (GMTs) against MenA, 1-month post-vaccination. Results In both studies, for each between-group ratio of MenA hSBA GMTs, lower limits of the 95% confidence intervals (CIs) were greater than the prespecified non-inferiority margin (0.5), thus meeting the non-inferiority immunogenicity objective. Irrespectively of the vaccine presentation tested, over 82% of participants achieved MenA hSBA titers ≥ 8 in study 1 and at least 92% in study 2. The immunogenicity of MenACWY-CRM Liquid was similar to that of MenACWY-CRM(Lyo/Liq) when analyzed by serogroup, overall. No related serious adverse events were reported for both presentations. Conclusion After ageing, the new MenACWY-CRM Liquid demonstrated the ability to elicit non-inferior bactericidal responses against MenA compared to licensed formulation. The new full-liquid presentation is expected to increase the user-friendliness of the vaccine as well as to reduce reconstitution errors in the future, with a similar safety profile to that of the licensed vaccine presentation. Disclosures Javier Díez-Domingo, MD, PhD, GSK (Grant/Research Support)Sanofi (Grant/Research Support) Corinne Vandermeulen, MD PhD, GSK (Grant/Research Support)MSD (Grant/Research Support)Pfizer (Grant/Research Support) Tauseefullah Akhund, MD, MSc, MPH, GSK (Employee, Shareholder) Marco Costantini, MSc, MBA, EMPHA, GSK (Employee) Puneet Vir Singh, MBBS, PGDCD, GSK (Employee, Shareholder) Venere Basile, MSc, GSK (Employee, Shareholder) Elena Fragapane, MD, GSK (Employee, Shareholder) Maria Lattanzi, MD, PhD, GSK (Employee, Shareholder) Michele Pellegrini, MD, PhD, Michele Pellegrini (Employee, Shareholder)

Single injection of very mild dose BOTOX in the vastus lateralis improves testicular spermatogenesis and sperm motility in ageing experimental mice

Acetylcholine (ACh), a key neurochemical messenger that plays key roles in neuroplasticity and muscle contraction. While ACh is important for the physiological function of the testis, abnormal levels of ACh cause testicular atrophy and male infertility. BOTOX is a therapeutic form of the botulinum neurotoxin that blocks the excessive release of ACh at the neuromuscular junction. Previously, repeated intracremasteric injections and slight overdose of BOTOX have been reported to induce adverse effects in the testicular parameter of experimental rodents. However, a mild dose of BOTOX is highly beneficial against skin ageing, neurological deficits, overactive urinary bladder problems, testicular pain and erectile dysfunctions. Considering the facts, the possible therapeutic benefit of BOTOX on the testis might be achieved via its minimal dose and indirect mode of action rather than repeated high quantity in the local supply. Therefore, we revisited the effect of BOTOX but with a trace amount injected into the vastus lateralis of the thigh muscle, and analyzed histological parameters of testis and quality of semen in ageing experimental mice. Experimental animals injected with 1 U/kg bodyweight of BOTOX showed enhanced spermatogenesis in associations with increased activities of key antioxidants in the testis, leading to increased total sperm count and motility. This study signifies that a mild intramuscular dose of BOTOX can be considered as a potential treatment strategy to manage and prevent male infertility.

Pharmacokinetic Behaviour of Enrofloxacin after Single Intramuscular Dosage in American Black Vultures (Coragyps atratus)

The aim of the study was to investigate the intramuscular pharmacokinetics of enrofloxacin in black vultures (Coragyps atratus). The pharmacokinetics of a single intramuscular dose (10 mg/kg) of enrofloxacin was studied in six vultures. Plasma concentrations of enrofloxacin and its active metabolite, ciprofloxacin, were determined by high-performance liquid chromatography (HPLCuv). Pharmacokinetic parameters were estimated using non-compartmental and compartmental analysis. After intramuscular administration, enrofloxacin showed a rapid and complete absorption, reaching a Cmax value of 3.26 ± 0.23 μg/mL at 1.75 ± 0.53 h. A long terminal half-life of 19.58 h has been observed. Using previously published MIC values to perform a PK/PD analysis, cumulative fraction responses obtained after Monte Carlo simulation for AUC/MIC > 30, 50 and 125 were 72.93%, 72.34% and 30.86% for E. coli and 89.29%, 88.89% and 58.57% for Mycoplasma synoviae, respectively. Cumulative fraction responses obtained for Cmax/MIC index were 33.93% and 40.18% for E. coli and M. synoviae, respectively. The intramuscular administration of 10 mg/kg could be appropriate to treat infectious diseases caused by gram-positive bacteria with MIC value lower than 1 µg/mL; however, although enrofloxacin showed a slow elimination in black vultures, plasma concentrations were insufficient to reach the gram-negative stablished breakpoints.

Case of Guillain-Barré syndrome following COVID-19 vaccine

Guillain-Barré syndrome (GBS) is a rare immune-mediated disorder of the peripheral nerves. Although its cause is not fully understood, the syndrome often follows infection with a virus or bacteria, although in rare occasions, vaccination may precede GBS. We describe a case of a 62-year-old woman who presented with paraesthesia and progressive weakness of both lower limbs over 3 days. Clinical examination and investigation findings including lumbar puncture and nerve conduction studies were consistent with the diagnosis of GBS. She had no history of either diarrhoea or respiratory tract infections preceding her presentation. However, she had her first intramuscular dose of the Oxford/AstraZeneca COVID-19 vaccine 11 days prior to her presentation. Although no direct link could be ascertained, the purpose of this report is to highlight the incidence and consider this issue while evaluating any case of GBS in the light of the current pandemic and vaccination programme.

StreptInCor, a Group A Streptococcal Adsorbed Vaccine: Evaluation of Repeated Intramuscular Dose Toxicity Testing in Rats

Streptococcus pyogenes infections continue to be a worldwide public health problem, causing various diseases in humans, with rheumatic fever and rheumatic heart disease being the most harmful manifestations. Impetigo and post-streptococcal glomerulonephritis are also important sequelae of skin infections. We have developed a candidate vaccine epitope (StreptInCor) that presents promising results in diverse animal models. To assess whether the StreptInCor alum-adsorbed vaccine could induce undesirable effects, a certified independent company conducted a repeated intramuscular dose toxicity evaluation in Wistar rats, a choice model for toxicity studies. We did not observe significant alterations in clinical, hematological, biochemical, anatomical, or histopathological parameters due to vaccine administration, even when the animals received the highest dose. In conclusion, repeated intramuscular doses did not show signs of macroscopic or other significant changes in the clinical or histopathological parameters, indicating that StreptInCor can be considered a safe candidate vaccine.

Enhanced elimination of betamethasone in dichorionic twin pregnancies

Aims: No study has evaluated the BET pharmacokinetics in twin pregnancies separated by chorionicity. The aim this study is to describe and compare the BET pharmacokinetic parameters in singleton, dichorionic (DC) and monochorionic (MC) twin pregnancies in the third trimester of pregnancy. Methods: Twenty-six pregnant women received an intramuscular dose of 6 mg of BET sodium phosphate plus 6 mg BET acetate. Serial blood samples were collected for 24 hours after the first intramuscular BET esters dose. BET plasma concentrations were quantified using a validated HPLC analytical method. BET pharmacokinetic parameters were obtained employing a non-compartment model, and were compared using ANOVA’s test with Tukey’s multiple comparisons test. Correlations between clinical features and pharmacokinetic parameters were analyzed using Pearson’s correlation. Preliminary data on the BET placental transfer were also presented. Results: The geometric mean (IC 95%) of AUC0-∞ 670.0 (504.3-805.2) vs 434.9 (311.2-539.6) ng.h/mL and the CL/F 18.38 (13.84-22.65) vs 29.40 (21.17-36.69) were significantly lower and higher, respectively, in DC twin pregnancies compared to singleton. Others pharmacokinetic parameters did not differ among the groups. Conclusions: Data from this study suggest that the presence of two fetoplacental units may increase the BET metabolism by CYP3A4 enzyme and increase its elimination. Pharmacokinetic-pharmacodynamic clinical studies are needed to investigate whether this BET pharmacokinetic changes have clinical repercussions for the newborns and require dose adjustment in DC twin pregnancies.

Is There a Benefit of Vitamin D Supplementation in Deficient Children and Adolescents Suffering from Obesity? A Meta-Analysis

This systematic review/meta-analysis aims to highlight the effect of vitamin D supplementation in deficient children suffering from obesity. Published clinical studies on vitamin D supplementation in obese children and adolescents with vitamin D deficiency were identified through a comprehensive MEDLINE/PubMed search (from July 1966 to November 2017). Outcomes intended after vitamin D supplementation were improvements in vitamin D status, BMI alterations and appetite changes. The inclusion criteria were children aged 2 to 18 years of both sexes in clinical trials that specified the oral and/or intramuscular dose of vitamin D supplementation. Ten studies were retrieved, but only 6 were relevant. First, supplemented obese children and adolescents were compared to non-obese controls; thereafter, supplemented obese children and adolescents were compared to matching obese peers given placebo. Pooled risks from the 2 studies that evaluated the number of obese and non-obese children and adolescents who improved upon vitamin D supplementation revealed that obesity poses a risk for not benefiting from the vitamin D supplementation regardless of the dose and the duration of supplementation. Pooled results from the 6 retrieved studies that compared supplemented obese children and adolescents to matching non-obese or obese peers given placebo revealed significantly lower vitamin D levels in obese participants than in non-obese peers. Vitamin D levels are significantly lower in obese children and adolescents with obesity, posing a risk for not benefiting from vitamin D supplementation regardless of the dose and duration of supplementation.

Intradermal versus Intramuscular Administration of Influenza Vaccination: Rapid Review and Meta-analysis

BackgroundVaccinations are essential for prevention of influenza. We synthesized the published literature on the immunogenicity and safety of the influenza vaccine at reduced or full intradermal doses compared with full intramuscular doses.MethodsA rapid review of the literature was completed. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for studies published from 2010 until June 5th, 2020. All studies comparing intradermal and intramuscular influenza vaccinations were included. Random-effects meta-analyses of immunogenicity and safety outcomes were conducted.ResultsA total of 30 relevant studies were included. Seroconversion rates were equivalent between the 3 mcg, 6 mcg, 7.5 mcg, and 9 mcg intradermal vaccine doses and the 15 mcg intramuscular vaccine dose for each of the H1N1, H3N2, and B strains, but significantly higher with the 15 mcg intradermal compared with the 15 mcg intramuscular dose, for the H1N1 (RR 1.10, 95% CI: 1.01-1.20) and B strains (RR 1.40, 95% CI: 1.13-1.73). Seroprotection rates for the 9 mcg and 15 mcg intradermal doses were equivalent with the 15 mcg intramuscular dose for all the three strains, except for the 15 mcg intradermal dose for the H1N1 strain which was significantly higher (RR 1.05, 95% CI: 1.01-1.09). Local adverse events were significantly higher with intradermal doses. Fever and chills were significantly higher with the 9 mcg intradermal dose, while all other systemic adverse events were equivalent for all doses.ConclusionReduced dose intradermal influenza vaccination appears to be a reasonable alternative to standard dose intramuscular vaccination because of the similarity in immunogenicity.