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International Journal of Nanomedicine 2024Given the unique physiological and pathological characteristics of the lung, the direct, inhalable route is more conducive to pulmonary drug delivery and disease control... (Review)
Review
Given the unique physiological and pathological characteristics of the lung, the direct, inhalable route is more conducive to pulmonary drug delivery and disease control than traditional systemic drug delivery, significantly circumventing drug loss, off-target effects, systemic and organ toxicity, etc., and is widely regarded as the preferred regimen for pulmonary drug delivery. However, very few lung diseases are currently treated with the preferred inhaled formulations, such as asthma, chronic obstructive pulmonary disease and pulmonary hypertension. And there is a lack of appropriate inhaled formulations for other critical lung diseases, such as lung cancer and pulmonary fibrosis, due to the fact that the physicochemical properties of the drugs and their pharmacokinetic profiles do not match the physiology of the lung, and conventional inhalation devices are unable to deliver them to the specific parts of the lung. Phytochemicals of natural origin, due to their wide availability and clear safety profile, hold great promise for the preparation of inhalable formulations to improve the current dilemma in the treatment of lung diseases. In particular, the preparation of inhalable formulations based on nano- and microparticulate carriers for drug delivery to deep lung tissues, which overcome the shortcomings of conventional inhalation therapies while targeting the drug activity directly to a specific part of the lung, may be the best approach to change the current dilemma of lung disease treatment. In this review, we discuss recent advances in nano- and micron-carrier-based inhalation formulations for the delivery of natural products for the treatment of pulmonary diseases, which may represent an opportunity for practical clinical translation of natural products.
Topics: Humans; Biological Products; Lung Diseases; Drug Delivery Systems; Lung; Administration, Inhalation; Pharmaceutical Preparations
PubMed: 38414528
DOI: 10.2147/IJN.S451206 -
Medicine Jun 2024Magnesium Sulfate (MgSO4) is a widely used adjuvant in anesthesia. Often administered with local anesthetics, it is known to reduce analgesic and opioid consumption... (Review)
Review
Magnesium Sulfate (MgSO4) is a widely used adjuvant in anesthesia. Often administered with local anesthetics, it is known to reduce analgesic and opioid consumption while extending the duration of analgesia. MgSO4 applications extend to orthopedic surgeries, cardiovascular and urogenital procedures, offering extended postoperative pain relief. While commonly administered through various routes, there is a research gap concerning the comparative efficacy of intrathecal (IT) and intravenous (IV) MgSO4 administration. This narrative review aims to provide a comparison between IT and IV administration of MgSO4 particularly following orthopedic procedures, where pain management is paramount. A comprehensive literature search was conducted across several electronic databases, trial registries, and gray literature from inception to 2023. Inclusion criteria encompassed studies investigating the effects of perioperative IT administration of magnesium compared to perioperative IV administration of MgSO4 in patients undergoing surgery, with no language restrictions. Our search identified 4326 articles, of which 9 randomized controlled trials met our inclusion criteria. We summarized these selected articles. Four studies discussed IT magnesium sulfate (MgSO4) administration, 2 focused on IT administration in orthopedic surgeries, and 3 explored both IV and IT administration of MgSO4 in orthopedic surgery. IT MgSO4 shows promise in postoperative pain management, delaying block onset and extending duration. Personalized administration choice, considering patient factors and surgery type, is crucial. Further research is needed to refine strategies for better patient outcomes, particularly following orthopedic surgeries.
Topics: Magnesium Sulfate; Humans; Pain, Postoperative; Orthopedic Procedures; Injections, Spinal; Administration, Intravenous; Pain Management; Analgesics
PubMed: 38875416
DOI: 10.1097/MD.0000000000038522 -
Pharmaceutics May 2024Lung diseases have received great attention in the past years because they contribute approximately one-third of the total global mortality. Pulmonary drug delivery is... (Review)
Review
Lung diseases have received great attention in the past years because they contribute approximately one-third of the total global mortality. Pulmonary drug delivery is regarded as one of the most appealing routes to treat lung diseases. It addresses numerous drawbacks linked to traditional dosage forms. It presents notable features, such as, for example, a non-invasive route, localized lung drug delivery, low enzymatic activity, low drug degradation, higher patient compliance, and avoiding first-pass metabolism. Therefore, the pulmonary route is commonly explored for delivering drugs both locally and systemically. Inhalable nanocarrier powders, especially, lipid nanoparticle formulations, including solid-lipid and nanostructured-lipid nanocarriers, are attracting considerable interest in addressing respiratory diseases thanks to their significant advantages, including deep lung deposition, biocompatibility, biodegradability, mucoadhesion, and controlled drug released. Spray drying is a scalable, fast, and commercially viable technique to produce nanolipid powders. This review highlights the ideal criteria for inhalable spray-dried SLN and NLC powders for the pulmonary administration route. Additionally, the most promising inhalation devices, known as dry powder inhalers (DPIs) for the pulmonary delivery of nanolipid powder-based medications, and pulmonary applications of SLN and NLC powders for treating chronic lung conditions, are considered.
PubMed: 38794342
DOI: 10.3390/pharmaceutics16050680 -
Farmacia Hospitalaria : Organo Oficial... 2024The off-label use in clinical practice of non-approved syringes for intravitreal drug administration has resulted in the detection of silicone oil drops in the vitreous... (Review)
Review
OBJECTIVE
The off-label use in clinical practice of non-approved syringes for intravitreal drug administration has resulted in the detection of silicone oil drops in the vitreous of some patients. This situation derives from the lack of approved syringes for intraocular use in the Spanish market. The aim of this work is to review the use of syringes for intraocular administration, as well as to search for alternatives that meet the legal requirements for these unmet needs.
METHOD
A systematic review was performed following the PRISMA 2020 guidelines by searching PubMed with the descriptors: (silicone) AND (syringes) AND ((intraocular) OR (intravitreal)) and filtering all existing publications from January 2006 to December 2023, including all those articles dealing with silicone oil release in intravitreal injections and analysing the possible consequences.
RESULTS
Sixty-eight results were found, 23 of which were excluded because they did not deal with the subject under study, leaving a total of 45 articles for the systematic review. These were classified according to the conclusions obtained in 4 groups: the adverse reactions produced by silicone; the administration technique; the physicochemical aspects of silicone release; and the characteristics of the medical device. After reviewing the current manufacturers and technical data sheets of commercialised syringes, the existing syringes for this use have been collected, finding 2 that will probably be commercialised in Spain at the beginning of 2024: Zero Residual™ 0.2 ml SiO-free and VitreJect® Ophthalmic.
CONCLUSIONS
From the results obtained, it can be interpreted that the use of syringes and needles with silicone for intravitreal use is a concern for health professionals due to the implications and consequences that may arise in patients, the most important being adverse reactions, so it is necessary to have silicone-free syringes on the market that are specific for intraocular use. Safety and legality in the use of intraocular syringes and needles is essential to guarantee ocular integrity and patient health.
Topics: Syringes; Humans; Silicone Oils; Intravitreal Injections; Off-Label Use; Spain
PubMed: 38705829
DOI: 10.1016/j.farma.2024.04.011 -
Pharmaceutical Research Aug 2023Niclosamide is approved as an oral anthelminthic, but its low oral bioavailability hinders its medical use requiring high drug exposure outside the gastrointestinal...
PURPOSE
Niclosamide is approved as an oral anthelminthic, but its low oral bioavailability hinders its medical use requiring high drug exposure outside the gastrointestinal tract. An optimized solution of niclosamide for nebulization and intranasal administration using the ethanolamine salt has been developed and tested in a Phase 1 trial. In this study we investigate the pulmonary exposure of niclosamide following administration via intravenous injection, oral administration or nebulization.
METHODS
We characterized the plasma and pulmonary pharmacokinetics of three ascending doses of nebulized niclosamide in sheep, compare it to intravenous niclosamide for compartmental PK modelling, and to the human equivalent approved 2 g oral dose to investigate in the pulmonary exposure of different niclosamide delivery routes. Following a single-dose administration to five sheep, niclosamide concentrations were determined in plasma and epithelial lining fluid (ELF). Non-compartmental and compartmental modeling was used to characterize pharmacokinetic profiles. Lung function tests were performed in all dose groups.
RESULTS
Administration of all niclosamide doses were well tolerated with no adverse changes in lung function tests. Plasma pharmacokinetics of nebulized niclosamide behaved dose-linear and was described by a 3-compartmental model estimating an absolute bioavailability of 86%. ELF peak concentration and area under the curve was 578 times and 71 times higher with nebulization of niclosamide relative to administration of oral niclosamide.
CONCLUSIONS
Single local pulmonary administration of niclosamide via nebulization was well tolerated in sheep and resulted in substantially higher peak ELF concentration compared to the human equivalent oral 2 g dose.
Topics: Humans; Animals; Sheep; Anti-Bacterial Agents; Administration, Inhalation; Niclosamide; Ethanolamine; Lung; Ethanolamines
PubMed: 37498498
DOI: 10.1007/s11095-023-03559-0 -
European Journal of Pharmaceutical... Jan 2024Early-stage clinical evaluation of tinengotinib (TT-00420) demonstrated encouraging preliminary efficacies in multiple types of refractory cancers, including fibroblast...
In vitro and in vivo pharmacokinetics, disposition, and drug-drug interaction potential of tinengotinib (TT-00420), a promising investigational drug for treatment of cholangiocarcinoma and other solid tumors.
Early-stage clinical evaluation of tinengotinib (TT-00420) demonstrated encouraging preliminary efficacies in multiple types of refractory cancers, including fibroblast growth factor receptors (FGFR) inhibitors relapsed cholangiocarcinoma (CCA), castrate-resistant prostate cancer (CRPC), and HR+/HER2- breast cancer and triple negative breast cancer (TNBC). To further evaluate drug-like properties of the drug candidate, it is imperative to understand its metabolism and pharmacokinetic properties. This manuscript presented the investigation results of in vitro permeability, plasma protein binding, metabolic stability, metabolite identification, and drug-drug interaction of tinengotinib. Preclinical ADME (absorption, distribution, excretion, and metabolism) studies in rats and dogs was also conducted using a radioactive labeled tinengotinib, [C]tinengotinib. Tinengotinib was found to have high permeability and high plasma protein binding and equally distributed between blood and plasma. There were no unique metabolites in human liver microsomes and tinengotinib showed moderate hepatic clearance. Tinengotinib is neither a potential inhibitor nor an inducer of P450 enzymes at clinically relevant concentrations, and unlikely to cause drug-drug interactions when used in combination with other drugs mediated by a key transporter, either as victim or perpetrator. Taken together, tinengotinib demonstrated a minimal risk of clinically relevant drug-drug interactions. Tinengotinib showed good oral bioavailability and dose-dependent exposures in both rat and dog after oral administration. The total radioactivity was largely distributed in the gastrointestinal system and liver, and tinengotinib could not easily pass through the blood-brain barrier. The major drug-related component in rat and dog plasma was unchanged drug (>89 %) with primary route of elimination via feces (>93 % of the dose) and minor via renal excretion (<4 % of the dose). Tinengotinib metabolism is mediated largely by CYP3A4, with minor contributions from CYP2D6 and CYP2C8. Major metabolic pathways include oxidation, oxidative cleavage of the morpholine ring, glucuronide and glutathione conjugations. The overall preclinical pharmacokinetics profile supported the selection and development of tinengotinib as a clinical candidate.
Topics: Male; Rats; Humans; Animals; Dogs; Drugs, Investigational; Drug Interactions; Pharmaceutical Preparations; Biological Availability; Protein Kinase Inhibitors; Administration, Oral; Microsomes, Liver; Cholangiocarcinoma
PubMed: 38048851
DOI: 10.1016/j.ejps.2023.106658 -
Systematic Reviews Jul 2023Self-administered depot medroxyprogesterone acetate subcutaneous injectable contraception (DMPA-SC) is registered in many countries. It shows great potential for... (Review)
Review
BACKGROUND
Self-administered depot medroxyprogesterone acetate subcutaneous injectable contraception (DMPA-SC) is registered in many countries. It shows great potential for improving contraceptive access, continuation, and autonomy. However, there are challenges in rolling out this new efficacious intervention, and major implementation problems have been encountered during scale-up.
OBJECTIVE
To describe the implementation strategies to scale up self-administered DMPA-SC and the barriers, facilitators, and outcomes of these programs.
METHOD
Recent guidelines, including the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews, were used to design and report this review. An article or report was eligible for inclusion if it reported interventions that could scale up self-administered DMPA-SC implementation or its facilitators, barriers, or outcomes. We searched six electronic databases and the grey literature for eligible articles and reports. Two reviewers independently screened the document titles, abstracts, and full texts to identify eligible documents. Data were extracted using structured forms. Using the Effective Practice and Organization of Care (EPOC) taxonomy of health systems framework for thematic analysis, data were presented in a narrative approach.
RESULTS
Of the 755 retrieved documents, 34 were included in this review. Most of the documents included were multi-country reports (n = 14), and all documents were published within the last 5 years (2018-2021). This review identified documents that reported interventions in all EPOC domains. The most-reported interventions were: task-sharing amongst health workforce cadres, engaged leadership, encouraging policies, training and education, DMPA-SC demand generation, integration into existing programs, improved funding mechanisms, collaboration with development partners, and supply chain strengthening. The main barriers were suboptimal funding, inadequate human resources, and poor logistics supply of DMPA-SC. There was minimal evidence of scale-up outcomes.
CONCLUSION
This scoping review reported a wide range of interventions employed by countries and programs to scale up DMPA-SC self-administration but minimal evidence of the scale-up outcomes. Evidence from this review can help design better programs that improves access to quality family planning services to achieve the Sustainable Development Goals (SDG) targets 3.7. However, efforts should focus on rigorous implementation research that assess scaled up self-administered DMPA-SC interventions and report their outcomes.
REGISTRATION
The protocol for this review was registered in the protocols.io repository ( https://www.protocols.io/view/a-protocol-for-a-scoping-review-of-implementation-x54v9yemmg3e/v1 ).
Topics: Female; Humans; Contraception; Contraceptive Agents, Female; Injections, Subcutaneous; Medroxyprogesterone Acetate; Self Administration
PubMed: 37403147
DOI: 10.1186/s13643-023-02216-2 -
Carbohydrate Polymers Nov 2023Carvedilol, a β-blocker prescribed for chronic heart failure, suffers from poor bioavailability and rapid first pass metabolism when administered orally. Herein, we...
Carvedilol, a β-blocker prescribed for chronic heart failure, suffers from poor bioavailability and rapid first pass metabolism when administered orally. Herein, we present the development of tip microarray patches (MAPs) composed of ternary cyclodextrin (CD) complexes of carvedilol for transdermal delivery. The ternary complex with hydroxypropyl γ-cyclodextrin (HPγCD) and poly(vinyl pyrrolidone) (PVP) reduced the crystallinity of carvedilol, as evidenced by DSC, XRD, NMR, and SEM analysis. MAPs were fabricated using a two-step process with the ternary complex as the needle layer. The resulting MAPs were capable of breaching ex vivo neonatal porcine skin to a depth ≈600 μm with minimal impact to needle height. Upon insertion, the needle dissolved within 2 h, leading to the transdermal delivery of carvedilol. The MAPs displayed minimal toxicity and acceptable biocompatibility in cell assays. In rats, MAPs achieved significantly higher AUC levels of carvedilol than oral administration, with a delayed T and sustained plasma levels over several days. These findings suggest that the carvedilol-loaded dissolving MAPs have the potential to revolutionise the treatment of chronic heart failure.
Topics: Swine; Animals; Rats; Carvedilol; Cyclodextrins; Heart Failure; Administration, Oral; Biological Availability
PubMed: 37659788
DOI: 10.1016/j.carbpol.2023.121194 -
Iranian Journal of Medical Sciences Jan 2024Monkeypox is an infectious and contagious zoonotic disease caused by the Orthopoxvirus species and was first identified in Africa. Recently, this infectious disease has... (Review)
Review
Monkeypox is an infectious and contagious zoonotic disease caused by the Orthopoxvirus species and was first identified in Africa. Recently, this infectious disease has spread widely in many parts of the world. Fever, fatigue, headache, and rash are common symptoms of monkeypox. The presence of lymphadenopathy is another prominent and key symptom of monkeypox, which distinguishes this disease from other diseases and is useful for diagnosing the disease. This disease is transmitted to humans through contact with or eating infected animals as well as objects infected with the virus. One of the ways to diagnose this disease is through PCR testing of lesions and secretions. To prevent the disease, vaccines such as JYNNEOS and ACAM2000 are available, but they are not accessible to all people in the world, and their effectiveness and safety need further investigation. However, preventive measures such as avoiding contact with people infected with the virus and using appropriate personal protective equipment are mandatory. The disease therapy is based on medicines such as brincidofovir, cidofovir, and Vaccinia Immune Globulin Intravenous. The injectable format of tecovirimat was approved recently, in May 2022. Considering the importance of clinical care in this disease, awareness about the side effects of medicines, nutrition, care for conjunctivitis, skin rash, washing and bathing at home, and so on can be useful in controlling and managing the disease.
Topics: Humans; Animals; Mpox (monkeypox); Administration, Intravenous; Africa; Benzamides; Cidofovir; Exanthema
PubMed: 38322157
DOI: 10.30476/IJMS.2022.96738.2837 -
Proceedings of the National Academy of... Mar 2024Treating pregnancy-related disorders is exceptionally challenging because the threat of maternal and/or fetal toxicity discourages the use of existing medications and...
Treating pregnancy-related disorders is exceptionally challenging because the threat of maternal and/or fetal toxicity discourages the use of existing medications and hinders new drug development. One potential solution is the use of lipid nanoparticle (LNP) RNA therapies, given their proven efficacy, tolerability, and lack of fetal accumulation. Here, we describe LNPs for efficacious mRNA delivery to maternal organs in pregnant mice via several routes of administration. In the placenta, our lead LNP transfected trophoblasts, endothelial cells, and immune cells, with efficacy being structurally dependent on the ionizable lipid polyamine headgroup. Next, we show that LNP-induced maternal inflammatory responses affect mRNA expression in the maternal compartment and hinder neonatal development. Specifically, pro-inflammatory LNP structures and routes of administration curtailed efficacy in maternal lymphoid organs in an IL-1β-dependent manner. Further, immunogenic LNPs provoked the infiltration of adaptive immune cells into the placenta and restricted pup growth after birth. Together, our results provide mechanism-based structural guidance on the design of potent LNPs for safe use during pregnancy.
Topics: Female; Pregnancy; Humans; Animals; Mice; RNA, Messenger; Endothelial Cells; Fetus; Prenatal Care; Liposomes; Nanoparticles
PubMed: 38437545
DOI: 10.1073/pnas.2307810121