Polyelectrolyte Microcapsules: An Extended Release System for the Antiarrhythmic Complex of Allapinin with Glycyrrhizic Acid Salt.

Allapinin has antiarrhythmic activity and can be used to prevent and treat various supraventricular and ventricular arrhythmias. Nevertheless, it is highly toxic and has a number of side effects associated with non-specific accumulation in various tissues. The complex of this substance with the monoammonium salt of glycyrrhizic acid (Al:MASGA) has less toxicity and improved antiarrhythmic activity. However, the encapsulation of Al:MASGA in polyelectrolyte microcapsules (PMC) for prolonged release will reduce the residual adverse effects of this drug. In this work, the possibility of encapsulating the allapinin-MASGA complex in polyelectrolyte microcapsules based on polyallylamine and polystyrene sulfonate was investigated. The encapsulation methods of the allapinin-MASGA in polyelectrolyte microcapsules by adsorption and coprecipitation were compared. It was found that the coprecipitation method did not result in the encapsulation of Al:MASGA. The sorption method facilitated the encapsulation of up to 80% of the original substance content in solution in PMC. The release of the encapsulated substance was further investigated, and it was shown that the release of the encapsulated Al:MASGA was independent of the substance content in the capsules, but at pH 5, a two-fold decrease in the rate of drug release was observed.

A randomised double-blind trial to determine the bleeding profile of the prolonged-release contraceptive dienogest 2 mg/ethinylestradiol 0.02 mg versus an immediate-release formulation of drospirenone 3 mg/ethinylestradiol 0.02 mg.

BACKGROUND: Dienogest (DNG) 2 mg/ethinylestradiol (EE) 0.02 mg is the first low-dose combined oral contraceptive (COC) with a prolonged-release formulation that allows stable plasma concentrations and has high contraceptive efficacy (Pearl index: 0.2). The aim of this trial was to determine the bleeding profile of this contraceptive compared to an immediate release formulation. METHODS: This prospective double-blind randomised controlled trial evaluated the bleeding patterns of DNG 2 mg/EE 0.02 mg compared with immediate-release drospirenone (DRSP) 3 mg/EE 0.02 mg in a 24/4-day regimen over nine cycles (randomisation ratio, 5:2). Participants recorded scheduled and unscheduled bleeding/spotting data using an electronic diary. A non-inferiority analysis for the proportion of participants with unscheduled bleeding/spotting was prespecified for Cycles 2-6. Safety, including adverse events, were monitored throughout the trial. RESULTS: Seven-hundred six and 288 participants received DNG/EE and DRSP/EE, respectively. Scheduled bleeding patterns per each 28-day cycle were similar in both groups. During Cycles 2-6, the proportion of participants with unscheduled bleeding/spotting was significantly lower in the DNG/EE group (50.5% [280/574] than in the DRSP/EE group (72.8% [171/235]]; treatment difference 22.3% [95% CI 15.9, 28.6%]; p < 0.0001). A low proportion of participants discontinued the trial due to bleeding disorders (1.7% and 0.7%, respectively). The safety profiles were similar for both treatments. CONCLUSIONS: The prolonged-release DNG 2 mg/EE 0.02 mg offers a significant decrease in unscheduled bleeding/spotting compared with an immediate-release COC, DRSP/EE, combined with high contraceptive efficacy and a very low adverse event profile.

The prolonged-release DNG 2 mg/EE 0.02 mg offers a significant decrease in unscheduled bleeding compared with an immediate-release COC while maintaining contraceptive efficacy and with no new safety signals.

Efficacy and safety of non-ergot dopamine-receptor agonists as an adjunct to levodopa in advanced Parkinson's disease: A network meta-analysis.

BACKGROUND AND PURPOSE: Non-ergot dopamine agonists (NEDAs) have been used as an adjunct therapy to levodopa in advanced Parkinson's disease (PD) for many years. However, there is no strong evidence that a given NEDA is more potent than another. To compare and rank the efficacy, tolerability, and safety of six commonly used NEDAs as an adjunct to levodopa in advanced PD, which includes long-acting and standard formulations, a network meta-analysis was performed. METHODS: The MEDLINE, Embase, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, and Wanfang databases were searched from January 1996 to June 2022 for eligible randomized controlled trials (RCTs). Six NEDAs, including rotigotine transdermal patch, ropinirole immediate-release (IR)/prolonged-release (PR), pramipexole IR/extended-release (ER), and piribedil, were investigated. RESULTS: A total of 34 RCTs (7868 patients) were included in the current study. The surface under the cumulative ranking curve indicated that ropinirole PR was associated with the best improvement in Unified Parkinson's Disease Rating Scale (UPDRS)-II, UPDRS-III, and UPDRS-II + III (0.811, 0.742, and 0.827). For OFF time reduction, pramipexole IR ranked first (0.979), and ropinirole PR ranked first in OFF time responder rate (0.927). Pramipexole ER ranked first in overall withdrawals, and rotigotine transdermal patch ranked first in the incidence of adverse events (≥1 AEs). CONCLUSIONS: This network meta-analysis suggests six commonly used NEDAs are effective as an adjunct to levodopa in advanced PD. In comprehensive consideration of better symptomatic management, ropinirole PR may be a better choice than other NEDAs in advanced PD. Six NEDAs showed different profiles of AEs.

Long-term prolonged-release tacrolimus outcomes in living donor kidney transplantation: The Japan Academic Consortium of Kidney Transplantation study-II.

OBJECTIVES: To evaluate the 10-year efficacy and safety of a prolonged-release tacrolimus-based combination immunosuppressive regimen on longer-term outcomes in living donor kidney transplantation. METHODS: Data from Japanese living donor kidney transplant recipients (n = 410) maintained on continuous prolonged-release tacrolimus-based immunosuppression from 2009-2013 were analyzed with a median follow-up of 9.9 years. RESULTS: A prolonged-release, tacrolimus-based combination regimen provided death-censored graft failure and all-cause death rates at 10 years of 7.0% and 6.8%, respectively. In multivariable analyses, acute and chronic rejection and 'throughout' (new-onset plus preexisting) diabetes mellitus were risk factors for death-censored graft failure. Recipient age ≥ 65 years, throughout diabetes mellitus and malignancy were common risk factors for all-cause death. Throughout diabetes mellitus was the most common risk factor for both death-censored graft failure and all-cause death. Additional analyses showed 10-year cumulative rates of death-censored graft failure were 14.0% and 5.4% for recipients with or without preexisting diabetes mellitus, respectively (log-rank test: p = 0.009). All-cause death rates were 12.7% and 5.4% in the preexisting and non-diabetes mellitus groups, respectively (log-rank test: p = 0.023). CONCLUSIONS: In this real-world, retrospective, living donor kidney transplantation study, a prolonged-release tacrolimus-based immunosuppressive combination regimen provided 10-year death-censored graft failure rates of 14.0% and 5.4% in diabetes mellitus and non-diabetes mellitus patients, respectively; Similarly, 10-year all-cause death rates were 12.7% and 5.4% in diabetes mellitus and non-diabetes mellitus patients, respectively. To our knowledge, the data in this study are the first to provide 10-year transplant outcomes in living donor kidney transplant recipients under prolonged-release tacrolimus-based regimen.

Intestinal Permeability in Patients Early after Kidney Transplantation Treated with Two Different Formulations of Once-Daily Tacrolimus.

Adequate tacrolimus blood exposure is crucial in the early post-renal transplant period and a gut epithelial barrier integrity may play a role. We prospectively investigated several markers of intestinal permeability in recent kidney transplant recipients (KTRs) treated with different tacrolimus extended-release formulations. Within each of the 49 KTR pairs that received grafts from the same donor, an early randomized conversion was performed from twice-daily (Prograf) to once-daily tacrolimus formulation: Advagraf or Envarsus. Plasma zonulin, calprotectin, circulating lipopolysaccharide (LPS), LPS-binding protein (LBP), intestinal fatty acid binding protein (FABP-2), and CD-14 levels were measured. There was no difference in the recipient age, dialysis vintage, BMI, and residual diuresis between Advagraf and Envarsus groups. FABP-2 and LPS levels were significantly associated with tacrolimus trough level, 3-h level, and area under the curve (AUC) in the Envarsus but not in the Advagraf group. AUC was independently increased by LPS and decreased by age, FABP-2 concentration, and the use of Envarsus formulation as compared with Advagraf. Functional changes of gastrointestinal tract in patients treated with Envarsus may influence intestinal tacrolimus absorption to a greater extent than in Advagraf-treated KTRs and may lead to inadequate variability of tacrolimus exposure early after kidney transplantation.

Oxygen Nanocarriers for Improving Cardioplegic Solution Performance: Physico-Chemical Characterization.

Nanocarriers for oxygen delivery have been the focus of extensive research to ameliorate the therapeutic effects of current anti-cancer treatments and in the organ transplant field. In the latter application, the use of oxygenated cardioplegic solution (CS) during cardiac arrest is certainly beneficial, and fully oxygenated crystalloid solutions may be excellent means of myocardial protection, albeit for a limited time. Therefore, to overcome this drawback, oxygenated nanosponges (NSs) that can store and slowly release oxygen over a controlled period have been chosen as nanocarriers to enhance the functionality of cardioplegic solutions. Different components can be used to prepare nanocarrier formulations for saturated oxygen delivery, and these include native α-cyclodextrin (αCD), αcyclodextrin-based nanosponges (αCD-NSs), native cyclic nigerosyl-nigerose (CNN), and cyclic nigerosyl-nigerose-based nanosponges (CNN-NSs). Oxygen release kinetics varied depending on the nanocarrier used, demonstrating higher oxygen release after 24 h for NSs than the native αCD and CNN. CNN-NSs presented the highest oxygen concentration (8.57 mg/L) in the National Institutes of Health (NIH) CS recorded at 37 °C for 12 h. The NSs retained more oxygen at 1.30 g/L than 0.13 g/L. These nanocarriers have considerable versatility and the ability to store oxygen and prolong the amount of time that the heart remains in hypothermic CS. The physicochemical characterization presents a promising oxygen-carrier formulation that can prolong the release of oxygen at low temperatures. This can make the nanocarriers suitable for the storage of hearts during the explant and transport procedure.

The Effect of Design and Size of the Fluid-Bed Equipment on the Particle Size-Dependent Trend of Particle Coating Thickness and Drug Prolonged-Release Profile.

The focus of the current work is to study and demonstrate the impact of the design, the scale, and settings of fluid-bed coating equipment on the differences in pellet coating thickness, which in case of prolonged-release pellets dictates the drug release. In the first set of coating experiments, the pellet cores were coated with the Tartrazine dye with the aim of estimating the coating equipment performance in terms of coating thickness distribution, assessed through color hue. In the second set, drug-layered pellets were film-coated with prolonged-release coating and dissolution profile tests were performed to estimate the thickness and uniformity of the coating thickness among differently sized pellets. In both study parts, film coating was performed at the laboratory and the pilot scale and essentially two types of distribution plate and different height adjustments of the draft tube were compared. The dye coating study proved to be extremely useful, as the results enable process correction and the optimal use of the process equipment in combination with the appropriate process parameters. Preferential film coating of larger drug-containing pellets was confirmed on the laboratory scale, while on the pilot scale, it was possible to achieve preferential coating of smaller pellets using rational alternatives of settings, which is desirable in terms of particle size-independent drug release profile of such prolonged-release dosage forms.

Caffeic Acid-Grafted PLGA as a Novel Material for the Design of Fluvastatin-Eluting Nanoparticles for the Prevention of Neointimal Hyperplasia.

Drug-eluting nanoparticles (NPs) administered by an eluting balloon represent a novel tool to prevent restenosis after angioplasty, even if the selection of the suitable drug and biodegradable material is still a matter of debate. Herein, we provide the proof of concept of the use of a novel material obtained by combining the grafting of caffeic acid or resveratrol on a poly(lactide-co-glycolide) backbone (g-CA-PLGA or g-RV-PLGA) and the pleiotropic effects of fluvastatin chosen because of its low lipophilic profile which is challenging for the encapsulation in NPs and delivery to the artery wall cells. NPs made of such materials are biocompatible with macrophages, human smooth muscle cells (SMCs), and endothelial cells (ECs). Their cellular uptake is demonstrated and quantified by confocal microscopy using fluorescent NPs, while their distribution in the cytoplasm is verified by TEM images using NPs stained with an Ag-PVP probe appositely synthetized. g-CA-PLGA assures the best control of the FLV release from NP sizing around 180 nm and the faster SMC uptake, as demonstrated by confocal analyses. Interestingly and surprisingly, g-CA-PLGA improves the FLV efficacy to inhibit the SMC migration, without altering its effects on EC proliferation and migration. The improved trophism of NPs toward SMCs, combined with the excellent biocompatibility and low modification of the microenvironment pH upon polymer degradation, makes g-CA-PLGA a suitable material for the design of drug-eluting balloons.

Perception of a New Prolonged-Release Buprenorphine Formulation in Patients with Opioid Use Disorder: The PREDEPO Study.

AIM: The aim of the study was to assess the acceptance of patients with opioid use disorder (OUD) to switching their opioid dependence treatment (ODT) for a prolonged-release buprenorphine (PRB) injection according to their prior ODT (buprenorphine/naloxone [B/N] or methadone). METHODS: This was an observational, retrospective/cross-sectional, multicentre study of adult patients diagnosed with OUD on ODT. Data collected from diaries were analysed to know their interest and opinion on PRB. Questions with fixed response options were included, and several Likert scales were used. RESULTS: A total of 98 patients were enrolled (B/N: 50.0%, methadone: 50.0%). The mean age was 46.9 ± 8.43 years and 79.6% were males. PRB was similarly perceived by both groups in most variables analysed, receiving a mean score of 7.2/10 (B/N: 7.4, methadone: 7.0; p = 0.520), and approximately 65% of patients said they were willing to switch to PRB (B/N: 63.3%, methadone: 65.3%; p = 0.833). Of these, a higher percentage in the B/N group considered that switching would be easy/very easy (B/N: 90.3%, methadone: 46.9%; p < 0.001) and that they would start PRB when available (B/N: 64.5%, methadone: 34.3%; p = 0.005). More than 90% would prefer the monthly injection (B/N: 93.6%, methadone: 100%; p = 0.514). One-third of patients in both groups were unsure/would not switch their ODT to PRB (B/N: 36.7%, methadone: 34.7%; p = 0.833). The main reason was administration by injection. CONCLUSION: Two-thirds of patients would switch their treatment for PRB, and most patients on B/N considered that switching would be easy. PRB could be a suitable alternative for OUD management.

In Vivo Metabolic Responses to Different Formulations of Amino Acid Mixtures for the Treatment of Phenylketonuria (PKU).

Phenylketonuria (PKU) is a rare autosomal recessive inborn error of metabolism where the mainstay of treatment is a Phe restricted diet consisting of a combination of limited amounts of natural protein with supplementation of Phe-free or low-Phe protein substitutes and special low protein foods. Suboptimal outcomes may be related to the different absorption kinetics of free AAs, which have lower biological efficacy than natural proteins. Physiomimic TechnologyTM is a technology engineered to prolong AA (AA-PT) release allowing physiological absorption and masking the odor and taste of free AAs. The aim of these studies was to assess the impact of AA-PT formulation on selected functional and metabolic parameters both in acute and long-term experimental studies. Adult rats in fasting conditions were randomized in different groups and treated by oral gavage. Acute AA-PT administration resulted in significantly lower BUN at 90 min versus baseline. Both BUN and glycemia were modulated in the same direction as intact casein protein. Long-term treatment with AA-PT significantly reduces the protein expression of the muscle degradation marker Bnip3L (-46%) while significantly increasing the proliferation of market myostatin (+58%). Animals dosed for 15 days with AA-PT had significantly stronger grip strength (+30%) versus baseline. In conclusion, the results suggest that the AA-PT formulation may have beneficial effects on both AA oxidation and catabolism with a direct impact on muscle as well as on other metabolic pathways.

Formulation and Evaluation of Eudragit® RL Polymeric Double Layer Films for Prolonged-Release Transdermal Delivery of Tamsulosin Hydrochloride.

Transdermal drug delivery systems (TDDSs) were developed for prolonged tamsulosin (TMS) delivery. Double layer (DL) TDDSs were prepared using Eudragit® RL by conventional film-forming. Ethylene-vinyl acetate was used as the backing layer, triethylcitrate as plasticizer, and Capmul® PG-8-70 NF and Captex 170 EP as penetration enhancers (PEs). An increase in either drug or PE concentration caused a significant increase in drug permeation flux. Modulation of drug permeation across Strat-M® membrane was examined using a single layer (SL) having the same thickness and drug content as the DLs, while the DLs were formulated to have variable drug spatial distribution across each layer (DL 4:6 and DL 6:4). SL/TDDS showed significantly higher daily drug permeation than DL/TDDSs for the first 4 days which could be related to the presence of high TMS concentration located on the upper surface of SL/TDDS as a result of solute migration of TMS during the drying process. However, this increase was followed by a progressive linear decrease after 5 days. Deflection points that were characterized by lower drug flux had been shown by SL/TDDS at more than one-point times. In contrast, DL 4:6 and DL 6:4 TDDSs demonstrated an ability to sustain TMS delivery for up to 2 weeks.

Prolonged-release pirfenidone prevents obesity-induced cardiac steatosis and fibrosis in a mouse NASH model.

PURPOSE: Obesity is associated with systemic insulin resistance and cardiac hypertrophy with fibrosis. Peroxisome proliferator-activated receptors (PPARs) regulate carbohydrate and lipid metabolism, improving insulin sensitivity, triglyceride levels, inflammation, and oxidative stress. We previously demonstrated that prolonged-release pirfenidone (PR-PFD) is an agonistic ligand for Pparα with anti-inflammatory and anti-fibrotic effects, and might be a promising drug for cardiac diseases-treatment. Here, we investigated the effects of PR-PFD in ventricular tissue of mice with nonalcoholic steatohepatitis (NASH) and obesity induced by high-fat/high-carbohydrate (HFHC) diet. METHODS: Five male C57BL/6 J mice were fed with normal diet (ND) and ten with HFHC diet for 16 weeks; at 8 weeks of feeding, five mice with HFHC diet were administered PR-PFD (350 mg/kg/day) mixed with HFHC diet. RESULT: Systemic insulin resistance, heart weight/body weight ratio, myocardial steatosis with inflammatory foci, hypertrophy, and fibrosis were prevented by PR-PFD. In addition, HFHC mice showed significantly increased desmin, Tgfß1, Timp1, collagen I (Col I), collagen III (Col III), TNF-α, and Nrf2 mRNA levels, including α-SMA, NF-kB, Nrf2, troponin I, Acox1, Cpt1A, and Lxrα protein levels compared with the ND ventricular tissues. Mechanistically, HFHC mice with PR-PFD treatment significantly decreased these genes overexpressed by HFHC diet. Furthermore, PR-PFD overexpressed the Pgc1a mRNA levels and Pparα, Pparγ, Acox1, and Cpt1A protein levels. CONCLUSIONS: The results suggest that PR-PFD could be a promising drug for the prevention and treatment of cardiac steatosis and fibrosis induced by obesity.

Nicardipine Prolonged Release Implants for Prevention of Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Hemorrhage: A Meta-Analysis.

OBJECTIVES: A paucity of treatments to prevent delayed cerebral ischemia (DCI) has stymied recovery after aneurysmal subarachnoid hemorrhage (aSAH). Nicardipine has long been recognized as a potent cerebrovascular vasodilator with a history off-label use to prevent vasospasm and DCI. Multiple centers have developed nicardipine prolonged release implants (NPRI) that are directly applied during clip ligation to locally deliver nicardipine throughout the vasospasm window. Here we perform a systematic review and meta-analysis to assess whether NPRI confers protection against DCI and improves functional outcomes after aSAH. MATERIALS AND METHODS: A systematic search of PubMed, Ovid Embase, and Cochrane databases was performed for studies reporting the use of NPRI after aSAH published after January 1, 1980. We included all studies assessing the association of NPRI with DCI and or functional outcomes. Findings from studies with control arms were analyzed using a random effects model. A separate network meta-analysis was performed, including controlled NPRI studies, single-arm NPRI reports, and the control-arms of modern aSAH randomized clinical trials as additional comparators. RESULTS: The search identified 214 unique citations. Three studies with 284 patients met criteria for the random effects model. The pooled summary odds ratio for the association of NPRI and DCI was 0.21 (95% CI 0.09-0.49, p = 0.0002) with no difference in functional outcomes (OR 1.80, 95% CI 0.63 - 5.16, p = 0.28). 10 studies of 866 patients met criteria for the network meta-analysis. The pooled summary odds ratio for the association of NPRI and DCI was 0.30 (95% CI 0.13-0.89,p = 0.017) with a trend towards improved functional outcomes (OR 1.68, 0.63 - 4.13 95% CI, p = 0.101). CONCLUSIONS: In these meta-analyses, NPRI decreases the incidence of DCI with a non-significant trend towards improvement in functional outcomes. Randomized trials on the role of intrathecal calcium channel blockers are warranted to evaluate these observations in a prospective manner.

Porous Core/Dense Shell PLA Microspheres Embedded with High Drug Loading of Bupivacaine Crystals for Injectable Prolonged Release.

Objective of the study was to design an injectable microsphere preparation with high drug loading of bupivacaine for prolonged release and local anesthetic. PLA or PLGA was used as the biodegradable matrix material to fabricate microspheres with the o/w emulsification-solvent evaporation method. The characterization of bupivacaine microspheres was observed by SEM, DSC, and XRPD. The microsphere preparation and extended drug release, as well as the plasma drug concentration and sciatic nerve blockade after injection of the microsphere formulation to rats were investigated. High drug-loading microspheres of more than 70% were successfully obtained with extended drug release over 5 days in vitro depending on the type of matrix and the feed ratio of drug to polymer. SEM, DSC, and XRPD results verified a novel microsphere structure characterized as the porous core composed of PLA material and form II bupivacaine crystals and dense shell formed of PLA layer. The mechanism that bupivacaine was dissolved inside the microsphere and diffused across the dense shell was suggested for drug release in vitro. The optimized PLA microsphere formulation showed low and steady plasma drug concentration over 5 days and prolonged duration of sensory and motor blockade of sciatic nerve lasted more than 3 days. Results indicated that the porous core-shell structure of PLA microsphere formulation would provide enormous potential as an injectable depot for locally prolonged delivery of bupivacaine and control of postoperative pain.

Effectiveness and safety of the conversion to MeltDose® extended-release tacrolimus from other formulations of tacrolimus in stable kidney transplant patients: A retrospective study.

Tacrolimus is the cornerstone of immunosuppressive therapy after kidney transplantation. Its narrow therapeutic window mandates serum level strict monitoring and dose adjustments to ensure the optimal risk-benefit balance. This observational retrospective study analyzed the effectiveness and safety of conversion from twice-daily immediate-release tacrolimus (IR-Tac) or once-daily prolonged-release tacrolimus (PR-Tac) to the recent formulation once-daily MeltDose® extended-release tacrolimus (LCP-Tac) in 365 stable kidney transplant recipients. We compared kidney function three months before and three months after the conversion. Three months after conversion, the total daily dose was reduced ~35% (P < .0001), and improved bioavailability and stable serum LCP-Tac concentrations were observed. There was no increase in the number of patients requiring tacrolimus dose adjustments after conversion. Renal function was unaltered, and no cases of BPAR were reported. Reports of tremors, as collected in the clinical histories for each patient, decreased from pre-conversion (20.8%) to post-conversion (11.8%, P < .0001). LCP-Tac generated a cost reduction of 63% compared with PR-Tac. In conclusion, the conversion strategy to LCP-Tac from other tacrolimus formulations in stable kidney transplant patients showed safety and effectiveness in a real-world setting, confirming the data from RCTs. The specific pharmacokinetic properties of LCP-Tac could be potentially advantageous in patients with tacrolimus-related adverse events.

Long-term, prolonged-release tacrolimus-based immunosuppression in de novo kidney transplant recipients: 5-year prospective follow-up of the ADHERE study patients.

The objectives of this study were to assess long-term graft survival, patient survival, renal function, and acute rejections in de novo kidney transplant recipients, treated with once-daily prolonged-release tacrolimus-based therapy. The study was a 5-year non-interventional prospective follow-up of patients from the ADHERE study, a Phase IV 12-month open-label assessment of patients randomized to receive prolonged-release tacrolimus in combination with mycophenolate mofetil (MMF) (Arm 1) or sirolimus (Arm 2). From 838 patients in the randomized study, 587 were included in the long-term follow-up, of whom 510 completed the study at year 5. At 1 year post-transplant, graft and patient survival rates were 93.0% and 97.8%, respectively, and at 5 years were 84.0% and 90.8%, respectively. Cox proportional hazards analysis showed no association between graft loss, initial randomized treatment arm, donor age, donor type, or sex. The 5-year acute rejection-free survival rate was 77.4%, and biopsy-confirmed acute rejection-free survival rate was 86.0%. Renal function remained stable over the follow-up period: mean ± SD eGFR 4-variable modification diet in renal disease formula (MDRD4) was 52.3 ± 21.6 ml/min/1.73 m2 at 6 months and 52.5 ± 23.0 ml/min/1.73 m2 at 5 years post-transplant. These findings support the role of long-term once-daily prolonged-release tacrolimus-based immunosuppression, in combination with sirolimus or MMF, for renal transplant recipients in routine clinical practice.

Comparison of long-term use of prolonged-release ropinirole and immediate-release dopamine agonists in an observational study in patients with Parkinson's disease.

PURPOSE: To estimate the risk of dyskinesia and impulse control disorders (ICDs) in patients with Parkinson's disease (PD) prescribed ropinirole prolonged-release (R-PR) compared to those prescribed immediate-release dopamine agonists (IR-DA) as monotherapy. METHODS: PD patients initiating R-PR or IR-DA as monotherapy between 2008 and 2013 were identified on the Clinical Practice Research Datalink. The cohorts were propensity score matched on a 1:1 basis. The incidence of dyskinesia and ICD in each treatment cohort and the incidence rate ratios were calculated. Adherence to medication and time to levodopa initiation were also evaluated. RESULTS: We identified 341 patients in each treatment cohort after propensity score matching. The baseline characteristics were generally comparable. Dyskinesia incidence in R-PR and IR-DA cohorts was 2.98 (95% CI: 0.74-11.9) and 3.93 (95% CI: 0.98-15.7) per 1000 person-years, respectively (incidence rate ratio of R-PR vs ID-DA: 0.76, 95% CI: 0.11-5.38). Less than five cases of ICD were identified and all occurred in the IR-DA cohort. The patients in the R-PR cohort remained on treatment for a significantly longer duration than those in the IR-DA cohort (682 days vs 444 days; P < .0001) and had greater adherence to the medication. The median time to levodopa initiation was 417 days (IQR: 205-736) in R-PR vs 297 days (IQR: 111-552) in IR-DA cohort. CONCLUSIONS: The number of dyskinesia and ICD events was lower than expected, resulting in an underpowered study. A significantly longer persistence and greater adherence to medication was observed in patients receiving R-PR compared to IR-DA.

Improving the in-vivo biological activity of fingolimod loaded PHBV nanoparticles by using hydrophobically modified alginate.

Uncontrolled distribution of nanoparticles (NPs) within the body can significantly decrease the efficiency of drug therapy and is considered among the main restrictions of NPs application. The aim of this study was to develop a depot combination delivery system (CDS) containing fingolimod loaded poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) NPs dispersed into a matrix of oleic acid-grafted-aminated alginate (OA-g-AAlg) to minimize the nonspecific biodistribution (BD) of PHBV NPs. OA-g-AAlg was synthesized in two step; First, Alg was aminated by using adipic dihydrazide (ADH). The degree of hyrazide group substitution of Alg was determined by trinitro-benzene-sulfonic acid (TNBS) assay. Second, OA was attached to AAlg through formation of an amide bond. Chemical structure of OA-g-AAlg was confirmed with FTIR and HNMR spectroscopy. Furthermore, rheological properties of OA-g-AAlg with different grafting ratios were evaluated. In-vitro release studies indicated that 47% of fingolimod was released from the CDS within 28 days. Blood and tissue samples were analyzed using liquid chromatography/tandem mass spectrometry following subcutaneous (SC) injection of fingolimod-CDS into Wistar rats. The elimination phase half-life of CDS-fingolimod was significantly higher than that of fingolimod (∼32 d vs. ∼20 h). To investigate the therapeutic efficacy, lymphocyte count was assessed over a 40 day period in Wistar rats. Peripheral blood lymphocyte count decreased from baseline by 27 ± 8% in 2 days after injection. Overall, the designed CDS represented promising results in improving the pharmacokinetic properties of fingolimod. Therefore, we believe that this sustained release formulation has a great potential to be applied to delivery of various therapeutics.

Mesoporous Silica as a Drug Delivery System for Naproxen: Influence of Surface Functionalization.

In this work we describe the relationship between surface modification of hexagonally ordered mesoporous silica SBA-15 and loading/release characteristics of nonsteroidal anti-inflammatory drug (NSAID) naproxen. Mesoporous silica (MPS) was modified with 3-aminopropyl, phenyl and cyclohexyl groups by grafting method. Naproxen was adsorbed into pores of the prepared MPS from ethanol solution using a solvent evaporation method. The release of the drug was performed in buffer medium at pH 2 and physiological solution at pH 7.4. Parent MPSs as well as naproxen loaded MPSs were characterized using physicochemical techniques such as nitrogen adsorption/desorption, thermogravimetric analysis (TG), Zeta potential analysis, Fourier transform infrared spectroscopy (FT-IR), and elemental analysis. The amount of naproxen released from the MPSs into the medium was determined by high-performance liquid chromatography (HPLC). It was shown that the adsorption and desorption characteristics of naproxen are dependent on the pH of the solution and the surface functionalization of the host.

Prolonged-release opioid agonist therapy: qualitative study exploring patients' views of 1-week, 1-month, and 6-month buprenorphine formulations.

BACKGROUND: Options for opioid agonist therapy (OAT) are expanding with the development of prolonged-release (also known as extended-release) 1-week, 1-month, and 6-month formulations of buprenorphine. There is an assumption that patients will welcome these new treatments and medication adherence will correspondingly increase. However, there has been little research exploring patients' views of prolonged-release buprenorphine. This paper aims to understand which durations patients prefer and why, and to consider the findings with reference to the development of future OAT products. METHODS: Data were generated as part of a qualitative interview study. Fieldwork was conducted in London, UK, during 2018 (before any prolonged-release OAT formulations were licensed in Europe). Participants (n = 36) were taking daily oral OAT (methadone or buprenorphine) or using heroin daily without OAT. They included 26 men and 10 women, aged 24-63 years. All were asked for their views on weekly, monthly, and six-monthly duration buprenorphine. Responses were audio-recorded, transcribed, and analyzed by Iterative Categorization. RESULTS: Participants generally stated that having buprenorphine of different prolonged durations was positive. They tended to believe that 'longer' prolonged-release formulations would be beneficial for patients who wanted to avoid thinking about drugs and drug-using associates, wished to evade the stigma of substance use, and desired 'normality' and 'recovery.' In contrast, participants favored 'shorter' prolonged-release formulations for patients who are new to OAT, worried about the safety and reliability/effectiveness of OAT, want a 'break' from street opioids, and need contact with services to monitor/support them. Participants indicated that transitioning between OAT medications of different duration would be a very individual process. Some also linked prolonged-release OAT duration to political, philosophical, and ethical issues, such as patient coercion and mental capability. CONCLUSIONS: Medication duration is an important but complex feature of prolonged-release buprenorphine, with patients' views and preferences likely to be influenced by a wide range of factors. We need further qualitative research to explore the experiences of people who have actually used prolonged-release OAT. Meanwhile, drug developers should continue to build flexibility and choice into OAT products to ensure that future treatment is acceptable to patients and able to accommodate their diverse individual needs.