The effect of phenylephrine hydrochloride 2.5 % and sodium hyaluronate solution on visual functions and accommodation in children with myopia and its local tolerability

Purpose: to evaluate visual functions, accommodation, and local tolerance in children instilled with Phenylephrine hydrochloride 2.5 % and sodium hyaluronate solution (Stelphrin Supra). Material and methods. 30 children (60 eyes) aged 8 to 12 (ave. 10.04 ± 0.24) with low (28 eyes) and moderate (32 eyes) myopia (ave. -2.96 ± 0.17 D) were tested. Refractometry, subjective and objective accommodation, optical biometry, anterior corneal surface examination, Norn test, and polling were performed prior to one-time instillation, 30 minutes after it, and after 1 month of daily bedtime instillations of Stelphrin Supra. Results. We noted a significant decrease in the tone of accommodation in the open field by 90 % from the initial value, an approximation of the nearest point of clear vision by 27 %, an increase in the volume of absolute accommodation by 57 % and the objective amplitude of accommodation by 20 %, which indicates an increase in the accommodation ability. The pupil width increased 30 minutes after a single instillation of Stelphrin Supra, which coincided with an increase in the relative accommodation reserve by 25 % from the initial one. After a month, the pupil width significantly decreased, and the positive relative accommodation reserve decreased to a level only 12 % higher than the original one. Tear film break time significantly increased by 0.89 sec, singular spot stainings disappeared in 2 out of 6 patients, lacrimation — in 6 out of 10, pain — in 1 out of 2, blurring in 4 out of 6, feeling of “sand” — in 7 out of 9 patients who had these symptoms before instillations. Conclusion. Regular instillations of Stelphrin Supra reduce the habitual tone of accommodation, increase the accommodation ability, and improve the condition of the eye surface.

PORT (OP-109): Phase 2, Randomized, Pharmacokinetic (PK), Cross-over Study of Peripheral Vs Central Intravenous Administration of Melflufen in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

Introduction: Melphalan flufenamide (melflufen) is a peptide-drug conjugate with unique PK properties that rapidly penetrates cells, where it is metabolized to melphalan either directly or through an intermediate metabolite, desethyl-melflufen. Melflufen has only been administered via central venous catheter (CVC); however, peripheral venous catheter (PVC) administration may be preferred by patients if safety and tolerability are acceptable. The ongoing PORT study (NCT04412707) aims to compare the PK of melphalan after central and peripheral administration of melflufen, and to assess the local tolerability of peripheral administration of melflufen. The overall efficacy and safety of melflufen in patients with RRMM will also be evaluated. Methods: Patients (following ≥2 lines of prior therapy) were randomized (1:1) to melflufen 40 mg (administered on Day 1 of each cycle; combined with weekly oral dexamethasone 40 mg [20 mg for patients aged ≥75 years] on Days 1, 8, 15, and 22) either via PVC in Cycle 1 then CVC in Cycle 2 (Arm A) or via CVC in Cycle 1 and then PVC in Cycle 2 (Arm B). From Cycle 2 (Arm A) or Cycle 3 (Arm B) onward, patients received melflufen via CVC. PK sampling was performed frequently during and after the 30-minute melflufen infusion. Primary endpoints were maximum observed concentration (C max), area under the concentration-time profile from start of infusion to both last measurable concentration (AUC 0-t) and infinity (AUC 0-inf) for melphalan, and frequency and severity of PVC-related local infusion-site reactions. Secondary endpoints included PK variables for melflufen and desethyl-melflufen and general safety and tolerability. PK parameters after CVC and PVC administration were compared using bioequivalence methods. Patient satisfaction and nurse convenience after CVC and PVC administration (Day 1 of Cycles 1 and 2) were also explored. Results: At data cutoff (June 2, 2021), 27 patients had received melflufen (median age 67 years; 48.1% male), of whom 19 patients received at least 2 doses and were evaluable for PK analysis. Melphalan C max, AUC 0-t, and AUC 0-inf met bioequivalence criteria for CVC and PVC administration, as demonstrated by a 90% confidence interval (CI) for the ratio of means within 80-125%. Geometric mean melphalan concentration over time by CVC vs PVC is shown in Figure 1. For melflufen, the ratio of means was 107-117% for the PK parameters, with all upper 90% CIs above 125%. For desethyl-melflufen, AUC 0-t and AUC 0-inf met bioequivalence criteria and the 90% CI for C max was marginally above the upper limit (127%). Melflufen disappeared rapidly from plasma after the end of infusion, with an average half-life of 5-7 minutes. Melphalan C max was observed on average 7-9 minutes after the end of melflufen infusion for both routes of administration, which reflects the delay in distribution of melphalan from tissues to plasma. Furthermore, there were no local or systemic tolerability issues reported, and patient-reported satisfaction and nurse-reported convenience were comparable for CVC and PVC melflufen administration. The overall melflufen safety profile was in line with previous studies. Conclusions: Systemic melphalan exposure is similar after melflufen PVC and CVC administration. Differences between PVC- and CVC-related PK parameters for melflufen and desethyl-melflufen are considered to have no clinical consequences because their plasma-exposure duration is short. There were no local reactions after melflufen PVC administration. Figure 1 Figure 1. Disclosures Minarik: Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Micheva: Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Andzhelini Farma: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Usenko: AbbVie: Consultancy, Honoraria, Other: Clinical Trials Investigator; Janssen: Consultancy, Honoraria, Other: Clinical Trials Investigator; Pfizer: Consultancy, Honoraria; Acerta: Other: Clinical Trials Investigator; Ascentage: Other: Clinical Trials Investigator; Celgene: Other: Clinical Trials Investigator; Il-Yang: Other: Clinical Trials Investigator; Karyopharm: Other: Clinical Trials Investigator; Oncopeptides: Other: Clinical Trials Investigator; Rigel: Other: Clinical Trials Investigator; Takeda: Other: Clinical Trials Investigator; UCB: Other: Clinical Trials Investigator. Mikala: Takeda: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Abbvie: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Janssen: Honoraria. Thuresson: Oncopeptides AB: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Jerling: Oncopeptides: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Xie: Oncopeptides: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company.

Bio-Distribution and Pharmacokinetics of Topically Administered γ-Cyclodextrin Based Eye Drops in Rabbits

The purpose of this study was to evaluate the ocular pharmacokinetics, bio-distribution and local tolerability of γ-cyclodextrin (γCD) based irbesartan 1.5% eye drops and candesartan 0.15% eye drops after single and multiple topical administration in rabbit eyes. In this randomized, controlled study, a total number of 59 New Zealand White albino rabbits were consecutively assigned to two study groups. Group 1 (n = 31) received irbesartan 1.5% and group 2 (n = 28) candesartan 0.15% eye drops. In both groups, single dose and multiple administration pharmacokinetic studies were performed. Rabbits were euthanized at five predefined time points after single-dose administration, whereas multiple-dose animals were dosed for 5 days twice-daily and then euthanized 1 h after the last dose administration. Drug concentration was measured by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the retinal tissue, vitreous humor, aqueous humor, corneal tissue and in venous blood samples. Pharmacokinetic parameters including maximal drug concentration (Cmax), time of maximal drug concentration (Tmax), half-life and AUC were calculated. To assess local tolerability, six additional rabbits received 1.5% irbesartan eye drops twice daily in one eye for 28 days. Tolerability was assessed using a modified Draize test and corneal sensibility by Cochet Bonnet esthesiometry. Both γCD based eye drops were rapidly absorbed and distributed in the anterior and posterior ocular tissues. Within 0.5 h after single administration, the Cmax of irbesartan and candesartan in retinal tissue was 251 ± 142 ng/g and 63 ± 39 ng/g, respectively. In the vitreous humor, a Cmax of 14 ± 16 ng/g for irbesartan was reached 0.5 h after instillation while Cmax was below 2 ng/g for candesartan. For multiple dosing, the observed Cmean in retinal tissue was 338 ± 124 ng/g for irbesartan and 36 ± 10 ng/g for candesartan, whereas mean vitreous humor concentrations were 13 ± 5 ng/g and <2 ng/g, respectively. The highest plasma concentrations of both irbesartan (Cmax 5.64 ± 4.08 ng/mL) and candesartan (Cmax 4.32 ± 1.04 ng/mL) were reached 0.5 h (Tmax) after single administration. Local tolerability was favorable with no remarkable differences between the treated and the control eyes. These results indicate that irbesartan and candesartan in γCD based nanoparticle eye drops can be delivered to the retinal tissue of the rabbit’s eye in pharmacologically relevant concentrations. Moreover, safety and tolerability profiles appear to be favorable in the rabbit animal model.

The “NOMINAL” trial: Clinical efficacy, cosmetic acceptability, and local tolerability of topical 5% minoxidil lotion without propylene glycol: A 6-month, multicentre, real-life, prospective, assessor-blinded study in 196 subjects with hair loss.

Background and Trial Objectives: A new propylene glycol (PG)-free 5% minoxidil (Mnx) (PG-Free-Mnx) lotion has been recently commercialized. Clinical efficacy and local tolerability have been, so far, documented in a limited number of patients. The aim of this study was to evaluate the clinical efficacy, cosmetic acceptability, and local tolerability of 6-month application of this new PG-Free Mnx lotion in a real-life situation. Materials and Methods: The NOMINAL (NO-PG MINoxidil reAL life study) trial was performed in 22 out-patients Italian dermatology clinics. A total of 196 subjects of both sexes with a diagnosis of androgenic alopecia (AGA) and female androgenic alopecia (FAGA) were enrolled in the trial, after their written informed consent. PG-Free-Mnx lotion was applied 1 ml twice daily for 6 months. Clinical efficacy was evaluated in an open fashion in all the enrolled subjects with a 5-grade scale score (from-2: severe worsening, to +2: very good improvement in comparison with baseline condition). In a subgroup of subjects (n=60) an assessor-blinded clinical efficacy evaluation has been also performed using high definition standardized and coded scalp global pictures at baseline, and after 6 months by an assessor unaware of the temporal sequence using a 3-grade score (from 0: no improvement to 3: very high improvement). Cosmetic acceptability evaluation was assessed using a 7-item questionnaire using a 10-point scale score, with score 1 meaning not at all and score 10 meaning the worst possible condition. Cosmetic acceptability and clinical efficacy were evaluated after 12 and 24 weeks of treatment. Global tolerability, assessed at week 24, was evaluated with a 4-grade scale score (from -1: very low tolerability to +2: very good tolerability). Results: All but seven (3.6%) subjects concluded the study. Clinical efficacy scores (open evaluation) were 0.8±0.7 and 1.0±0.7 at week 12 and 24, respectively. Good or very good clinical response (score +1 or +2) at week 12 and week 24 was observed in 64% and 74% respectively of the subjects with a similar response in women (75%) and men (73%). Baseline severity of AGA/FAGA was inversely correlated with the clinical response with a better outcome in subjects with AGA type II in comparison with subjects with types III/IV AGA. The clinical efficacy was confirmed by the assessor-blinded evaluation of the subgroup of 60 subjects’ pictures at baseline (clinical score at baseline: 0.2±0.4 vs. 1.8±0.7 after 6 months; p=0.0001; absolute mean difference: 1.6; 95% CI: 1.1 to 2.0). Cosmetic acceptability score mean values were always <2 at each time-point evaluation, demonstrating good or very good acceptability. Global Tolerability score mean±SD value was 1.7±0.4 with 94% of the subjects reporting good or very good tolerability with no differences between men and women. No subjects reported severe or very severe (Tolerability score >7) burning, itching or redness sensations. Conclusions: This new PG-free lotion shows, in real-life conditions, a very good cosmetic acceptability and tolerability profile. Clinical efficacy, evaluated both in open and assessor-blinded fashions, was also documented, and it was in line with the available data of traditional Mnx formulations with propylene glycol.

Outpatient Subcutaneous Antimicrobial Therapy (OSCAT) as a Measure to Improve the Quality and Efficiency of Healthcare Delivery for Patients With Serious Bacterial Infections

Since the 1970s, outpatient parenteral antimicrobial therapy (OPAT) has been a viable option for patients who require intravenous antibiotics when hospitalization is not warranted. While the benefits of OPAT as a measure to improve the efficiency of healthcare delivery (i.e., reduced hospital days) and patient satisfaction are well-documented, OPAT is associated with a number of challenges, including line complications and reliance on daily healthcare interactions in some cases at home or in a clinic. To minimize the continued need for intensive healthcare services in the outpatient setting, there is trend toward patients self-administering antibiotics at home without the presence of healthcare workers, after adequate training. In most cases, patients administer the antibiotics through an established intravenous catheter. While this OPAT practice is becoming more accepted as a standard of care, the potential for line complications still exists. Outpatient subcutaneous antimicrobial therapy (OSCAT) has become an increasingly accepted alternative route of administration of antibiotics to IV by French infectious diseases physicians and geriatricians; however, currently, no antibiotics are approved to be administered subcutaneously. Antibiotics with longer half-lives that are completely absorbed and have a favorable local tolerability profile are ideal candidates for OSCAT and have the potential to maximize the quality and efficiency of parenteral antibiotic delivery in the outpatient setting. The increasing development of wearable, on-body subcutaneous delivery systems make OSCAT even more viable as they increase patient independence while avoiding line complications and potentially removing the need for direct healthcare professional observation.

Tolerability and Pharmacokinetic Evaluation of Inhaled Dry Powder Hydroxychloroquine in Healthy Volunteers

ABSTRACTRationaleInhaled antimicrobials enable high local concentrations where needed and, compared to orally administration, greatly reduce the potential for systemic side effects. In SARS-CoV-2 infections, hydroxychloroquine (HCQ) administered as dry powder via inhalation could be safer than oral HCQ allowing for higher and therefore more effective pulmonary concentrations without dose limiting toxic effects.ObjectivesTo assess the local tolerability, safety and pharmacokinetic parameters of HCQ inhalations in single ascending doses of 5, 10 and 20 mg using the Cyclops dry powder inhaler.Methods12healthy volunteers were trained in inhaling HCQ correctly. Local tolerability and safety were assessed by pulmonary function tests, ECG and recording adverse events. To estimate systemic exposure, serum samples were collected before and 0.5, 2 and 3.5 h after inhalation.Results and discussionDry powder HCQ inhalations were well tolerated by the participants, except for transient bitter taste in all participants and minor coughing irritation. There was no significant change in QTc-interval or drop in FEV1 post inhalation. The serum HCQ concentration remained below 10 µg/L in all samples.ConclusionInhaled dry powder HCQ is safe and well tolerated. Our data support further studies with inhaled HCQ dry powder to evaluate pulmonary pharmacokinetics and efficacy is warranted.

Local Tolerance and Biodegradability of a Novel Artificial Dura Mater Graft Following Implantation Onto a Dural Defect in Rabbits

Dura mater defects are a common problem following neurosurgery. Dural grafts are used to repair these defects; among them are biodegradable polymeric synthetic grafts. ArtiFascia is a novel synthetic and fibrous Dural graft, composed of poly(l-lactic-co-caprolactone acid) (PLCL) and poly(d-lactic-co-caprolactone acid). In this study, the biodegradability and local tolerance of ArtiFascia was evaluated in rabbits and compared with a bovine collagen matrix as a reference control. ArtiFascia implantation resulted in the formation of neo-dura at the site of implantation and recovery of the dural damage and the calvaria bone above. The implanted graft was completely absorbed after 12 months and the remaining macrophages were morphologically consistent with the anti-inflammatory M2-like phenotype, which contributes to tissue healing and are not pro-inflammatory. The site of the drilled skull bone had a continuous smooth surface, without exuberant tissue or inflammation and a newly formed trabecular bone formation indicated the healing process of the bone. These results support the local tolerability and biodegradability of ArtiFascia when used as a dural graft in rabbits. This study suggests that PLCL-based grafts including ArtiFascia are safe and effective to repair Rabbit Dura.

Clinical evaluation of polyabsorbent TLC-NOSF dressings on chronic wounds: a prospective, observational, multicentre study of 1140 patients

Objective: The superior wound healing properties and cost-effectiveness of TLC-NOSF dressings in the local treatment of chronic wounds have already been demonstrated by several randomised controlled trials (RCTs) at a high quality level. Therefore, this study aimed to evaluate the efficacy and safety of new TLC-NOSF dressings with polyabsorbent fibres in an unselected population of patients under real-life conditions. Method: A large, prospective, multicentre, observational study with two polyabsorbent TLC-NOSF dressings (UrgoStart Plus Pad and UrgoStart Plus Border, Laboratoires Urgo, France) was conducted in Germany between July 2017 and December 2018. Main outcomes included wound healing rate, clinical assessment of wound healing progression, local tolerability and acceptance of dressings. Results: A total of 1140 patients with chronic wounds of various aetiologies (leg ulcers, diabetic foot ulcers, pressure ulcers, etc.) were treated with the investigated dressings in 130 centres, for a mean duration of 56±34 days. By the final visit, 48.5% of wounds had healed and 44.8% had improved. Similar results were reported regardless of wound aetiology or regardless of proportions of sloughy and granulation tissue at the start of treatment. According to the subgroup analysis by wound duration, the sooner the TLC-NOSF treatment was initiated, the better the clinical outcomes for all types of wounds. The dressings were very well tolerated and accepted by the patients. Conclusion: These results are consistent with those from RCTs conducted on TLC-NOSF dressings. They complete the evidence on the good healing properties and safety profile of these dressings, especially in non-selected patients treated in current practice, and regardless of the characteristics of wounds and patients. They support the use of the dressings as a first-line intervention and until wound healing in the management of chronic wounds, in association with appropriate standard of care.