PEGylated-liposomal astaxanthin ameliorates Aß neurotoxicity and Alzheimer-related phenotypes by scavenging formaldehyde.

Alzheimer's disease (AD), which is a prevailing type of dementia, presents a significant global health concern. The current therapies do not meet clinical expectations. Amyloid-beta (Aß) has been found to induce endogenous formaldehyde (FA) accumulation by inactivating FA dehydrogenase (FDH); in turn, excessive FA triggers Aß aggregation that eventually leads to AD onset. Hence, scavenging FA by astaxanthin (ATX, a strong exogenous antioxidant) may be pursued as a promising disease-modifying approach. Here, we report that liposomal nanoparticles coupled with PEG (PEG-ATX@NPs) could enhance water-solubility of ATX and alleviate cognitive impairments by scavenging FA and reducing Aß deposition. To enable drug delivery to the brain, liposomes were used to encapsulate ATX and then coupled with PEG, which produced liposomal nanoparticles (PEGATX@NPs) with a diameter of <100 nm. The PEG-ATX@NPs reduced Aß neurotoxicity by both degrading FA and reducing FA-induced Aß assembly in vitro. Intraperitoneal administration of PEG-ATX@NPs in APPswe/PS1dE9 mice (APP/PS1, a familial model of AD), not only decreased the levels of brain FA and malondialdehyde (MDA, a typical product of oxidative stress), but also attenuated both intracellular Aß oligomerization and extracellular Aß-related senile plaque (SP) formation. These pathological changes were accompanied by rescued ability of spatial learning and memory. Collectively, PEG-ATX@NPs improved the water-solubility, bioavailability, and effectiveness of ATX. Thus, it has the potential to be developed as a safe and effective strategy for treating AD.

A therapeutic dose and its pharmacokinetics of ropeginterferon Alfa-2b for hepatitis C treatment.

AIM: Ropeginterferon alfa-2b is a novel mono-pegylated proline-interferon. Its biweekly dosing schema has demonstrated tolerability and clinical efficacy for treating chronic hepatitis in previous clinical studies. This trial evaluates the pharmacokinetics of 400 µg ropeginterferon alfa-2b in patients with chronic hepatitis C virus (HCV) and provides the data to support the clinical utility of ropeginterferon alfa-2b at 400 µg. METHODS: Seventeen patients with chronic HCV genotype 2 were enrolled to receive a single injection of 400 µg ropeginterferon alfa-2b plus 14-day treatment of ribavirin. Pharmacokinetics, safety, and HCV RNA reduction/clearance were assessed. RESULTS: Tmax was 154.003 h and T1/2 was 114.273 h. The Cmax was 29.823 ng mL-1. AUClast was 9364.292 h∗ng mL-1 and AUCinf was 11084.317 h∗ng mL-1. All adverse events were mild or moderate, and there were no serious adverse events. A 1000-fold reduction in the geometric mean of HCV RNA was observed 14 d after the single injection of ropeginterferon alfa-2b. Two patients achieved clearance of HCV RNA, and the other five patients had HCV RNA levels lower than 200 IU mL-1. CONCLUSION: Ropeginterferon alfa-2b at 400 µg led to PK exposures associated with safety and notable clinical activity in patients with chronic HCV. This study suggests that ropeginterferon alfa-2b at 400 µg is an acceptable dosing regimen for treating chronic HCV and also provides supporting data for the clinical use of ropeginterferon alfa-2b at a higher starting dose for other indications.

1-L polyethylene glycol + ascorbic acid versus sodium picosulfate + magnesium citrate bowel preparations for colonoscopy: effectiveness and safety

Background: adequate bowel preparation is crucial for the protective effect of colonoscopy. Commonly used preparation regimens like polyethylene glycol (PEG) or sodium picosulfate with magnesium citrate (SPMC) have shown similar results in clinical trials, but low-volume PEG + ascorbic acid (1-L PEG + ASC) versus SPMC have never been compared in a real-life setting. Aim: to evaluate the effectiveness and safety of 1-L PEG + ASC versus SPMC in a real-life setting for the overall population, for patients aged ≥ 65 years, and males versus females. Methods: out-patients aged ≥ 18 years who underwent colonoscopy for any indication were randomly assigned to the 1-L PEG + ASC or SPMC group. Using the Boston Bowel Preparation Scale (BBPS), the primary endpoints were the bowel cleansing success of the overall colon and right colon, as well as high-quality (HQ) cleansing. Furthermore, the effectiveness and safety outcomes for age groups and males versus females were compared. Results: 1-L PEG + ASC showed significantly better bowel cleansing success than SPMC. Particularly remarkable is the HQ cleansing reached with 1-L PEG + ASC compared with SPMC (55.5 % versus 25.4 % in the overall colon, and 58.7 % versus 27.2 % in the right colon). 1-L PEG + ASC was equally effective for men and women while SPMC showed significant differences between genders (men had worse bowel cleansing). Age did not affect the cleansing effectiveness. 1-L PEG + ASC versus SPMC showed significant differences in tolerance and safety; women also had significantly worse tolerance than men for both solutions, but these did not affect the quality of bowel cleansing. Conclusions: in our real-life setting, 1-L PEG + ASC offered better adequate and HQ bowel cleansing than SPMC, achieving excellent cleansing quality, regardless of gender or tolerance. (AU)

Dried lemon slices improve bowel cleansing quality of polyethylene glycol for colonoscopy preparation: randomized controlled trial

Background: adequate bowel preparation is related to the quality of colonoscopy. Dried lemon slices can increase gastrointestinal peristalsis, which has shown potential as an adjuvant of bowel preparation. We hypothesized that the combination of dried lemon slices and polyethylene glycol (PEG) could improve the efficacy of bowel preparation and be more acceptable to participants. Aim: to investigate the effectiveness of lemon slices combined with PEG for colonoscopy preparation. Methods: a prospective, single-center, randomized, controlled trial was performed of 521 patients randomly assigned to two groups. A total of 254 patients were given lemon slices based on conventional 4-L PEG treatment for the bowel, while 267 patients received only 4-L PEG treatment. Patients’ basic information, procedure-related parameters, adverse effects, and subjective feelings were collected by questionnaires. Intestinal tract cleanliness was scored according to the Boston Bowel Preparation Scale (BBPS) by experienced endoscopists. Data were analyzed by the two-sample t-test or the Chi-squared test. Results: the BBPS scores were significantly higher in the PEG + lemon slice group (p < 0.05). The taste acceptability, satisfaction, and willingness to repeat bowel preparation were significantly higher in the PEG+ lemon slice group (p < 0.05). However, a larger proportion of patients from the PEG+ lemon slice group (30.7 %) suffered abdominal distension compared with the PEG group (20.6 %), while the incidence of other adverse effects was comparable between the two groups. Conclusion: the addition of dried lemon slices to conventional PEG showed its superiority for bowel preparation (AU)

Efficacy and safety of Dynavisc® gel in prevention of scar adhesions recurrence after flexor tendons tenolysis in zone 2. Multicenter retrospective cohort study.

AIM: Dynavisc® is a novel surgical product made of carboxymethylcellulose (CMC) and Polyethylene Oxide (PEO) designed to reduce post-surgical adhesions in tendons surgery. A multicenter retrospective cohort study was performed to investigate the clinical safety and efficacy of the Dynavisc® gel in reducing post-surgical adhesions after flexor tenolysis in zone 2. MATERIAL OF STUDY: Thirty-one patients suffering from stiff finger after flexor tendon repairs in zone 2 treated with standard release with (18 Dynavisc®-treated group) or without (13 controls) anti-adhesion gel application into the flexor tendon sheath and around the site of the tenolysis, were collected in five different hand surgery units. Safety profile and functional outcomes (based on TAM test and the The Quick-DASH questionnaire) were examined from patients' charts and analyzed. RESULTS: The application of Dynavisc® posed no safety concerns and it was not related to any additional complication. The Dynavisc®-treated group showed greater progressive improvement of TAM value in all visits with superior TAM value at T(90) and T(180) compared to the control group. DISCUSSION: Tendon adhesions are the main cause of flexor tendon surgery failure. Multiple strategies (i.e. robust tendon repair, early rehabilitation and lubricant or barrier agents) have been proposed to minimize their formation. Among different products described in the literature Dynavisc® showed a significant role in limiting adhesions formation in a recent experimental study. CONCLUSIONS: This clinical study confirm the safety of Dynavisc® gel application in hand surgery demonstrating its potential long-term benefits after flexor tendon tenolysis. KEY WORDS: Flexor Tendon Repair, Tendon Adhesions, Tenolysis.

Protocolo de tratamiento con polietilenglicol 3350 con electrolitos para el estreñimiento en el niño crítico / Protocol for treatment of constipation with polyethylene glycol 3350 plus electrolytes in critically ill children

Introducción y objetivos: Ningún estudio ha analizado la efectividad del tratamiento del estreñimiento en niños críticamente enfermos. El objetivo de este estudio fue evaluar la implementación, la eficacia y la seguridad de un protocolo de tratamiento con polietilenglicol 3350 con electrolitos (PEG 3350+E) para el estreñimiento en niños en estado crítico. Métodos: Estudio prospectivo unicéntrico, incluyendo niños que ingresaron en cuidados intensivos pediátricos durante más de 72h y que desarrollaron estreñimiento. Se excluyeron los niños con trastornos o afecciones gastrointestinales previas. Los pacientes fueron tratados con enemas rectales o con PEG 3350+E oral a criterio del médico tratante. Se compararon variables clínicas, demográficas y efectos secundarios (diarrea, distensión abdominal y desequilibrio electrolítico). Resultados: Se estudiaron 56 pacientes de 48,2±11,9 meses de edad, siendo el 55,4% varones. Cuarenta y cuatro pacientes (78,6%) fueron tratados con PEG 3350+E y 12 pacientes (21,4%) con enemas rectales. El porcentaje de efectividad del PEG 3350+E (79,5%) fue mayor que el de los enemas (58,3%), pero la diferencia no fue estadísticamente significativa (p=0,151). No existieron diferencias significativas en ninguno de los efectos secundarios entre los 2 grupos. El PEG 3350+E fue más efectivo en los niños menores de 2 años (100%) que en los mayores de esa edad (65,4%), p<0,01, sin diferencias significativas en la aparición de efectos secundarios. Conclusiones: El tratamiento del estreñimiento en los niños en estado crítico con PEG 3350+E es eficaz y tiene pocos efectos secundarios, incluso en niños menores de 2 años. (AU)

Introduction and objectives: No studies have analysed the effectiveness of treatment for constipation in critically ill children. The aim of this study was to assess the implementation, efficacy and safety of a treatment protocol using polyethylene glycol 3350 with electrolytes (PEG 3350+E) for constipation in critically ill children. Methods: We conducted a single-centre prospective study in children admitted to the paediatric intensive care unit for a minimum of 72h and who developed constipation. Children with previous gastrointestinal disorders or diseases were excluded. The patients were treated with rectal enemas or with the oral PEG 3350+E protocol at the discretion of the treating physician. We compared clinical and demographic variables as well as adverse events (diarrhoea, abdominal distension and electrolyte imbalances). Results: The sample included 56 patients with a mean age of 48.2±11.9 months, of who 55.4% were male. Forty-four patients (78.6%) were treated with PEG 3350+E and 12 (21.4%) with rectal enemas. The proportion of patients who responded well to treatment was greater in the PEG 3350+E group (79.5%) compared to the enema group (58.3%), but the difference was not statistically significant (P=.151). There were no significant differences between the groups in any of the adverse effects. Treatment with PEG 3350+E was more effective in children aged less than 2 years (100%) compared to older children (100% vs. 65.4%; P<.01), with no significant differences in the development of adverse events. Conclusions: The PEG 3350+E treatment protocol for constipation in critically ill children was effective and associated with few adverse events, even in children aged less than 2 years. (AU)

Evaluation of bowel preparation regimens for colonoscopy including a novel low volume regimen (Plenvu): CLEANSE study.

BACKGROUND: Poor bowel preparation is the leading cause of failed colonoscopies and increases costs significantly. Several, split preparation, 2 day regimens are available and recently, Plenvu, a low-volume preparation which can be given on 1 day has been introduced. AIMS: Assess efficacy and tolerability of commonly used purgative regimens including Plenvu. METHOD: In this service evaluation, patients undergoing screening colonoscopy at St Mark's Hospital, London (February 2020-December 2021) were provided Plenvu (1 or 2 days), Moviprep (2 days) or Senna & Citramag (2 days).Boston Bowel Preparation Scale (BBPS) score, fluid volumes and procedure times were recorded. A patient experience questionnaire evaluated taste, volume acceptability, completion and side effects. RESULTS: 563 patients were invited to participate and 553 included: 218 Moviprep 2 days, 108 Senna & Citramag 2 days, 152 Plenvu 2 days and 75 Plenvu 1 day.BBPS scores were higher with Plenvu 1 and 2 days vs Senna & Citramag (p=0.003 and 0.002, respectively) and vs Moviprep (p=0.003 and 0.001, respectively). No other significant pairwise BBPS differences and no difference in preparation adequacy was seen between the groups.Patients rated taste as most pleasant with Senna & Citramag and this achieved significance versus Plenvu 1 day and 2 days (p=0.002 and p<0.001, respectively) and versus Moviprep (p=0.04). CONCLUSION: BBPS score was higher for 1 day and 2 days Plenvu versus both Senna & Citramag and Moviprep. Taste was not highly rated for Plenvu but it appears to offer effective cleansing even when given as a same day preparation.

Early Treatment with Pegylated Interferon Lambda for Covid-19.

BACKGROUND: The efficacy of a single dose of pegylated interferon lambda in preventing clinical events among outpatients with acute symptomatic coronavirus disease 2019 (Covid-19) is unclear. METHODS: We conducted a randomized, controlled, adaptive platform trial involving predominantly vaccinated adults with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Brazil and Canada. Outpatients who presented with an acute clinical condition consistent with Covid-19 within 7 days after the onset of symptoms received either pegylated interferon lambda (single subcutaneous injection, 180 µg) or placebo (single injection or oral). The primary composite outcome was hospitalization (or transfer to a tertiary hospital) or an emergency department visit (observation for >6 hours) due to Covid-19 within 28 days after randomization. RESULTS: A total of 933 patients were assigned to receive pegylated interferon lambda (2 were subsequently excluded owing to protocol deviations) and 1018 were assigned to receive placebo. Overall, 83% of the patients had been vaccinated, and during the trial, multiple SARS-CoV-2 variants had emerged. A total of 25 of 931 patients (2.7%) in the interferon group had a primary-outcome event, as compared with 57 of 1018 (5.6%) in the placebo group, a difference of 51% (relative risk, 0.49; 95% Bayesian credible interval, 0.30 to 0.76; posterior probability of superiority to placebo, >99.9%). Results were generally consistent in analyses of secondary outcomes, including time to hospitalization for Covid-19 (hazard ratio, 0.57; 95% Bayesian credible interval, 0.33 to 0.95) and Covid-19-related hospitalization or death (hazard ratio, 0.59; 95% Bayesian credible interval, 0.35 to 0.97). The effects were consistent across dominant variants and independent of vaccination status. Among patients with a high viral load at baseline, those who received pegylated interferon lambda had lower viral loads by day 7 than those who received placebo. The incidence of adverse events was similar in the two groups. CONCLUSIONS: Among predominantly vaccinated outpatients with Covid-19, the incidence of hospitalization or an emergency department visit (observation for >6 hours) was significantly lower among those who received a single dose of pegylated interferon lambda than among those who received placebo. (Funded by FastGrants and others; TOGETHER ClinicalTrials.gov number, NCT04727424.).

Ciprofloxacin and pegylated G-CSF combined therapy mitigates brain hemorrhage and mortality induced by ionizing irradiation.

Introduction: Brain hemorrhage was found between 13 and 16 days after acute whole-body 9.5 Gy 60Co-γ irradiation (IR). This study tested countermeasures mitigating brain hemorrhage and increasing survival from IR. Previously, we found that pegylated G-CSF therapy (PEG) (i.e., Neulasta®, an FDA-approved drug) improved survival post-IR by 20-40%. This study investigated whether Ciprofloxacin (CIP) could enhance PEG-induced survival and whether IR-induced brain hemorrhage could be mitigated by PEG alone or combined with CIP. Methods: B6D2F1 female mice were exposed to 60Co-γ-radiation. CIP was fed to mice for 21 days. PEG was injected on days 1, 8, and 15. 30-day survival and weight loss were studied in mice treated with vehicles, CIP, PEG, or PEG + CIP. For the early time point study, blood and sternums on days 2, 4, 9, and 15 and brains on day 15 post-IR were collected. Platelet numbers, brain hemorrhage, and histopathology were analyzed. The cerebellum/pons/medulla oblongata were detected with glial fibrillary acidic protein (GFAP), p53, p16, interleukin-18 (IL-18), ICAM1, Claudin 2, ZO-1, and complement protein 3 (C3). Results: CIP + PEG enhanced survival after IR by 85% vs. the 30% improvement by PEG alone. IR depleted platelets, which was mitigated by PEG or CIP + PEG. Brain hemorrhage, both surface and intracranial, was observed, whereas the sham mice displayed no hemorrhage. CIP or CIP + PEG significantly mitigated brain hemorrhage. IR reduced GFAP levels that were recovered by CIP or CIP + PEG, but not by PEG alone. IR increased IL-18 levels on day 4 only, which was inhibited by CIP alone, PEG alone, or PEG + CIP. IR increased C3 on day 4 and day 15 and that coincided with the occurrence of brain hemorrhage on day 15. IR increased phosphorylated p53 and p53 levels, which was mitigated by CIP, PEG or PEG + CIP. P16, Claudin 2, and ZO-1 were not altered; ICAM1 was increased. Discussion: CIP + PEG enhanced survival post-IR more than PEG alone. The Concurrence of brain hemorrhage, C3 increases and p53 activation post-IR suggests their involvement in the IR-induced brain impairment. CIP + PEG effectively mitigated the brain lesions, suggesting effectiveness of CIP + PEG therapy for treating the IR-induced brain hemorrhage by recovering GFAP and platelets and reducing C3 and p53.

PVP solid dispersions containing Poloxamer 407 or TPGS for the improvement of ursolic acid release

Abstract Solid dispersions (SDs) of ursolic acid (UA) were developed using polyvinylpyrrolidone K30 (PVP K30) in combination with non-ionic surfactants, such as D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) or poloxamer 407 (P407) with the aim of enhancing solubility and in vitro release of the UA. SDs were investigated using a 24 full factorial design, subsequently the selected formulations were characterized for water solubility, X-ray diffractometry (XRD), differential scanning calorimetry (DSC), particle diameter, scanning electron microscopy, drug content, physical-chemical stability and in vitro release profile. SDs showed higher UA water-solubility than physical mixtures (PMs), which was attributed by transition of the drug from crystalline to amorphous or molecular state in the SDs, as indicated by XRD and DSC analyses. SD1 (with P407) and SD2 (with TPGS) were chosen for further investigation because they had higher drug load. SD1 proved to be more stable than SD2, revealing that P407 contributed to ensure the stability of the UA. Furthermore, SD1 and SD2 increased UA release by diffusion and swelling-controlled transport, following the Weibull model. Thus, solid dispersions obtained with PVP k-30 and P407 proved to be advantageous to enhance aqueous solubility and stability of UA.

¿Sin salida? / No exit?

El síndrome de obstrucción intestinal distal (SOID) es una complicación digestiva propia de los pacientes con fibrosis quística. Se caracteriza por la acumulación de materia fecal viscosa y secreciones espesas. Afecta a íleon distal, ciego o colon ascendente. Puede derivar en la aparición de obstrucción intestinal total o parcial. Para su tratamiento, se aconseja administrar polietilenglicol oral o a través de una sonda nasogástrica. La cirugía se reserva para los casos refractarios (AU)

Distal intestinal obstruction syndrome (SOID) is a digestive complication specific of patients with cystic fibrosis, characterized by the accumulation of viscous fecal matter and thick secretions. It can lead to the appearance of total or partial intestinal obstruction, affecting the distal ileum, cecum, or ascending colon. For its treatment, it is suggested the administration of oral polyethylene glycol or through a nasogastric tube. Surgery is reserved for refractory cases. (AU)

Development, Characterization, and In Vitro Evaluation of Cytotoxic Activity of Rutin Loaded PCL-PEG Nanoparticles Against Skov3 Ovarian Cancer Cell.

BACKGROUND AND PURPOSE: Rutin (RUT) is one of the phenolic compounds found in the invasive plant species, Carpobrotus edulis. Several studies have confirmed numerous pharmacological properties of RUT, including antioxidant, antidiabetic, anti-inflammatory, antimicrobial and anticancer activities. As a result, the goal of this work was to make RUT-loaded PCL-PEG and test its anti-cancer effects against the Skov3 human ovarian cancer cell line. MATERIALS AND METHODS: The NPs were made using the W1/O/W2 process, and their physicochemical properties were assessed by FE-SEM, FTIR, and DLS. MTT assay were used to investigate the anti-proliferative characteristics of drug-loaded NPs. Real-time PCR was also utilized to  examine the expression levels of apoptotic genes including caspase-8, -9, -3, and Bax, as well as anti-apoptotic genes like Bcl-2. RESULTS: Cytotoxicity testing revealed that RUT-loaded PCL-PEG improved cytotoxicity in a dose- and time-dependent manner. In treated MDA-MB-231 cells with RUT-loaded PCL-PEG, there was a significant up-regulation of caspase-8, -9, -3, and Bax genes compared to treated cells with free RUT. CONCLUSION: Finally, RUT-loaded PCL-PEG NPs are recommended as ideal delivery nanocarriers for enhancing RUT's anticancer characteristics for ovarian cancer treatment.

CD73 downregulation by EGFR-targeted liposomal CD73 siRNA potentiates antitumor effect of liposomal doxorubicin in 4T1 tumor-bearing mice.

Blocking CD73 ectonucleotidase has been proposed as a potential therapeutic approach for cancer treatment. The present study aimed to investigate the antitumor effect of a novel EGFR-Targeted liposomal CD73 siRNA formulation in combination therapy with liposomal doxorubicin in the 4T1 mouse model. CD73 siRNA was encapsulated into nanoliposomes by the ethanol injection method. After preparation, characterization, morphology, and stability evaluation of formulations, the toxicity was measured by MTT assay. Uptake assay and efficiency of the liposomal formulations were investigated on the 4T1 cell line. The liposomal formulation containing CD73 siRNA was targeted with GE11 peptide for in vivo evaluations. Following biodistribution analysis, the antitumor activity of prepared formulations in combination with liposomal doxorubicin was studied in mice bearing 4T1 metastatic breast cancer cells. Finally, the induction of immune response of formulations in concomitant treatment with liposomal doxorubicin was evaluated in the tumor microenvironment of a mouse model of breast cancer. The size of prepared liposomal formulations at N/P = 16 for the liposomal CD73 siRNA and GE11-liposomal CD73 siRNA groups were 89 nm ± 4.4 and 95 nm ± 6.6, respectively. The nanoparticle's PDI was less than 0.3 and their surface charge was below 10 mV. The results demonstrated that N/P = 16 yielded the best encapsulation efficiency which was 94% ± 3.3. AFM results showed that the liposomes were spherical in shape and were less than 100 nm in size. The results of the MTT assay showed significant toxicity of the liposomes containing CD73 siRNA during the 48-h cell culture. Real-time PCR and flow cytometry results showed that liposomes containing CD73 siRNA could effectively downregulate CD73 expression. Liposomal formulations were able to significantly downregulate CD73 gene expression, in vivo. However, CD73 downregulation efficiency was significantly higher for the targeted form compared to the non-targeted formulation (P value < 0.01). The combination showed maximum tumor growth delay with remarkable survival improvement compared to the control group. Studying the immune responses in the treatment groups which received doxorubicin, showed decreased number of lymphocytes in the tumor environment. However, this decrease was lower in the combination therapy group. Finally, our results clearly showed that CD73 downregulation increases the activity of CD8+ lymphocytes (IFN-ℽ production) and also significantly decreases the Foxp3 in the CD25+ lymphocytes compared to the control group. GE11-Lipo CD73 siRNA formulation can efficiently knockdown CD73 ectonucleotidase. Also, the efficacy of liposomal doxorubicin is significantly enhanced via the downregulation of CD73 ectonucleotidase.

Peginterferon beta-1a concentrations in breast milk of lactating multiple sclerosis patients.

BACKGROUND: Peginterferon beta-1a is an interferon beta-1a formulation that has been pegylated, resulting in a longer half-life than other interferon beta formulations. We examined concentrations of peginterferon beta-1a in breast milk of lactating patients with multiple sclerosis (MS) receiving peginterferon beta-1a as their postpartum disease-modifying therapy. METHODS: After completion of titration to a full dose of peginterferon beta-1a and following a single full dose peginterferon beta-1a injection (125 µg), breast milk samples (≥10 mL) were collected by 5 women on days 1-14 post injection. Peginterferon beta-1a concentrations in breast milk samples were measured by a qualified enzyme-linked immunosorbent assay (detection threshold: 15 pg/mL). Mean and median daily concentrations and median maximum concentration (Cmax), time of Cmax (Tmax), time of last measurable concentration (Tlast), area under the concentration-time curve (AUClast), and relative infant dose (RID) were determined. RESULTS: After receiving a single full dose peginterferon beta-1a injection, the maximum breast milk concentration recorded in an individual patient was 126.2 pg/mL (0.00013 µg/mL) on day 6. The remaining patients all had maximum breast milk concentrations <72 pg/mL. The geometric mean of Cmax was 48.9 pg/mL and the median Tmax and Tlast were 4 and 7 days, respectively. The median AUClast was 210.9 day*pg/mL. Among the 5 study patients, the mean breast milk concentration across all study days was 35.95 pg/mL, with an estimated RID of 0.0054% of the maternal dose. CONCLUSION: Minimal concentrations of peginterferon beta-1a were detected in the breast milk samples. These findings may be useful for clinicians considering postpartum MS treatment options.

Stealth Liposomes (PEGylated) Containing an Anticancer Drug Camptothecin: In Vitro Characterization and In Vivo Pharmacokinetic and Tissue Distribution Study.

Numerous attempts to overcome the poor water solubility of cam ptothecin (CPT) by various nano drug delivery systems are described in various sources in the literature. However, the results of these approaches may be hampered by the incomplete separation of free CPT from the formulations, and this issue has not been investigated in detail. This study aimed to promote the solubility and continuous delivery of CPT by developing long-lasting liposomes using various weights (M.W. 2000 and 5000 Daltons) of the hydrophilic polymer polyethylene glycol (PEG). Conventional and PEGylated liposomes containing CPT were formulated via the lipid film hydration method (solvent evaporation) using a rotary flash evaporator after optimising various formulation parameters. The following physicochemical characteristics were investigated: surface morphology, particle size, encapsulation efficiency, in vitro release, and formulation stability. Different molecular weights of PEG were used to improve the encapsulation efficiency and particle size. The stealth liposomes prepared with PEG5000 were discrete in shape and with a higher encapsulation efficiency (83 ± 0.4%) and a prolonged rate of drug release (32.2% in 9 h) compared with conventional liposomes (64.8 ± 0.8% and 52.4%, respectively) and stealth liposomes containing PEG2000 (79.00 ± 0.4% and 45.3%, respectively). Furthermore, the stealth liposomes prepared with PEG5000 were highly stable at refrigeration temperature. Significant changes were observed using various pharmacokinetic parameters (mean residence time (MRT), half-life, elimination rate, volume of distribution, clearance, and area under the curve) of stealth liposomes containing PEG2000 and PEG5000 compared with conventional liposomes. The stealth liposomes prepared with PEG5000 showed promising results with a slow rate of release over a long period compared with conventional liposomes and liposomes prepared with PEG2000, with altered tissue distribution and pharmacokinetic parameters.

Rapidly Self-Deactivating and Injectable Succinyl Ester-Based Bioadhesives for Postoperative Antiadhesion.

Postoperative adhesion not only causes severe complications for patients but also increases their economic burden. Injectable bioadhesives with adhesiveness to tissues can cover irregular wounds and stay stable in situ, which is a promising barrier for antiadhesion. However, the potential tissue adhesion caused by bioadhesives' indiscriminate adhesiveness between normal and wounded tissue is still a problem. Herein, by using poly(ethylene glycol) succinimidyl succinate (PEG-SS) and gelatin, a succinyl ester-based bioadhesive (SEgel) was fabricated with self-deactivating properties for postoperative antiadhesion. Because N-hydroxysuccinimide esters (NHS-esters) were used as the adhesive group, the bioadhesives' side in contact with the tissue built covalent anchors quickly to maintain the stability, but the superficial layer facing outward withstood fast hydrolysis and then lost its adhesion within minutes, avoiding the indiscriminate adhesiveness. In addition, because of the specific degradation behavior of succinyl ester, the SEgel with proper in vivo retention was achieved without the worry of causing foreign body reactions and unexpected tissue adhesion. Both the cecum-sidewall adhesion and hepatic adhesion models showed that the SEgel markedly reduced the severity of tissue adhesion. These results, together with the ease of the preparation process and well-proven biocompatibility of raw materials, revealed that the SEgel might be a promising solution for postoperative antiadhesion.

AVP-eGFP was significantly upregulated by hypovolemia in the parvocellular division of the paraventricular nucleus in the transgenic rats.

Arginine vasopressin (AVP) is produced in the paraventricular (PVN) and supraoptic nuclei (SON). Peripheral AVP, which is secreted from the posterior pituitary, is produced in the magnocellular division of the PVN (mPVN) and SON. In addition, AVP is produced in the parvocellular division of the PVN (pPVN), where corticotrophin-releasing factor (CRF) is synthesized. These peptides synergistically modulate the hypothalamic-pituitary-adrenal (HPA) axis. Previous studies have revealed that the HPA axis was activated by hypovolemia. However, the detailed dynamics of AVP in the pPVN under hypovolemic state has not been elucidated. Here, we evaluated the effects of hypovolemia and hyperosmolality on the hypothalamus, using AVP-enhanced green fluorescent protein (eGFP) transgenic rats. Polyethylene glycol (PEG) or 3% hypertonic saline (HTN) was intraperitoneally administered to develop hypovolemia or hyperosmolality. AVP-eGFP intensity was robustly upregulated at 3 and 6 h after intraperitoneal administration of PEG or HTN in the mPVN. While in the pPVN, eGFP intensity was significantly increased at 6 h after intraperitoneal administration of PEG with significant induction of Fos-immunoreactive (-ir) neurons. Consistently, eGFP mRNA, AVP hnRNA, and CRF mRNA in the pPVN and plasma AVP and corticosterone were significantly increased at 6 h after intraperitoneal administration of PEG. The results suggest that AVP and CRF syntheses in the pPVN were activated by hypovolemia, resulting in the activation of the HPA axis.

mPEG-b-P(Glu-co-Phe) nanoparticles increase gastric retention time and gastric ulcer treatment efficacy of 20(S)-ginsenoside Rg3.

BACKGROUND: Gastric ulcer (GU) belongs to gastric mucosal irritation and damage. 20(S)-ginsenoside Rg3 (Rg3) has shown anti-oxidant, antiinflammation, and tissue repair effects which are essential for GU treatment. However, the solubility of Rg3 is poor and low gastrointestinal absorption may limit its anti-ulcer effects. As a result, we aim to increase the gastric retention time and gastric absorption of Rg3 to achieve better GU treatment efficacy. METHODS: The mPEG-b-P(Glu-co-Phe) nanoparticles loaded with Rg3 (Rg3-NPs) were developed. The characteristics of Rg3-NPs, including the morphology, diameter, and stability were analyzed. The Rg3 release profiles, gastric retention of Rg3, in vitro cytotoxicity, and pharmacokinetics of Rg3 were assessed. An alcohol-induced rats GU model was performed, and the rats were randomly separated into five treatment groups. Biochemical analysis, gross evaluation, histopathology, and immunohistochemical analysis were applied to further analyze the anti-ulcer effects of Rg3-NPs. RESULTS: Rg3-NPs were successfully prepared and the Rg3 release was pH sensitive. The gastric retention time of Rg3 is longer in Rg3-NPs group than that in Rg3 group. By slightly increasing nitric oxide (NO), obviously increasing epidermal growth factor (EGF), EGF receptor (EGFR), and superoxide dismutase (SOD), and decreasing endothelin-1 (ET-1) and nitric oxide synthase (NOS2), Rg3-NPs possess better GU treatment efficacy than Rg3. CONCLUSIONS: Rg3-NPs can increase gastric retention time and gastric absorption of Rg3 and promote its GU treatment efficacy.

PIVOT-12: a phase III study of adjuvant bempegaldesleukin plus nivolumab in resected stage III/IV melanoma at high risk for recurrence.

Bempegaldesleukin (BEMPEG: NKTR-214) is an immunostimulatory IL-2 cytokine prodrug engineered to deliver a controlled, sustained and preferential IL-2 pathway signal. Nivolumab (NIVO), a PD-1 inhibitor, has been shown to prolong survival in patients with advanced melanoma and recurrence-free survival in the adjuvant setting. PIVOT-02 showed that BEMPEG plus NIVO was well-tolerated and demonstrated clinical activity as first-line therapy in metastatic melanoma. PIVOT-12 is a randomized, phase III, global, multicenter, open-label study comparing adjuvant therapy with BEMPEG plus NIVO versus NIVO alone in adult and adolescent patients with completely resected cutaneous stage III/IV melanoma at high risk of recurrence. The primary objective is to compare the efficacy, as measured by recurrence-free survival, of BEMPEG plus NIVO versus NIVO.

Following surgery, patients with advanced melanoma may require further treatment to reduce the likelihood of disease recurrence. Nivolumab (NIVO), a checkpoint inhibitor, reduces the risk of melanoma recurrence by enhancing the ability of the immune system to fight disease. Despite the availability of NIVO and other therapies, many patients with melanoma still experience disease recurrence after surgery. This article presents information on a clinical trial named PIVOT-12, which aims to assess the effectiveness of a new investigational drug called bempegaldesleukin that modifies the immune system and is given with NIVO to patients with stage III/IV melanoma following surgery. The main end point being measured is recurrence-free survival, which measures the time between a patient starting the study and the date of disease recurrence. Clinical Trial Registration: NCT04410445 (ClinicalTrials.gov).

Phase I study of pegylated liposomal doxorubicin and cisplatin in patients with advanced osteosarcoma.

PURPOSE: The repeated use of doxorubicin is limited due to dose-limiting cardiac toxicity. Pegylated liposomal doxorubicin (PEG-LD, Duomeisu) has a reduced cardiac toxicity. This phase I study aimed to investigate the maximum tolerated doses (MTDs) and dose-limiting toxicities (DLTs) of the PEG-LD and cisplatin combination in patients with metastatic and recurrent osteosarcoma. METHODS: Patients were given PEG-LD at a dose of 40, 50, or 60 mg/m2 on day 1 of each 21-day cycle, according to a 3 + 3 approach for dose escalation. Cisplatin was administered as a fixed dose of 100 mg/m2 for every cycle. Toxicities and tumor response were observed. RESULTS: A total of 15 patients were enrolled in this trial, and nine of the patients had received prior doxorubicin. The MTD of PEG-LD was reached at 50 mg/m2 in this regimen, with neutropenic fever and stomatitis as DTLs. The main adverse event (AE) was myelosuppression. The most common non-hematological AEs were vomiting, hypoproteinemia, stomatitis and transient sinus arrhythmia. Grade 3-4 toxicity was neutropenia, leukopenia, thrombocytopenia, anemia and stomatitis in the whole cohort. All the AEs were relieved after symptomatic and supportive treatment. Totally, the overall response rate was 13.3% and disease control rate was 66.7%. For the six patients who have not received prior doxorubicin, one partial response and five stable diseases were observed. CONCLUSION: We provide the data showing that PEG-LD 50 mg/m2 combined with cisplatin 100 mg/m2 demonstrated an acceptable safety profile and promising clinical activity in advanced osteosarcoma, which merits further evaluation in phase II studies. TRIAL REGISTRATION: ChiCTR1900021550.