Elpen Pharmaceutical (Greece)

Develop a biorelevant in vitro methodology to screen adsorbents for their safety and for their efficacy to remove unabsorbed drugs from the colonic lumen using activated charcoal (AC) as a model adsorbent; Evaluate AC's usefulness in preventing drug-induced intestinal dysbiosis based on in vitro data. Published clinical data with AC and moxifloxacin were used to evaluate biorelevance of the in vitro methodology. In vitro data with four drugs were used to evaluate the usefulness of AC in preventing drug-induced intestinal dysbiosis. In line with human data, in vitro data indicated that AC has no impact on osmolality and bacterial enzyme activity, and that complete removal of moxifloxacin accumulating in the colon after daily dosing requires the dispersion of >7g Filtercarb Pharma-A to the colonic lumen. In vitro data with rosuvastatin, azithromycin, and metformin indicated that complete removal after daily dosing requires the dispersion of >3g, ≈25g, and >45g Filtercarb Pharma-A, respectively, to the colonic lumen. An in vitro methodology to screen adsorbents for their safety and for their efficacy in removing unabsorbed drugs from the colonic lumen was developed. The effectiveness of AC may be limited by the size and the performance variability of the colon-targeting product.

Background/Objectives: Perinatal asphyxia constitutes a major complication of the perinatal period with well-described effects on multiple organs and systems of the neonate; its impact, though, on the ovaries is hardly known. The objective of the present study was to investigate potential histological alterations of the ovaries in an animal model of perinatal asphyxia with or without resuscitation. Methods: This was a prospective, randomized animal study; 26 female Large White/Landrace piglets, aged 1-4 days, were the study subjects and were randomly allocated in 3 groups. In Group A (control), the animals had their ovaries surgically removed without any manipulation other than the basic preparation and mechanical ventilation. The other 2 groups, B (asphyxia) and C (asphyxia/resuscitation), underwent asphyxia until bradycardia and/or severe hypotension occurred. At the hemodynamic compromise, animals in group B had their ovaries surgically removed, while animals in group C were resuscitated. Following return of spontaneous circulation (ROSC), the latter were left for 30 min to stabilize and subsequently had their ovaries surgically removed. The ovarian tissues were assessed by the pathologists for the presence of apoptosis, balloon cells, vacuolated oocytes, and hyperplasia of the stroma. The histological parameters were graded from 0 (absence) to 3 (abundant presence). Results: The presence of balloon cells and apoptosis was found to be more prominent in the ovaries of animals in groups B and C, compared to that of the control group at a statistically significant degree (p = 0.0487 and p = 0.036, respectively). A significant differentiation in balloon cell presence was observed in cases with higher grading (2-3) in the asphyxia group (with or without resuscitation) (p value: 0.0214, OR: 9, 95% CI: 1.39-58.4). Although no statistically significant difference was noted regarding the other 2 histological parameters that were studied, there was a marked negative correlation between the duration of asphyxia and grade of vacuoles in oocytes when the potential effect of the duration of asphyxia or resuscitation on the histological findings was investigated (r = -0.54, p = 0.039). Conclusions: We aimed at investigating the potential effect on the neonatal ovaries in our animal model of perinatal asphyxia. Given that the presence of apoptosis and balloon cells was more prominent in cases of asphyxia, it can be speculated that perinatal asphyxia might have an impact on the neonatal ovaries in addition to the other, better-studied systemic effects. More research is needed in order to clarify the potential effect of perinatal asphyxia on the ovaries.

<bold>Background & Aim:</bold> Adjustments to asthma treatment are made based on patients’ symptom control and risk assessment¹. The NOTOS study assessed asthma control in Greek patients treated with the fixed dose combination (FDC) of budesonide/formoterol (BUD/FOR) via Elpenhaler^® device as controller, with or without treatment with low-dose (LD) BUD/FOR or short-acting beta-agonist (SABA) as a reliever. <bold>Methods:</bold> In the NOTOS study (<ext-link>NCT04835961</ext-link>) 1008 patients were categorized, according to their controller treatment, into three groups: A₁ (as-needed treatment with LD BUD/FOR), B₁ (maintenance treatment with FDC BUD/FOR 200/6μg), and C₁ (maintenance treatment with FDC BUD/FOR 400/12μg) and according to their reliever treatment with LD BUD/FOR (groups B₂, C₂) or SABA (A₂, B₃, C₃). Asthma control was assessed using the Greek version of Asthma Control Questionnaire (ACQ-6). <bold>Results:</bold> Clinically significant improvement in asthma control (MCID≥0.50 in ACQ) was observed across all groups after 6 months. The mean change (Δ) (SD) in ACQ-6 score for each group was: A₁=-0.95 (0.91), A₂=-1.11 (0.59), B₁=-1.32 (0.98), B₂=-1.40 (0.92), B₃=-1.32 (0.77), C₁=-1.58 (0.88), C₂=-1.85 (1.30) and C₃=-1.81 (0.94). <bold>Conclusion:</bold> The NOTOS study demonstrated a clinically significant improvement in asthma control for patients under controller treatment with FDC of BUD/FOR after 6 months. Notable improvement was observed in patients using LD BUD/FOR as the preferred reliever compared to those using SABA as reliever treatment.

BackgroundRetinopathy of prematurity (ROP) eye examination screening presupposes adequate mydriasis for an informative fundoscopy of preterm infants at risk, on a weekly basis. Systemic absorption of the instilled mydriatic regimens has been associated with various adverse events in this fragile population. This report aims to present the fully developed protocol of a full-scale trial for testing the hypothesis that the reduced mydriatic drop volume achieves adequate mydriasis while minimizing systemic adverse events.MethodsA non-inferiority crossover randomized controlled trial will be performed to study the efficacy and safety of combined phenylephrine 1.67% and tropicamide 0.33% microdrops compared with standard drops in a total of 93 preterm infants requiring ROP screening. Primary outcome will be the pupil diameter at 45 (T45) min after instillation. Pupil diameter at T90 and T120 will constitute secondary efficacy endpoints. Mixed-effects linear regression models will be developed, and the 95% confidence interval approach will be used for assessing non-inferiority. Whole blood samples will be analyzed using hydrophilic liquid chromatography–tandem mass spectrometry method (HILIC–MS/MS), for gathering pharmacokinetic (PK) data on the instilled phenylephrine, at nine specific time points within 3 h from mydriasis. Pooled PK data will be used due to ethical restrictions on having a full PK profile per infant. Heart rate, oxygen saturation, blood pressure measurements, and 48-h adverse events will also be recorded.DiscussionThis protocol is designed for a study powered to assess non-inferiority of microdrops compared with standard dilating drops. If our hypothesis is confirmed, microdrops may become a useful tool in ROP screening.Trial registrationClinicalTrials.govNCT05043077. Registered on 2 September 2021

Background: Short bowel syndrome (SBS) remains an unsolved issue in modern medicine. Numerous experimental surgical techniques have been proposed in the attempt to increase the intestinal absorptive capacity. Materials and Methods: Ten female Landrace pigs, divided in two groups of 5 (A and B), were explored through a midline incision. A spindle-shaped vascularized full-thickness gastric wall flap (GWF) consisting of part of the major curvature with the gastroepiploic arch preserved was de-epithelialized and then placed as a “patch” to cover an antimesenteric border defect of either a nonfunctional blind intestinal loop (group A) or a functional intestinal loop of the gastrointestinal tract (group B). A spindle-shaped curved, rigid, low density polyethylene (LDPE) splint was sutured on the external surface of the patch in order to prevent shrinkage of GWF and collapse of the intestinal wall in group A. Results: There was a decrease of both dimensions of the patch. Microscopically a thin layer of columnar epithelial cells covered the center of the patch, evolving in shorter, blunt, poorly developed villi with increasing maturation laterally. The patch surface was covered by nearly 90%. In the three animals that died prematurely the coverage of GWF was negligent or suboptimal directly dependent on the length of survival. Conclusions: The hereby-described patching technique demonstrated the growth of intestinal neomucosa on the GWF. The capability of the stomach to provide large flaps and the advantages of the use of native tissues render this animal model valuable for the future research in the field.

BackgroundSevere and prolonged asphyxia can result in either intrauterine fetal death and stillbirth or multiorgan failure in surviving neonates. Establishing effective ventilation is the primary aim of resuscitation in newborns with asphyxia. The objective of this study was to compare the outcome of resuscitation by applying an endotracheal tube (ETT) with less, an ETT with moderate, and an ETT with high leakage during mechanical ventilation in swine neonates after prolonged perinatal asphyxia.Materials and methodsA prospective, randomized controlled laboratory study was performed. Thirty Landrace/large white pigs, aged one to four days and weighted 1.754±218 gr, were randomly allocated into three groups depending on the ETT size: Group C (less leak: ETT no 4.0, n=10); Group A (high leak: ETT no 3.0, n=10); and Group B (moderate leak: ETT no 3.5, n=10). Mechanical asphyxia was performed until their heart rate was less than 60 bpm or their mean arterial pressure was below 15 mmHg. All animals with return of spontaneous circulation (ROSC) were monitored for four hours for their hemodynamic parameters, arterial oxygen saturation, and lactate acid levels.ResultsWe demonstrate that 70% of the surviving animals were ventilated with an ETT with a leak (no. 3.5 and 3). A statistically significant difference was noted in PO2 (p=0.032) between Group B (126.4±53.4 mmHg) compared to Group A (72.28±29.18 mmHg) and Group C (94.28±20.46 mmHg) as well as in the right atrial pressure (p<0.001) between Group C (4.5 mmHg) vs Groups A (2 mmHg) and B (2 mmHg) during ROSC time. Lactate levels were statistically significantly lower (p=0.035) in Group C (mean=0.92 ± 0.07mmol/L) as compared to Group A (mean=1.13 ± 0.1 mmol/L) and Group B (mean= 1.08 ± 0.07 mmol /L; p = 0.034) at 4h post-ROSC.ConclusionWe provide preliminary evidence that ventilation with ETT with moderate leakage improves survival after 2h of ROSC, along with oxygenation and hemodynamic parameters, in a porcine model of neonatal asphyxia and resuscitation, compared to less leakage ETT.

Colchicine is widely investigated for cardioprotection of COVID-19 patients since it can prevent the phenomenon of ‘cytokine storm’ and may reduce the complications arising from COVID-19. Despite the potentially beneficial effects of colchicine, there is no consensus on the appropriate dosage regimen and numerous schemes are currently used. In this study, simulations were performed to identify the ability of dosage regimens to attain plasma levels in CVOID-19 patients, known to be generally safe and efficacious. Since renal and hepatic impairment, as well as, drug-drug interactions have been identified to be the most significant factors increasing colchicine toxicity, the impact of these interactions was assessed in the simulations. Some dosage regimens lead to high colchicine concentrations, while others result in sub-therapeutic levels. Additional dosage schemes were proposed in this study aiming to be applied in patients with clearance insufficiency. Colchicine administration of 0.5 mg twice daily, can be considered safe and effective. In cases of clearance impairment, doses as low as 0.25 mg thrice or twice daily should be applied. Colchicine is a narrow therapeutic index drug and dosage regimens tailored to patients’ needs should be designed.

Hardware removal after complete fracture healing is a laborious and traumatic procedure that bears the risks of refracture, infection, and soft tissue damage. Absorbable materials for fracture fixation have the advantage of eliminating the need for removal; however, they may stimulate a considerable inflammatory response. For that reason, we compared in a prospective randomized experimental animal model study the incidence of foreign-body reactions between Inion OTPSTM absorbable plate implants, consisting of carbon trimethylene, L-polylactic acid, and D, L-polylactic acid, and conventional titanium plates. Seventy rabbits were equally divided into two groups. Titanium (Group A) or absorbable (Group B) plates and screws were implanted in the femoral shaft of the rabbits. Wound reaction and laboratory tests including white blood cell count (WBC), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) values were measured and compared at different time points. Radiographs and histological analysis of tissue samples from all animals were also used to identify potential foreign-body reactions. WBC showed normal values in both groups. In Group A, ESR levels were higher at all time points but CRP values were normalized at 3 weeks postoperatively. In Group B, ESR and CRP levels reached a peak at 3 weeks and were above normal values throughout the whole experiment (p < 0.001). Radiologic examination revealed periosteal thickening and surrounding sclerosis in 23 out of 35 animals of Group B (66%). All Group A animals had normal radiographic findings. Histopathology showed a typical non-specific foreign-body reaction in all animals in Group B (100%) but none in Group A. However, only four of them (11.8%) developed non-infected wound complications and showed significantly elevated CRP and ESR values (p = 0.054). Although Inion OTPSTM Biodegradable Plating System stimulates a foreign-body reaction, only a small but not negligible percentage of almost 12% may lead to wound problems. However, this difference compared to titanium plates was of borderline not statistically significant. Future studies should focus on the development of absorbable implants with improved biocompatibility aiming to further decrease the potential of foreign-body reaction and eliminate the need for additional reoperative procedures.