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Molecular Therapy : the Journal of the... Sep 2021Non-human primates (NHPs) are a preferred animal model for optimizing adeno-associated virus (AAV)-mediated CNS gene delivery protocols before clinical trials. In spite...
Non-human primates (NHPs) are a preferred animal model for optimizing adeno-associated virus (AAV)-mediated CNS gene delivery protocols before clinical trials. In spite of its inherent appeal, it is challenging to compare different serotypes, delivery routes, and disease indications in a well-powered, comprehensive, multigroup NHP experiment. Here, a multiplex barcode recombinant AAV (rAAV) vector-tracing strategy has been applied to a systemic analysis of 29 distinct, wild-type (WT), AAV natural isolates and engineered capsids in the CNS of eight macaques. The report describes distribution of each capsid in 15 areas of the macaques' CNS after intraparenchymal (putamen) injection, or cerebrospinal fluid (CSF)-mediated administration routes (intracisternal, intrathecal, or intracerebroventricular). To trace the vector biodistribution (viral DNA) and targeted tissues transduction (viral mRNA) of each capsid in each of the analyzed CNS areas, quantitative next-generation sequencing analysis, assisted by the digital-droplet PCR technology, was used. The report describes the most efficient AAV capsid variants targeting specific CNS areas after each route of administration using the direct side-by-side comparison of WT AAV isolates and a new generation of rationally designed capsids. The newly developed bioinformatics and visualization algorithms, applicable to the comparative analysis of several mammalian brain models, have been developed and made available in the public domain.
Topics: Algorithms; Animals; Capsid Proteins; Central Nervous System; DNA, Viral; Databases, Genetic; Dependovirus; Drug Administration Routes; Genetic Vectors; High-Throughput Nucleotide Sequencing; Primates; RNA, Messenger; RNA, Viral; Tissue Distribution; Transduction, Genetic
PubMed: 34298128
DOI: 10.1016/j.ymthe.2021.07.010 -
Pharmaceutical Research Dec 2019Intraperitoneal (IP) route of drug administration in laboratory animals is a common practice in many in vivo studies of disease models. While this route is an easy to... (Review)
Review
Intraperitoneal (IP) route of drug administration in laboratory animals is a common practice in many in vivo studies of disease models. While this route is an easy to master, quick, suitable for chronic treatments and with low impact of stress on laboratory rodents, there is a common concern that it may not be an acceptable route for drug administration in experimental studies. The latter is likely due to sparsity of information regarding pharmacokinetics of pharmacological agents and the mechanisms through which agents get systemic exposure after IP administration. In this review, we summarize the main mechanisms involved in bioavailability of IP administered drugs and provide examples of pharmacokinetic profiles for small and large molecules in comparison to other routes of administration. We conclude with a notion that IP administration of drugs in experimental studies involving rodents is a justifiable route for pharmacological and proof-of-concept studies where the goal is to evaluate the effect(s) of target engagement rather than properties of a drug formulation and/or its pharmacokinetics for clinical translation.
Topics: Animals; Biological Availability; Drug Administration Routes; Drug Compounding; Humans; Injections, Intraperitoneal; Injections, Subcutaneous; Models, Animal; Particle Size; Pharmaceutical Preparations; Pharmacokinetics; Signal Transduction
PubMed: 31873819
DOI: 10.1007/s11095-019-2745-x -
BMC Pregnancy and Childbirth Jan 2019Oxytocin for postpartum hemorrhage (PPH) prophylaxis is commonly administered by either intramuscular (IM) injection or intravenous (IV) infusion with both routes... (Randomized Controlled Trial)
Randomized Controlled Trial
Intramuscular injection, intravenous infusion, and intravenous bolus of oxytocin in the third stage of labor for prevention of postpartum hemorrhage: a three-arm randomized control trial.
BACKGROUND
Oxytocin for postpartum hemorrhage (PPH) prophylaxis is commonly administered by either intramuscular (IM) injection or intravenous (IV) infusion with both routes recommended equally and little discussion of potential differences between the two. This trial assesses the effectiveness and safety of 10 IU oxytocin administered as IM injection versus IV infusion and IV bolus during the third stage of labor for PPH prophylaxis.
METHODS
In two tertiary level Egyptian maternity hospitals, women delivering vaginally without exposure to pre-delivery uterotonics were randomized to one of three prophylactic oxytocin administration groups after delivery of the baby. Blood loss was measured 1 h after delivery, and side effects were recorded. Primary outcomes were mean postpartum blood loss and proportion of women with postpartum blood loss ≥500 ml in this open-label, three-arm, parallel, randomized controlled trial.
RESULTS
Four thousand nine hundred thirteen eligible, consenting women were randomized. Compared to IM injection, mean blood loss was 5.9% less in the IV infusion arm (95% CI: -8.5, - 3.3) and 11.1% less in the IV bolus arm (95% CI: -14.7, - 7.8). Risk of postpartum blood loss ≥500 ml in the IV infusion arm was significantly less compared to IM injection (0.8% vs. 1.5%, RR = 0.50, 95% CI: 0.27, 0.91). No side effects were reported in any arm.
CONCLUSIONS
Intravenous oxytocin is more effective than intramuscular injection for the prevention of PPH in the third stage of labor. Oxytocin delivered by IV bolus presents no safety concerns after vaginal delivery and should be considered a safe option for PPH prophylaxis.
TRIAL REGISTRATION
clinicaltrials.gov # NCT01914419 , posted August 2, 2013.
Topics: Administration, Intravenous; Adult; Delivery, Obstetric; Egypt; Female; Humans; Infusions, Intravenous; Injections, Intramuscular; Labor Stage, Third; Oxytocics; Oxytocin; Postpartum Hemorrhage; Pregnancy; Treatment Outcome
PubMed: 30658605
DOI: 10.1186/s12884-019-2181-2 -
Anaesthesia Mar 2022
Topics: Anesthesia; Anesthetics; Drug Administration Routes; Drug Compounding; Humans; Infusions, Intravenous
PubMed: 34396509
DOI: 10.1111/anae.15561 -
The Journal of Pharmacology and... Sep 2019Advanced drug delivery technologies, in general, enable drug reformulation and administration routes, together contributing to life-cycle management and allowing the... (Review)
Review
Advanced drug delivery technologies, in general, enable drug reformulation and administration routes, together contributing to life-cycle management and allowing the innovator to maintain the product monopoly. Over the years, there has been a steady shift from mere life-cycle management to drug repurposing-applying delivery technologies to tackle solubility and permeability issues in early stages or safety and efficacy issues in the late stages of drug discovery processes. While the drug and the disease in question primarily drive the choice of route of administration, the oral route, for its compliance and safety attributes, is the most preferred route, particularly when it comes to chronic conditions, including pain, which is not considered a disease but a symptom of a primary cause. Therefore, the attempt of this review is to take a stock of the advances in oral delivery technologies that are applicable for injectable to oral transformation, improve risk-benefit profiles of existing orals, and apply them in the early discovery program to minimize the drug attrition rates.
Topics: Administration, Oral; Animals; Capsules; Drug Carriers; Drug Delivery Systems; Humans; Nanomedicine; Tablets
PubMed: 31010845
DOI: 10.1124/jpet.118.255828 -
JPMA. the Journal of the Pakistan... Aug 2021Proteins and peptide drugs have a great therapeutic potential and their usage in the treatment of various severe diseases has revolutionised the fields of... (Review)
Review
Proteins and peptide drugs have a great therapeutic potential and their usage in the treatment of various severe diseases has revolutionised the fields of pharmaceuticals and biotechnology. For successful therapeutic effects, various efforts have been made for effective delivery of proteins/peptide drugs through various routes of administrations. Parenteral and non-parenteral drug deliveries are regarded as significant routes of drug absorption. In addition to intravenous, subcutaneous and intramuscular routes, the oral route is more effective for protein and peptides therapeutics. However, there is a need to improve non-parenteral drug delivery systems (DDS) to increase drug absorption in a more effective way. The present narrative review was planned to describe routes and barriers for protein/peptide drugs and how to improve drug delivery systems in an effective way. For this purpose, numerous research articles were searched from year 2000-2021 using search engines like PubMed, Google Scholar, Medline and ISI Web of Knowledge, and Bioline International while applying different keywords such as 'protein and peptide drugs', 'drug delivery systems', 'parenteral and non-parenteral routes of drug delivery' and 'physicochemical barriers'. It was concluded that the success of the therapeutics is strongly influenced by the differential delivery of targeted antigen, the choice of targeting protein or peptide, and drug-release characteristics of the linker used. Furthermore, there should be an improvement in non-parenteral DDSs so that the drugs might be administered in an appropriate manner.
Topics: Administration, Oral; Drug Delivery Systems; Humans; Peptides; Proteins
PubMed: 34418025
DOI: 10.47391/JPMA.759 -
Drug Discovery Today Aug 2022Oral delivery is preferred over other routes of drug administration by both patients and physicians. The bioavailability of some therapeutics that are delivered via the... (Review)
Review
Oral delivery is preferred over other routes of drug administration by both patients and physicians. The bioavailability of some therapeutics that are delivered via the oral route is restricted due to the protease- and bacteria-rich environment in the gastrointestinal tract, and by the pH variability along the delivery route. Given these harsh environments, the oral delivery of therapeutic macromolecules is complicated and remains challenging. Various formulation approaches, including the use of permeation enhancers and nanosized carriers, as well as chemical alteration of the drug structure, have been studied as ways to improve the oral absorption of macromolecular drugs. Nevertheless, the bioavailability of marketed oral peptide medicines is often relatively poor. This review highlights the most recent and promising physical methods for improving the oral bioavailability of macromolecules such as peptides. These methods include microneedle injections, high-speed stream injectors, magnetic drug targeting, expandable hydrogels, and iontophoresis. We highlight the potential and challenges of these new technologies, which may impact the future approaches used by pharmaceutical companies to create more efficient and safer orally administered macromolecules.
Topics: Administration, Oral; Biological Availability; Drug Delivery Systems; Gastrointestinal Tract; Humans; Hydrogels; Macromolecular Substances; Peptides
PubMed: 35460891
DOI: 10.1016/j.drudis.2022.04.014 -
Advanced Drug Delivery Reviews Apr 2021Intercellular tight junctions represent a formidable barrier against paracellular drug absorption at epithelia (e.g., nasal, intestinal) and the endothelium (e.g.,... (Review)
Review
Intercellular tight junctions represent a formidable barrier against paracellular drug absorption at epithelia (e.g., nasal, intestinal) and the endothelium (e.g., blood-brain barrier). In order to enhance paracellular transport of drugs and increase their bioavailability and organ deposition, active excipients modulating tight junctions have been applied. First-generation of permeation enhancers (PEs) acted by unspecific interactions, while recently developed PEs address specific physiological mechanisms. Such target specific tight junction modulators (TJMs) have the advantage of a defined specific mechanism of action. To date, merely a few of these novel active excipients has entered into clinical trials, as their lack in safety and efficiency in vivo often impedes their commercialisation. A stronger focus on the development of such active excipients would result in an economic and therapeutic improvement of current and future drugs.
Topics: Animals; Drug Administration Routes; Drug Delivery Systems; Humans; Tight Junctions
PubMed: 33617902
DOI: 10.1016/j.addr.2021.02.008 -
Resuscitation Dec 2022Recent evidence showing the clinical effectiveness of drug therapy in cardiac arrest has led to renewed interest in the optimal route for drug administration in adult... (Review)
Review
Recent evidence showing the clinical effectiveness of drug therapy in cardiac arrest has led to renewed interest in the optimal route for drug administration in adult out-of-hospital cardiac arrest. Current resuscitation guidelines support use of the intravenous route for intra-arrest drug delivery, with the intraosseous route reserved for patients in whom intravenous access cannot be established. We sought to evaluate current evidence on drug route for administration of cardiac arrest drugs, with a specific focus on the intravenous and intraosseous route. We identified relevant animal, manikin, and human studies through targeted searches of MEDLINE in June 2022. Across pre-hospital systems, there is wide variation in use of the intraosseous route. Early administration of cardiac arrest drugs is associated with improved patient outcomes. Challenges in obtaining intravenous access mean that the intraosseous access may facilitate earlier drug administration. However, time from administration to the central circulation is unclear with pharmacokinetic data limited mainly to animal studies. Observational studies comparing the effect of intravenous and intraosseous drug administration on patient outcomes are challenging to interpret because of resuscitation time bias and other confounders. To date, no randomised controlled trial has directly compared the effect on patient outcomes of intraosseous compared with intravenous drug administration in cardiac arrest. The International Liaison Committee on Resuscitation has described the urgent need for randomised controlled trials comparing the intravenous and intraosseous route in adult out-of-hospital cardiac arrest. Ongoing clinical trials will directly address this knowledge gap.
Topics: Adult; Animals; Humans; Out-of-Hospital Cardiac Arrest; Pharmaceutical Preparations; Infusions, Intraosseous; Infusions, Intravenous; Administration, Intravenous; Cardiopulmonary Resuscitation
PubMed: 36309248
DOI: 10.1016/j.resuscitation.2022.10.015 -
European Journal of Pediatrics May 2022Experienced drug-handling problems and inadequately considered expectations for drug therapy have an unfavorable influence on therapy. We performed a questionnaire...
Experienced drug-handling problems and inadequately considered expectations for drug therapy have an unfavorable influence on therapy. We performed a questionnaire survey in (i) parents of 0-5-year-old children and (ii) 6-17-year olds and their parents. We assessed (A) experienced drug-handling problems and (B) expectations for drug therapy. (i) Forty-six parents and (ii) 103 children and their parents participated in the study. Experienced drug-handling problems were described by (i) 100% of parents and (ii) 62% of children and 70% of parents. Problems concerned with the preparation of the drug, dosing, compliance with the time interval, and acceptance. (i) Sixty-five percent of parents preferred a peroral route of drug administration, while (ii) 74% of children and 86% of parents did so. Preferred characteristics of peroral drug formulations, e.g., liquid versus solid drug formulations or flavor, were highly heterogeneous. Preferences of 6-17-year-old children and their parents matched in 43 to 66%. Conclusion: Most children and their parents had already experienced drug-handling problems. Preferences concerning the ideal pediatric drug were highly heterogeneous and in about half of cases, preferences of children and their parents differed. Thus, the children should be approached directly. If information is solely gained from parents, the children's needs might remain unmet. What is Known: • Pediatric drug administration is complex and therefore error-prone. • Experiences and expectations of children and their parents should be considered. What is New: •Most pediatric patients and their parents have already experienced drug-handling problems. • Expectations concerning the ideal pediatric drug are highly heterogeneous. Parents are often insufficiently aware of those expectations in their children.
Topics: Administration, Oral; Adolescent; Child; Child, Preschool; Humans; Motivation; Parents; Patient Compliance; Surveys and Questionnaires
PubMed: 35199240
DOI: 10.1007/s00431-022-04419-6