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Archives of Razi Institute Jun 2023Rasagiline is a selective and irreversible inhibitor of monoamine oxidase B (MAO-B) that is effective in the treatment of Parkinson's disease (PD). It had antioxidant...
Rasagiline is a selective and irreversible inhibitor of monoamine oxidase B (MAO-B) that is effective in the treatment of Parkinson's disease (PD). It had antioxidant and anti-apoptotic activity in experimental models. Moreover, it has low permeability and its oral bioavailability is weak and highly variable due to extensive first-pass hepatic metabolism (35%). This study aimed to formulate rasagiline mesylate (RM) as a lipid-polymer hybrid nanoparticle in order to enhance its permeation and increase its chance to be absorbed by lymphatic circulation to avoid metabolism and control its release. Successful formulation (PCL-2) was reached by the nanoprecipitation method using polycaprolactone with RM in the organic phase and lecithin in the aqueous phase DSPE-PEG. The lipid:polymer ratio of 24% and DSPE: lecithin of 50% resulted in stable nanoparticles having a particle size of 132±4.58 nm, polydispersity index of 0.273±0.02, zeta potential of -25.6±3.3, entrapment efficiency of 46±3.9%, and drug loading of 51.93±6.5. Results showed that the diffusion was more effective on the release profile than the degradation and resulted in a Fickian diffusion mechanism.
Topics: Animals; Monoamine Oxidase Inhibitors; Lecithins; Neuroprotective Agents; Mesylates
PubMed: 38028832
DOI: 10.22092/ARI.2022.360193.2563 -
Journal of Aerosol Medicine and... Dec 2022Oral tablets account for the majority of medications used to acutely treat migraine, but relief can be limited by their rates of dissolution and absorption. The nose is... (Review)
Review
Oral tablets account for the majority of medications used to acutely treat migraine, but relief can be limited by their rates of dissolution and absorption. The nose is an attractive alternative route of drug delivery since it provides patient convenience of at-home use, gastrointestinal (GI) avoidance, and rapid absorption of drugs into systemic circulation because of its large surface area. However, the site of drug deposition within the nasal cavity should be considered since it can influence drug absorption. Traditional nasal devices have been shown to target drug delivery to the lower nasal space where epithelium is not best-suited for drug absorption and where there is an increased likelihood of drug clearance due to nasal drip, swallowing, or mucociliary clearance, potentially resulting in variable absorption and suboptimal efficacy. Alternatively, the upper nasal space (UNS) offers a permeable, richly vascularized epithelium with a decreased likelihood of drug loss or clearance due to the anatomy of this area. Traditional nasal pumps deposit <5% of active drug into the UNS because of the nasal cavity's complex architecture. A new technology, Precision Olfactory Delivery (POD), is a handheld, manually actuated, propellant-powered, administration device that delivers drug specifically to the UNS. A dihydroergotamine (DHE) mesylate product, INP104, utilizes POD technology to deliver drug to the UNS for the acute treatment of migraine. Results from clinical studies of INP104 demonstrate a favorable pharmacokinetic profile, consistent and predictable dosing, rapid systemic levels known to be effective (similar to other DHE mesylate clinical programs), safety and tolerability on the upper nasal mucosa, and high patient acceptance. POD technology may have the potential to overcome the limitations of traditional nasal delivery systems, while utilizing the nasal delivery benefits of GI tract avoidance, rapid onset, patient convenience, and ease of use.
Topics: Humans; Dihydroergotamine; Administration, Intranasal; Administration, Inhalation; Migraine Disorders; Technology; Mesylates
PubMed: 36108289
DOI: 10.1089/jamp.2022.0005 -
IUCrData Jan 2024In the title complex, [Ni(CHN)](CFSO)·(CHCH)O, the central Ni atom is sixfold coordinated by three nitro-gen atoms of each 2,6-bis-(2-benzimidazol-yl)pyridine ligand in...
In the title complex, [Ni(CHN)](CFSO)·(CHCH)O, the central Ni atom is sixfold coordinated by three nitro-gen atoms of each 2,6-bis-(2-benzimidazol-yl)pyridine ligand in a distorted octa-hedral geometry with two tri-fluoro-methane-sulfonate ions and a mol-ecule of diethyl ether completing the outer coordination sphere of the complex. Hydrogen bonding contributes to the organization of the asymmetric units in columns along the axis generating a porous supra-molecular structure. The structure was refined as a two-component twin with a refined BASF value of 0.4104 (13).
PubMed: 38322034
DOI: 10.1107/S2414314624000889 -
Current Allergy and Asthma Reports Nov 2019Hematopoietic cell transplantation (HCT) is an established curative treatment for children with primary immunodeficiencies. This article reviews the latest developments... (Review)
Review
PURPOSE OF REVIEW
Hematopoietic cell transplantation (HCT) is an established curative treatment for children with primary immunodeficiencies. This article reviews the latest developments in conditioning regimens for primary immunodeficiency (PID). It focuses on data regarding transplant outcomes according to newer reduced toxicity conditioning regimens used in HCT for PID.
RECENT FINDINGS
Conventional myeloablative conditioning regimens are associated with significant acute toxicities, transplant-related mortality, and late effects such as infertility. Reduced toxicity conditioning regimens have had significant positive impacts on HCT outcome, and there are now well-established strategies in children with PID. Treosulfan has emerged as a promising preparative agent. Use of a peripheral stem cell source has been shown to be associated with better donor chimerism in patients receiving reduced toxicity conditioning. Minimal conditioning regimens using monoclonal antibodies are in clinical trials with promising results thus far. Reduced toxicity conditioning has emerged as standard of care for PID and has resulted in improved transplant survival for patients with significant comorbidities.
Topics: Busulfan; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Primary Immunodeficiency Diseases; Transplantation Conditioning; Vidarabine
PubMed: 31741098
DOI: 10.1007/s11882-019-0883-1 -
The Journal of Prevention of... 2022Hydromethylthionine mesylate is a tau aggregation inhibitor shown to have exposure-dependent pharmacological activity on cognitive decline and brain atrophy in two... (Randomized Controlled Trial)
Randomized Controlled Trial
Oral Tau Aggregation Inhibitor for Alzheimer's Disease: Design, Progress and Basis for Selection of the 16 mg/day Dose in a Phase 3, Randomized, Placebo-Controlled Trial of Hydromethylthionine Mesylate.
BACKGROUND
Hydromethylthionine mesylate is a tau aggregation inhibitor shown to have exposure-dependent pharmacological activity on cognitive decline and brain atrophy in two completed Phase 3 trials in mild/moderate Alzheimer's disease (AD).
OBJECTIVES
The present report summarises the basis for selection of 16 mg/day as monotherapy as the optimal treatment regime and the design rationale of a confirmatory Phase 3 trial (LUCIDITY).
DESIGN
The trial comprises a 12-month double-blind, placebo-controlled phase followed by a 12-month modified delayed-start open-label treatment phase.
SETTING
76 clinical research sites in North America and Europe.
PARTICIPANTS
545 patients with probable AD or MCI-AD in the final version of the protocol.
INTERVENTION
Participants were assigned randomly to receive hydromethylthione mesylate at doses of 16 mg/day, 8 mg/day or placebo at a 4:1:4 ratio during the double-blind phase. All participants in the open-label phase receive the 16 mg/day dose.
MEASUREMENTS
Co-primary clinical outcomes are the 11-item Alzheimer's Disease Assessment Scale (ADAS-cog11) and the 23-item Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL23). Secondary biomarker measures include whole-brain atrophy and temporal lobe 18F-fluorodeoxyglucose positron emission tomography.
RESULTS
446 participants are expected to complete the 12-month placebo-controlled phase in March 2022.
CONCLUSIONS
If the primary end points are met, the data will provide confirmatory evidence of the clinical and biomarker benefits of hydromethylthionine mesylate in minimal to moderate AD. As low-dose oral hydromethylthionine mesylate is simple to use clinically, does not cause amyloid-related imaging abnormalities and has a benign safety profile, it would likely improve AD management.
Topics: Humans; Alzheimer Disease; Activities of Daily Living; Fluorodeoxyglucose F18; Atrophy; Mesylates
PubMed: 36281683
DOI: 10.14283/jpad.2022.63 -
Clinical Pharmacokinetics Jul 2023Busulfan is commonly used in the chemotherapy prior to hematopoietic cell transplantation (HCT). Busulfan has a narrow therapeutic window and a well-established...
BACKGROUND
Busulfan is commonly used in the chemotherapy prior to hematopoietic cell transplantation (HCT). Busulfan has a narrow therapeutic window and a well-established exposure-response relationship with important clinical outcomes. Model-informed precision dosing (MIPD) based on population pharmacokinetic (popPK) models has been implemented in the clinical settings. We aimed to systematically review existing literature on popPK models of intravenous busulfan.
METHODS
We systematically searched Ovid MEDLINE, EMBASE, Cochrane Library, Scopus, and Web of Science databases from inception to December 2022 to identify original popPK models (nonlinear mixed-effect modeling) of intravenous busulfan in HCT population. Model-predicted busulfan clearance (CL) was compared using US population data.
RESULTS
Of the 44 eligible popPK studies published since 2002, 68% were developed predominantly in children, 20% in adults, and 11% in both children and adults. The majority of the models were described using first-order elimination or time-varying CL (69% and 26%, respectively). All but three included a body-size descriptor (e.g., body weight, body surface area). Other commonly included covariates were age (30%) and GSTA1 variant (15%). Median between-subject and between-occasion variabilities of CL were 20% and 11%, respectively. Between-model variabilities in predicted median CL were < 20% in all of the weight tiers (10-110 kg) in the simulation based on US population data.
CONCLUSION
Busulfan PK is commonly described using a first-order elimination or time-varying CL. A simple model with limited covariates were generally sufficient to attain relatively small unexplained variabilities. However, therapeutic drug monitoring may still be necessary to attain a narrow target exposure.
Topics: Child; Adult; Humans; Busulfan; Administration, Intravenous; Hematopoietic Stem Cell Transplantation; Body Surface Area; Drug Monitoring
PubMed: 37415003
DOI: 10.1007/s40262-023-01275-x -
Journal of Environmental Management Nov 2022As the most abundant greenhouse gas, atmospheric carbon dioxide (CO) is considered one of the main attributors to climate change. Atmospheric CO concentrations can be... (Review)
Review
As the most abundant greenhouse gas, atmospheric carbon dioxide (CO) is considered one of the main attributors to climate change. Atmospheric CO concentrations can be measured by ground-based monitoring networks, mobile monitoring campaigns, and carbon-observing satellites. However, the worldwide ground-based monitoring networks are composed of sparsely distributed sites and are inadequate to represent the spatiotemporal distributions of CO. Satellite-based remote sensing features repeated, long-term, and large-scale measurements, so it plays a crucial role in monitoring the global distributions of atmospheric CO. However, due to the presence of heavy clouds (or aerosols) and the limitation of satellite orbiting tracks, there exist large amounts of missing data in satellite retrievals. Various methods, including chemical transport models (CTMs), geostatistical methods, and regression-based models, have been employed to derive full-coverage spatiotemporal distributions of CO based on the limited CO measurements. This review summarizes the strengths and limitations of these methods. However, CTMs simulation results can have high uncertainty due to imperfect knowledge of the real world, and the interpolation accuracy of all geostatistical methods is limited by the large amount of data gaps in current satellite retrieved CO products. To overcome these limitations, regression-based methods (especially machine learning models) have the ability to predict CO with superior predictive performance, so this review also summarizes the framework of the machine learning approach. Leveraging the ongoing advancements of satellite instrumentation, the satellite-based CO products have been improving dramatically in recent decades, and this review will describe and critically assess the advantages and disadvantages of the currently used systems in detail. For future improvements, we recommend the fusion of data from multiple satellite retrievals and CTMs by using machine learning algorithms in order to obtain even longer-term, larger-scale, finer-resolution, and higher-accuracy CO datasets.
Topics: Aerosols; Carbon Dioxide; Cyclohexanes; Environmental Monitoring; Greenhouse Gases; Mesylates
PubMed: 36055102
DOI: 10.1016/j.jenvman.2022.116101 -
Reproductive Health Sep 2021Spermatogonial stem cells (SSCs) in the testis are crucial for transferring genetic information to the next generation. Successful transplantation of SSCs to infertile...
BACKGROUND
Spermatogonial stem cells (SSCs) in the testis are crucial for transferring genetic information to the next generation. Successful transplantation of SSCs to infertile men is an advanced therapeutic application in reproductive biology research.
METHODS
In this experimental research, both in vitro and in vivo characterization of undifferentiated and differentiated SSCs were performed by morphology-immunocytochemistry (ICC), immunohistochemistry (IMH), Fluidigm Real-Time polymerase chain reaction (RT-PCR) and flow cytometry analysis. The isolated SSCs were finally microinjected into the rete testis of busulfan-treated mice. The compact undifferentiated and more loosely connected round differentiated SSCs were isolated during testicular cell expansion from their specific feeder layer.
RESULTS
ICC analysis indicated high and low expression levels of Zbtb16 in undifferentiated and differentiated germ cells. Also, IMH analysis showed different expression levels of Zbtb16 in the two different germ stem cell populations of the testicular tissue. While Fluidigm RT-PCR analysis indicated overexpression of the TAF4B germ cell gene, the expression of DAZL, VASA, and Zbtb16 were down-regulated during the differentiation of SSCs (P < 0.05). Also, flow cytometry analysis confirmed the significant downregulation of Itgb1 and Itga4 during differentiation. By transplantation of SSCs into busulfan-treated NOD/SCID mice, GFP-labeled sperm cells developed.
CONCLUSIONS
In the current study, we performed a transplantation technique that could be useful for the future microinjection of SSCs during infertility treatment and for studying in vivo differentiation of SSCs into sperm.
Topics: Animals; Busulfan; Humans; Male; Mice; Mice, Inbred NOD; Mice, SCID; Seminiferous Tubules; Spermatogenesis; Spermatogonia; Stem Cells
PubMed: 34556135
DOI: 10.1186/s12978-021-01242-4 -
Journal of Labelled Compounds &... May 2022Histone deacetylases (HDACs) mediate epigenetic mechanisms implicated in a broad range of central nervous system dysfunction, including neurodegenerative diseases and...
Histone deacetylases (HDACs) mediate epigenetic mechanisms implicated in a broad range of central nervous system dysfunction, including neurodegenerative diseases and neuropsychiatric disorders. [ C]Martinostat allows in vivo quantification of class I/IIb HDACs and may be useful for the quantification of drug-occupancy relationship, facilitating drug development for disease modifying therapies. The present study reports a radiosynthesis of [ C]martinostat using [ C]methyl triflate in ethanol, as opposed to the originally described synthesis using [ C]methyl iodide and DMSO. [ C]Methyl triflate is trapped in a solution of 2 mg of precursor 1 dissolved in anhydrous ethanol (400 μl), reacted at ambient temperature for 5 min and purified by high-performance liquid chromatography; 1.5-1.8 GBq (41-48 mCi; n = 3) of formulated [ C]martinostat was obtained from solid-phase extraction using a hydrophilic-lipophilic cartridge in a radiochemical yield of 11.4% ± 1.1% (nondecay corrected to trapped [ C]MeI), with a molar activity of 369 ± 53 GBq/μmol (9.97 ± 1.3 Ci/μmol) at the end of synthesis (40 min) and validated for human use. This methodology was used at our production site to produce [ C]martinostat in sufficient quantities of activity to scan humans, including losses incurred from decay during pre-release quality control testing.
Topics: Adamantane; Carbon Radioisotopes; Ethanol; Humans; Hydroxamic Acids; Mesylates; Positron-Emission Tomography; Radiopharmaceuticals
PubMed: 35218059
DOI: 10.1002/jlcr.3968 -
Acta Pharmaceutica (Zagreb, Croatia) Dec 2020The aim of this work is to improve the solubility and bioavailability of chlortetracycline and the function of the immune response. Chlortetracycline bisulfate and...
The aim of this work is to improve the solubility and bioavailability of chlortetracycline and the function of the immune response. Chlortetracycline bisulfate and chlortetracycline mesylate were successfully synthesized and characterized with several techniques, including spectroscopy, chromatography and mass spectrometry, which demonstrated that the C4-dimethylamino group of chlortetracycline can accept a proton from sulfuric acid and methanesulfonic acid to form the corresponding salts. In addition, chlortetracycline bisulfate and chlortetracycline mesylate were more soluble in water than chlortetracycline hydrochloride, but the antibacterial activity was not enhanced. The influences of chlortetracycline hydrochloride, chlortetracycline bisulfate and chlortetracycline mesylate on chlortetracycline and immunoglobulin concentrations in mouse serum were also investigated. These results suggested that the chlortetracycline bisulfate and chlortetracycline mesylate have good bioavailability and strong immune response and have potential applications in animal breeding and formulation technologies.
Topics: Animals; Anti-Bacterial Agents; Bacteria; Biological Availability; Chlortetracycline; Immunity, Cellular; Immunoglobulins; Mesylates; Mice; Microbial Sensitivity Tests; Solubility; Sulfates
PubMed: 32412434
DOI: 10.2478/acph-2020-0041