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Biomaterials Jan 2021Hydrogels based on photocrosslinkable Hyaluronic Acid Methacrylate (HAMA) and Chondroitin Sulfate Methacrylate (CSMA) are presently under investigation for tissue... (Review)
Review
Hydrogels based on photocrosslinkable Hyaluronic Acid Methacrylate (HAMA) and Chondroitin Sulfate Methacrylate (CSMA) are presently under investigation for tissue engineering applications. HAMA and CSMA gels offer tunable characteristics such as tailorable mechanical properties, swelling characteristics, and enzymatic degradability. This review gives an overview of the scientific literature published regarding the pre-clinical development of covalently crosslinked hydrogels that (partially) are based on HAMA and/or CSMA. Throughout the review, recommendations for the next steps in clinical translation of hydrogels based on HAMA or CSMA are made and potential pitfalls are defined. Specifically, a myriad of different synthetic routes to obtain polymerizable hyaluronic acid and chondroitin sulfate derivatives are described. The effects of important parameters such as degree of (meth)acrylation and molecular weight of the synthesized polymers on the formed hydrogels are discussed and useful analytical techniques for their characterization are summarized. Furthermore, the characteristics of the formed hydrogels including their enzymatic degradability are discussed. Finally, a summary of several recent applications of these hydrogels in applied fields such as cartilage and cardiac regeneration and advanced tissue modelling is presented.
Topics: Cartilage; Chondroitin Sulfates; Hyaluronic Acid; Hydrogels; Tissue Engineering
PubMed: 33360302
DOI: 10.1016/j.biomaterials.2020.120602 -
Clinical Drug Investigation Jan 2021Long-acting injectable antipsychotics (LAIs) are associated with better treatment adherence and persistence than oral antipsychotics (OAPs) in patients with... (Comparative Study)
Comparative Study
BACKGROUND AND OBJECTIVE
Long-acting injectable antipsychotics (LAIs) are associated with better treatment adherence and persistence than oral antipsychotics (OAPs) in patients with schizophrenia. However, real-world evidence assessing the impact of treatment with LAIs in Germany is limited. To fill this gap, we compared antipsychotic medication adherence and risk of treatment discontinuation (TD) among schizophrenia patients newly initiated on LAI or who switched their OAP regimen (overall cohort; OC).
METHODS
Claims data of German schizophrenia patients who initiated LAIs or switched their OAP during 2012-2016 (index date) were retrospectively analyzed. Treatment switch was defined as add-on medication to existing prescription or terminating the existing prescription and initiating another OAP. Adherence and time to treatment discontinuation (TTD) were estimated. Determinants of treatment discontinuation were analyzed using two Cox regression models. Model 1 controlled for age, sex, and Charlson Comorbidity Index (CCI); model 2 also included insurance status, and medication, visit, and psychiatric inpatient stay costs. Sensitivity analysis on patients who terminated existing prescriptions and initiated new OAPs (complete switch cohort; CSC) was performed.
RESULTS
In OC (n = 2650), LAI users had better adherence (35.4% vs. 11.6%), persistence (no 60-day gap; 40.7% vs. 19.8%), and longer TTD (median [95% confidence interval (CI)] 216 [193-249] vs. 50 [46-56] days) than OAP users. OAP usage (hazard ratio [HR] 1.89, 95% CI 1.73-2.06; p < 0.001) and greater CCI (HR 1.04, 95% CI 1.00-1.07; p = 0.023) were associated with greater risk of TD in model 1. Model 2 showed similar results. LAI users in CSC also had better adherence, persistence, and longer TTD. In CSC too, OAP usage and greater CCI were associated with greater risk of TD in model 1, but only CCI was significant in model 2. Higher pre-index psychiatric inpatient costs were associated with lower risk of TD (HR 0.99, 95% CI 0.98-1.00; p = 0.014).
LIMITATIONS
Inherent limitations of claims data and lack of control on OAP administration may have influenced the results.
CONCLUSION
This real-world study associates LAIs with better medication adherence and lower antipsychotic discontinuation risk than OAPs.
Topics: Administration, Oral; Adolescent; Adult; Aged; Antipsychotic Agents; Cohort Studies; Delayed-Action Preparations; Female; Germany; Humans; Injections; Male; Medication Adherence; Middle Aged; Proportional Hazards Models; Retrospective Studies; Schizophrenia; Time Factors; Young Adult
PubMed: 33331979
DOI: 10.1007/s40261-020-00990-8 -
Drug Delivery and Translational Research Feb 2023There has been a constant evolution in the pharmaceutical market concerning the new technologies imbibed in delivering drug substances for various indications. This is... (Review)
Review
There has been a constant evolution in the pharmaceutical market concerning the new technologies imbibed in delivering drug substances for various indications. This is either market-driven or technology-driven to improve the overall therapeutic efficacy and patients' quality of life. The pharmaceutical industry has experienced rapid growth in the area of complex injectable products because of their effectiveness in the unmet market. These novel parenteral products, viz, the nanoparticles, liposomes, microspheres, suspensions, and emulsions, have proven their worth as "Safe and Effective" products. However, the underlying challenges involved in the development, scalability, and characterization of these injectable products are critical. Moreover, the guidelines available do not provide a clear understanding of these complex products, making it difficult to anticipate the regulatory requirements. Thus, it becomes imperative to comprehend the criticalities and develop an understanding of these products. This review discusses various complexities involved in the parenteral products such as complex drug substances, excipients, dosage forms, drug administration devices like pre-filled syringes and injector pens, and its different characterization tools and techniques. The review also provides a brief discussion on the regulatory aspects and associated hurdles with other parenteral products.
Topics: Humans; Quality of Life; Liposomes; Suspensions; Excipients; Nanoparticles
PubMed: 35963928
DOI: 10.1007/s13346-022-01223-5 -
The International Journal on Drug Policy Oct 2021In high-income countries, people who inject drugs (PWID) are a priority population for eliminating hepatitis C virus (HCV) by 2030. Despite evidence informing...
BACKGROUND
In high-income countries, people who inject drugs (PWID) are a priority population for eliminating hepatitis C virus (HCV) by 2030. Despite evidence informing micro-elimination strategies, little is known regarding efforts needed to maintain elimination targets in populations with ongoing acquisition risks. This model-based study investigates post-elimination transmission dynamics of HCV and HIV among PWID under different scenarios where harm reduction interventions and HCV testing and treatment are scaled-down.
METHODS
We calibrated a dynamic compartmental model of concurrent HCV and HIV transmission among PWID in Montréal (Canada) to epidemiological data (2003-2018). We then simulated achieving the World Health Organization elimination targets by 2030. Finally, we assessed the impact of four post-elimination scenarios (2030-2050): 1) scaling-down testing, treatment, opioid agonist therapy (OAT), and needle and syringe programs (NSP) to pre-2020 levels; 2) only scaling-down testing and treatment; 3) suspending testing and treatment, while scaling down OAT and NSP to pre-2020 levels; 4) suspending testing and treatment and maintaining OAT and NSP coverage required for elimination.
RESULTS
Scaling down interventions to pre-2020 levels (scenario 1) leads to a modest rebound in chronic HCV incidence from 2.4 to 3.6 per 100 person-years by 2050 (95% credible interval - CrI: 0.8-7.2). When only scaling down testing and treatment (scenario 2), chronic HCV incidence continues to decrease. In scenario 3 (suspending treatment and scaling down OAT and NSP), HCV incidence and mortality rapidly increase to 11.4 per 100 person-years (95%CrI: 7.4-15.5) and 3.2 per 1000 person-years (95%CrI: 2.4-4.0), respectively. HCV resurgence was mitigated in scenario 4 (maintaining OAT and NSP) as compared to scenario 3. All scenarios lead to decreases in the proportion of reinfections among incident cases and have little impact on HIV incidence and HIV-HCV coinfection prevalence.
CONCLUSION
Despite ongoing transmission risks, HCV incidence rebounds slowly after 2030 under pre-2020 testing and treatment levels. This is heightened by maintaining high-coverage harm reduction interventions. Overall, sustaining elimination would require considerably less effort than achieving it.
Topics: Antiviral Agents; Harm Reduction; Hepacivirus; Hepatitis C; Humans; Pharmaceutical Preparations; Substance Abuse, Intravenous
PubMed: 34215459
DOI: 10.1016/j.drugpo.2021.103343 -
Social Science & Medicine (1982) Jan 2022As part of their populist performances during disease outbreaks, public officials and politicians tend to offer 'miracle cures' or 'wonder drugs' that can supposedly...
As part of their populist performances during disease outbreaks, public officials and politicians tend to offer 'miracle cures' or 'wonder drugs' that can supposedly treat or prevent the disease in question. This article analyzes contemporary instances of what we call 'pharmaceutical messianism' and proposes four characteristics for this phenomenon, namely, that it: (1) emerges during times of extraordinary health crisis; (2) builds on pre-existing knowledge, practices, and sentiments; (3) borrows from medical, often heterodox, authority; and (4) involves accessible, affordable, and/or familiar substances. Demonstrating the analytic value of our framework, we present three case studies, constructed using academic and journalistic sources, during the COVID-19 pandemic: hydroxychloroquine in France, ivermectin in the Philippines, and Covid-Organics in Madagascar. We conclude by identifying some implications of our findings on public health and avenues for future research.
Topics: COVID-19; Humans; Hydroxychloroquine; Pandemics; Pharmaceutical Preparations; SARS-CoV-2
PubMed: 34794852
DOI: 10.1016/j.socscimed.2021.114567 -
Current HIV/AIDS Reports Aug 2021Recent HIV outbreaks among people who use drugs (PWUD) necessitate additional HIV prevention tools. Pre-exposure prophylaxis (PrEP) is highly efficacious yet uptake... (Review)
Review
PURPOSE OF REVIEW
Recent HIV outbreaks among people who use drugs (PWUD) necessitate additional HIV prevention tools. Pre-exposure prophylaxis (PrEP) is highly efficacious yet uptake among PWUD remains exceedingly low. To address multilevel, complex barriers to PrEP use among PWUD, a range of intervention strategies are needed.
RECENT FINDINGS
The literature on interventions to optimize PrEP use among PWUD is nascent, comprising small pilots and demonstration projects in early phases of intervention development. Initial studies suggest that structural, healthcare, interpersonal, and individual-level interventions can improve PrEP use for PWUD, and a number of efficacy trials are underway. Future studies are needed to optimize the use of new PrEP modalities (e.g., injectable PrEP), simultaneously target multilevel challenges to PrEP use, and evaluate the integration of PrEP into other service settings and substance use treatment modalities.
Topics: Anti-HIV Agents; HIV Infections; Humans; Pharmaceutical Preparations; Pre-Exposure Prophylaxis; Safe Sex
PubMed: 33907971
DOI: 10.1007/s11904-021-00556-z -
Acta Biomaterialia Apr 2021Biotherapeutics have achieved global economic success due to their high specificity towards their drug targets, providing exceptional safety and efficiency. The ongoing...
Biotherapeutics have achieved global economic success due to their high specificity towards their drug targets, providing exceptional safety and efficiency. The ongoing shift away from small molecule drugs towards biotherapeutics heightens the need to further improve the pharmacokinetics of these biological drugs. Three pervasive obstacles that limit the therapeutic capacity of biotherapeutics are proteolytic degradation, circulating half-life, and the development of anti-drug antibodies. These challenges can culminate in limited efficiency and consequently warrant the need for higher drug doses and more frequent administration. We have explored the coupling of biotherapeutics to long-lived and biocompatible red blood cells (RBCs) to address limited pharmacokinetics. Butyrylcholinesterase (BChE), for example, provides prophylactic protection against organophosphate nerve agents (OPNAs), yet the short circulation life of the drug requires extraordinary doses. Herein, we report the rapid and tunable chemical engineering of BChE to RBC membranes to create a cell-based delivery system that retains the enzyme activity and enhances stability. In a three-step process that first pre-modifies BChE with a cell-reactive polymer chain, primes the cells for engineering, and then grafts the conjugates to the cells, we attached over 2 million BChE molecules to the surface of each RBC without diminishing the bioscavenging capacity of the enzyme. Critically, this membrane-engineering approach was cell-tolerated with minimal hemolysis observed. These results provide strong evidence for the ability of engineered RBCs to serve as an enhanced biotherapeutic delivery vehicle. STATEMENT OF SIGNIFICANCE: Organophosphate nerve agents (OPNAs) are one of the most lethal forms of chemical warfare. After exposure to OPNAs, a patient is given life-saving therapeutics, such as atropine and oxime. However, these drugs are limited, and the patient can still suffer from irreparable injuries. Given the toxicity of OPNAs, access to a prophylactic is vital. We have created an enhanced delivery system for prophylactic butyrylcholinesterase (BChE) by engineering this biotherapeutic to the red blood cell (RBC) surface. In three simple steps that first pre-modifies BChE with a cell-reactive polymer, primes the cells for engineering, and then grafts the conjugates to the cells, we attached over 2 million BChE molecules to a single RBC while retaining the enzyme's activity and enhancing its stability.
Topics: Butyrylcholinesterase; Erythrocytes; Humans; Organophosphates; Oximes; Pharmaceutical Preparations
PubMed: 33529769
DOI: 10.1016/j.actbio.2021.01.043 -
International Journal of Nanomedicine 2021Pancreatic cancer is one of the most malignant tumors with one of the worst survival rates due to its insidious onset and resistance to therapies. Most therapeutics show... (Review)
Review
Pancreatic cancer is one of the most malignant tumors with one of the worst survival rates due to its insidious onset and resistance to therapies. Most therapeutics show a desired anticancer effect in vitro; however, very poor efficacy in vivo because of the limited drug delivery and penetration into pancreatic tumors attributed to the abundance of the tumor stroma, ie, the fibrotic tumor microenvironment surrounding the cancer cells. For a better understanding of the challenges posed by the pancreatic tumor stroma, we outline the key features of the tumor microenvironment. Then we highlight major strategies used to tackle the challenges to improve drug penetration into the tumor and achieve enhanced efficacy (pre)clinically. Furthermore, we describe nanomedicine strategies to modulate the tumor stroma, degrade the extracellular matrix, and co-deliver multi-functional drugs, to improve the chemotherapeutics delivery and penetration into pancreatic tumors.
Topics: Carcinoma, Pancreatic Ductal; Drug Delivery Systems; Humans; Nanomedicine; Pancreatic Neoplasms; Pharmaceutical Preparations; Tumor Microenvironment
PubMed: 34552327
DOI: 10.2147/IJN.S279192 -
Drug Design, Development and Therapy 2023To study and compare the pharmacokinetic characteristics of enteric-coated sustained-release (EcSr) aspirin tablets with enteric-coated (Ec) aspirin tablets (Bayer... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
PURPOSE
To study and compare the pharmacokinetic characteristics of enteric-coated sustained-release (EcSr) aspirin tablets with enteric-coated (Ec) aspirin tablets (Bayer S.p.A) in healthy Chinese participants.
PATIENTS AND METHODS
In this open, randomized, single-dose, three-way, crossover study, 18 healthy participants randomly received 100 mg EcSr tablets pre-prandially (a.c.), EcSr tablets post-prandially (p.c.), or Ec tablets a.c. in each period. The concentrations of acetylsalicylic acid (ASA) and salicylic acid (SA) in plasma were determined by the LC-MS/MS method, and the pharmacokinetic parameters were calculated using WinNonlin (version 8.1).
RESULTS
The essential PK parameters under the three treatment conditions (ie Ec a.c., EcSr a.c. and EcSr p.c.) were as follows: C: 758.38±455.34, 222.77±98.04 and 194.54±61.19 ng, T: 6.75(2,16), 4.5(2,11) and 8.25(5,11) h, T: 0.43±0.08, 1.44±0.59 and 4.32±10.04 h, AUC: 1008.88±452.27, 918.04±238.40 and 845.55±183.25 h·ng/mL; C: 6409.38±2098.52, 2863.53±679.73 and 2913.75±853.27ng/mL, T: 7.25(2,24), 10(3.5-14) and 10(7,14) h, T1/2, SA: 2.21±0.46, 2.69±0.72 and 3.51±2.06h, AUC: 29,131.41±9376.23, 27,243.97±7465.16, 27,240.25±7444.67 h·ng/mL. When taking EcSr aspirin tablets, the 90% confidence intervals of the geometric mean ratios (pre-prandial/post-prandial) of AUC and AUC, C, AUC and AUC were within the range of 80.00%-125.00%.
CONCLUSION
EcSr aspirin tablets showed less inter-individual variation in release and absorption than Ec aspirin tablets, which was well reflected by comparing essential PK parameters. Furthermore, meals had no significant effect on the pharmacokinetics of EcSr aspirin tablets.
Topics: Humans; Aspirin; Chromatography, Liquid; Cross-Over Studies; Delayed-Action Preparations; East Asian People; Healthy Volunteers; Salicylic Acid; Tandem Mass Spectrometry; Tablets, Enteric-Coated
PubMed: 37614377
DOI: 10.2147/DDDT.S409524 -
AAPS PharmSciTech Mar 2021Intravitreal (IVT) administration of therapeutics is the standard of care for treatment of back-of-eye disorders. Although a common procedure performed by retinal... (Review)
Review
Intravitreal (IVT) administration of therapeutics is the standard of care for treatment of back-of-eye disorders. Although a common procedure performed by retinal specialists, IVT administration is associated with unique challenges related to drug product, device and the procedure, which may result in adverse events. Container closure configuration plays a crucial role in maintaining product stability, safety, and efficacy for the intended shelf-life. Careful design of primary container configuration is also important to accurately deliver small volumes (10-100 μL). Over- or under-dosing may lead to undesired adverse events or lack of efficacy resulting in unpredictable and variable clinical responses. IVT drug products have been traditionally presented in glass vials. However, pre-filled syringes offer a more convenient administration option by reducing the number of steps required for dose preparation there by potentially reducing the time demand on the healthcare providers. In addition to primary container selection, product development studies should focus on, among other things, primary container component characterization, material compatibility with the formulation, formulation stability, fill volume determination, extractables/leachables, and terminal sterilization. Ancillary components such as disposable syringes and needles must be carefully selected, and a detailed administration procedure that includes dosing instructions is required to ensure successful administration of the product. Despite significant efforts in improving the drug product and administration procedures, ocular safety concerns such as endophthalmitis, increased intraocular pressure, and presence of silicone floaters have been reported. A systematic review of available literature on container closure and devices for IVT administration can help guide successful product development.
Topics: Drug Delivery Systems; Drug Packaging; Humans; Intravitreal Injections; Needles; Pharmaceutical Preparations; Sterilization; Syringes
PubMed: 33709236
DOI: 10.1208/s12249-021-01949-4