Computer Library Literature Review on Effectiveness of Antimotion Sickness Drugs
Physiological responses to antimotion sickness drugs - antihistamines, belladonnas, and phenothiazines
PHARMACOLOGY↗
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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.
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Comparison of effectiveness of some antimotion sickness drugs using recommended and larger than recommended doses as tested in the slow rotation room.
Effectiveness of antimotion sickness drugs compared by using recommended and larger than recommended doses as tested in slow rotation room
HUMAN CENTRIFUGE↗
The effect of drugs in altering susceptibility to motion sickness in aerobatics and the slow rotation room
Drugs altering susceptibility to motion sickness in aerobatics and slow rotation room
ROTATING ENVIRONMENT↗
Effect of drugs in altering susceptibility to motion sickness in aerobatics and the slow rotation room.
Antimotion sickness drugs and placebos effect on altering motion sickness susceptibility in Skyraider aircraft aerobatics and Slow Rotation Room dial test
PHARMACOLOGY↗
Intestinal transport of gentamicin with a novel, glycosteroid drug transport agent
PURPOSE: The objective was to investigate the ability of a glycosteroid (TC002) to increase the oral bioavailability of gentamicin. METHODS: Admixtures of gentamicin and TC002 were administered to the rat ileum by injection and to dogs by ileal or jejunal externalized ports, or PO. Bioavailability of gentamicin was determined by HPLC. 3H-TC002 was injected via externalized cannulas into rat ileum or jejunum, or PO and its distribution and elimination was determined. The metabolism of TC002 in rats was evaluated by solid phase extraction and HPLC analysis of plasma, urine and feces following oral or intestinal administration. RESULTS: The bioavailability of gentamicin was substantially increased in the presence of TC002 in both rats and dogs. The level of absorption was dependent on the concentration of TC002 and site of administration. Greatest absorption occurred following ileal orjejunal administration. TC002 was significantly more efficacious than sodium taurocholate, but similar in cytotoxicity. TC002 remained primarily in the GI tract following oral or intestinal administration and cleared rapidly from the body. It was only partly metabolized in the GI tract, but was rapidly and completely converted to its metabolite in plasma and urine. CONCLUSIONS: TC002 shows promise as a new drug transport agent for promoting intestinal absorption of polar molecules such as gentamicin.
Non-NASA Center↗
ESPC ESA Case Study: Energy Affordability at the Drug Enforcement Administration
The U.S. Drug Enforcement Administration (DEA) El Paso Intelligence Center (EPIC), located on Fort Bliss in El Paso, TX, installed 2.5 MW DC of photovoltaics (PV). This project was an energy sales agreement energy conservation measure (ESA ECM) using the U.S. Department of Energy (DOE) energy savings performance contract (ESPC) ENABLE contract vehicle. The project represents an economical clean-energy solution that provides excellent construction and other trades-related jobs, and provides information that will help future ESPC ESA projects provide cost savings to the government.
29 ENERGY PLANNING, POLICY, AND ECONOMY↗
Breast tumor-targeted drug delivery via polymer nanocarriers: Endogenous and exogenous strategies
Breast cancer, one of the most common types of cancer worldwide, has a high degree of malignancy while lacking efficient treatments. The off-target events frequently occurring in drug administration have been a major obstacle, which causes severe side effects to patients and reduces the therapeutic efficacy. An ideal medication should precisely target the specific site with precise control over concentration and duration. In recent years, there has been immense progress in polymer nanocarriers that demonstrate great potential in the targeted delivery. These nanocarriers are constructed from materials sensitive to a wide range of endogenous (e.g., pH, enzyme, redox) and exogenous stimuli (e.g., light, ultrasound, magnetic waves), driving cargo release to the targeted tissue or cells. Here, we elucidate the mechanism of current targeting strategies and the engineering methods to construct these targeting systems or to improve their targeting efficiency. Here we capture the recent progress in the targeted nanocarriers derived from polymers which span hydrogels and micelles, demonstrating their design and applications in chemo, hyperthermia, immuno, and gene therapies.
36 MATERIALS SCIENCE↗
Antitumor activity of a 5T4 targeting antibody drug conjugate with a novel payload derived from MMAF via C‐Lock linker
Abstract Antibody‐drug conjugates (ADCs) belong to a promising class of biopharmaceuticals in which target‐killing of tumor cells was achieved by marrying the potency of the cytotoxic payload with the tumor specificity of the antibody. Here we developed a novel ADC (ZV0508) that targets 5T4 oncofetal antigen, which is overexpressed in many carcinomas on both bulk tumor cells and cancer stem cells. A novel cytotoxic payload called Duostatin‐5 (Duo‐5) which was derived from monomethyl auristatin F (MMAF) was attached to a 5T4 targeting antibody (ZV05) by interchain cysteine cross‐linking conjugation via a disubstituted C‐Lock linker. We have investigated the antitumor efficacy of ZV0508 by in vitro and in vivo studies, and compared its antitumor activity with ZV05‐mcMMAF (ZV0501), in which MMAF was linked via a conventional noncleavable maleimidocaproyl linker. As results, ZV0508 exhibited ideal antiproliferative effects through blocking cell cycle and inducing cell apoptosis. The in vivo studies revealed that both ZV0501 and ZV0508 exhibited excellent antitumor activities even at a single dose. Although ZV0508 was inferior to ZV0501 in vitro, it elicited more durable antitumor responses than ZV0501 in vivo. The superior in vivo activity of ZV0508 may be due to the combined use of the disubstituted C‐Lock linker and the novel payload Duo‐5, resulting in a more stable and potent ADC. Taken together, these data suggest ZV0508 is a worthy candidate for the treatment of 5T4 positive cancers.
Shi, Baoying↗
A Ligand-Directed Nitrophenol Carbonate for Transient in situ Bioconjugation and Drug Delivery
Here we report the first use of ligand-directed proximity accelerated bioconjugation chemistry in the tandem delivery and release of a therapeutic payload. To do this, we designed a nitrophenol carbonate for ligand-directed in situ bioconjugation of a prodrug payload to a protein. The transient nature of our conjugation chemistry renders the protein a depot for timedependent release of active drug following hydrolysis and selfimmolation. In our model system, using an immunostimulant prodrug, biotin ligand, and avidin protein, we observe release of bioavailable immunostimulant both spectroscopically and with an immune cell line over 48 h. Avidin co-crystalized with the nitrophenolate directing group verified the binding pose of the ligand and offered insight into the mechanism of in situ bioconjugation. Overall, this scaffold warrants further investigation for the time-dependent delivery of therapeutics and use in protein ligand pairs beyond biotin and avidin used for this work.
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
Phosphodiesterase (PDE5) inhibition assay for rapid detection of erectile dysfunction drugs and analogs in sexual enhancement products
Abstract Products marketed as dietary supplements for sexual enhancement are frequently adulterated with phosphodiesterase‐5 (PDE5) inhibitors, which are erectile dysfunction drugs or their analogs that can cause adverse health effects. Due to widespread adulteration, a rapid screening assay was developed to detect PDE5 inhibitors in adulterated products. The assay employs fluorescence detection and is based on measuring inhibition of PDE5 activity, the pharmacological mechanism shared among the adulterants. Initially, the assay reaction scheme was established and characterized, followed by analysis of 9 representative PDE5 inhibitors ( IC 50 , 0.4–4.0 ng mL –1 ), demonstrating sensitive detection in matrix‐free solutions. Next, dietary supplements serving as matrix blanks ( n = 25) were analyzed to determine matrix interference and establish a threshold value; there were no false positives. Finally, matrix blanks were spiked with 9 individual PDE5 inhibitors, along with several mixtures. All 9 adulterants were successfully detected (≤ 5 % false negative rate; n = 20) at a concentration of 1.00 mg g –1 , which is over 5 times lower than concentrations commonly encountered in adulterated products. A major distinction of the PDE5 inhibition assay is the ability to detect adulterants without prior knowledge of their chemical structures, demonstrating a broad‐based detection capability that can address a continuously evolving threat of new adulterants. The PDE5 inhibition assay can analyze over 40 samples simultaneously within 15 minutes and involves a single incubation step and simple data analysis, all of which are advantageous for combating the widespread adulteration of sex‐enhancement products.
Santillo, Michael F.↗
Mechanistic Models as Framework for Understanding Biomarker Disposition: Prediction of Creatinine‐Drug Interactions
Creatinine is widely used as a biomarker of glomerular filtration, and, hence, renal function. However, transporter‐mediated secretion also contributes to its renal clearance, albeit to a lesser degree. Inhibition of these transporters causes transient serum creatinine elevation, which can be mistaken as impaired renal function. The current study developed mechanistic models of creatinine kinetics within physiologically based framework accounting for multiple transporters involved in creatinine renal elimination, assuming either unidirectional or bidirectional‐OCT2 transport (driven by electrochemical gradient). Robustness of creatinine models was assessed by predicting creatinine‐drug interactions with 10 perpetrators; performance evaluation accounted for 5% intra‐individual variability in serum creatinine. Models showed comparable predictive performances of the maximum steady‐state effect regardless of OCT2 directionality assumptions. However, only the bidirectional‐OCT2 model successfully predicted the minimal effect of ranitidine. The dynamic nature of models provides clear advantage to static approaches and most advanced framework for evaluating interplay between multiple processes in creatinine renal disposition.
Scotcher, Daniel↗
Drug-Eluting Beads Loaded With Doxorubicin (DEBDOX) Chemoembolisation Before Liver Transplantation for Hepatocellular Carcinoma: An Imaging/Histologic Correlation Study
Purpose Most transplant centers use chemoembolisation as locoregional bridge therapy for hepatocellular carcinoma (HCC) before liver transplantation (LT). Chemoembolisation using beads loaded with doxorubicin (DEBDOX) is a promising technique that enables delivery of a large quantity of drugs against HCC. We sought to assess the imaging–histologic correlation after DEBDOX chemoembolisation.Materials and Methods All consecutive patients who had undergone DEBDOX chemoembolisation before receiving liver graft for HCC were included. Tumour response was evaluated according to Response Evaluation Criteria in Solid Tumours (RECIST) and modified RECIST (mRECIST) criteria. The result of final imaging made before LT was correlated with histological data to predict tumour necrosis.ResultsTwenty-eight patients underwent 43 DEBDOX procedures for 45 HCC. Therapy had a significant effect as shown by a decrease in the mean size of the largest nodule (p = 0.02) and the sum of viable part of tumour sizes according to mRECIST criteria (p < 0.001). An objective response using mRECIST criteria was significantly correlated with mean tumour necrosis ≥90 % (p = 0.03). A complete response using mRECIST criteria enabled accurate prediction of complete tumour necrosis (p = 0.01). Correlations using RECIST criteria were not significant.ConclusionOur data confirm the potential benefit of DEBDOX chemoembolisation as bridge therapy before LT, and they provide a rational basis for new studies focusing on recurrence-free survival after LT. Radiologic evaluation according to mRECIST criteria enables accurate prediction of tumour necrosis, whereas RECIST criteria do not.
62 RADIOLOGY AND NUCLEAR MEDICINE↗
End-hole Versus Microvalve Infusion Catheters in Patients Undergoing Drug-Eluting Microspheres-TACE for Solitary Hepatocellular Carcinoma Tumors: A Retrospective Analysis
Introduction: Pre-transplant locoregional therapy for hepatocellular carcinoma (HCC) during bridge-to-transplant impacts recurrence and survival rates following liver transplantation. Optimizing the effectiveness of transarterial chemoembolization (TACE) in this population is imperative, and microvalve infusion catheters offer a means of such improvement. Methods: All treatment-naive patients with solitary HCC tumors < 6.5 cm who underwent drug-eluting microspheres (DEM) TACE between 04/2015 and 08/2017 were retrospectively reviewed. Eighty-eight included patients underwent DEM-TACE with either standard end-hole catheters (EH) or microvalve infusion catheters (MVI). The EH (n = 70) and MVI (n = 18) cohorts had similar baseline tumor size, laboratory values, and tumor etiologies. Results: Initial objective response rates were significantly higher in MVI vs. EH (100% vs. 76.5%, p = 0.019). There was no difference in adverse events between groups (p = 0.265). MVI patients exhibited lower AST (p = 0.003) and ALT (p = 0.044) at 6 months. Blinded pathological analysis of explanted livers showed greater concentrations of microspheres within the tumor relative to the surrounding tissue in MVI explants (88.7 ± 10.6%) versus the EH explants (55.3 ± 32.7%) (p = 0.002). There was significantly higher percentage tumor necrosis in the MVI group (89.0 ± 2.2%) compared with the EH group (56.1 ± 44.5%) (p = 0.006). Conclusion: In this retrospective study of a single-center cohort, DEM-TACE procedures with MVI were associated with improved tumor response, increased deposition of microspheres within tumor tissue, and higher percentage tumor necrosis at explant relative to those performed using EH catheters.
62 RADIOLOGY AND NUCLEAR MEDICINE↗
Does Drug-Eluting Bead TACE Enhance the Local Effect of IRE? Imaging and Histopathological Evaluation in a Porcine Model
Objectives: We conducted an in vivo trial on swine to compare the ablation volumes of irreversible electroporation (IRE) followed by drug-eluting beads transarterial chemoembolization (DEB-TACE) versus IRE only. Materials and Methods: Nine swine underwent CT-guided IRE in one liver lobe and IRE immediately followed by DEB-TACE in a different liver lobe. For DEB-TACE, 100–300 µm beads (DC-Beads{sup ®}) were loaded with 50 mg doxorubicin. For IRE, the NanoKnife{sup ®} was used employing two electrodes according to the vendor’s protocol. Imaging follow-up was performed including CT-based lesion volume assessment using contrast-enhanced CT (venous phase) on days 1, 3, and 7 after the procedure. Three animals were killed for histopathological analysis after each follow-up. Results: Ablation volumes in CT in the IRE + DEB-TACE group were 15.4 ± 10.5 ml on day 1, 8.7 ± 5.6 ml on day 3, and 1.6 ± 0.7 ml on day 7. In the IRE group, the corresponding values were 5.2 ± 5.2 ml on day 1, 1.0 ± 1.2 ml on day 3, and 0.1 ± 0.1 ml on day 7. On day 1 and day 3, ablation volumes of IRE + TACE group were significantly larger than in the IRE group (p < 0.05). 96% of beads were depicted in or around ablative lesions. 69% of these beads were found in the surrounding hemorrhagic infiltration and 31% within the ablative lesion itself. Conclusions: Combination of IRE immediately followed by DEB-TACE resulted in larger ablation volumes compared to IRE alone, suggesting that local efficacy of IRE can be enhanced by post-IRE DEB-TACE.
62 RADIOLOGY AND NUCLEAR MEDICINE↗
Imaging doxorubicin and polymer-drug conjugates of doxorubicin-induced cardiotoxicity with bispecific anti-myosin-anti-DTPA antibody and Tc-99m-labeled polymers
Background: Radiolabeled anti-myosin imaging is well-established for imaging doxorubicin-induced cardiotoxicity. However, to enable imaging of drug-induced cardiotoxicity in small experimental animals, pretargeting with bispecific anti-myosin-anti-DTPA-Fab-Fab’ and targeting with high-specific radioactivity Tc-99m-DTPA-succinylated-polylysine (DSPL) was developed. Methods: Mice were injected biweekly with 10 mg/kg Dox or its equivalent as D-Dox-PGA. Tc-99m-DSPL myocardial activity after pretargeting with bsAb-Fab-Fab’ was determined after gamma imaging performed at day 7 for Dox-treated mice and day 39 for all others. Results: Mice treated with 10 mg/kg Dox lost 10% total body weight in 1 week and 20% after a second dose. Pretargeted mice treated with 30 mg/kg cumulative D-Dox-PGA dose showed no loss of body weight for the duration of the study. Cardiotoxicity was confirmed by gamma imaging and scintillation counting (1.9 ± 0.25 [mean% ID/g ± SD]) after 1 dose of Dox. Mice injected with 3 × 10 mg/kg Dox equivalent as D-Dox-PGA (0.4 ± 0.04, P < .01) and untreated 2 control groups (0.20 ± 0.05 and 0.19 ± 0.04, P < .01) showed significantly lower myocardial anti-myosin radioactivity relative to the 10 mg/kg Dox group. Conclusion: Pretargeting with bsAb-Fab-Fab’ and targeting with Tc-99m labeled high-specific activity polymers enabled early visualization of doxorubicin induce cardiotoxicity in mice. Tolerated dose of D-Dox-PGA was greater than to 30 mg/kg Dox-equivalent dose with minimal cardiotoxicity.
62 RADIOLOGY AND NUCLEAR MEDICINE↗
Inhibiting and Remodeling Toxic Amyloid-Beta Oligomer Formation Using a Computationally Designed Drug Molecule That Targets Alzheimer’s Disease
Alzheimer’s disease (AD) is rapidly reaching epidemic status among a burgeoning aging population. Much evidence suggests the toxicity of this amyloid disease is most influenced by the formation of soluble oligomeric forms of amyloid β-protein, particularly the 42-residue alloform (Aβ42). Developing potential therapeutics in a directed, streamlined approach to treating this disease is necessary. Here we utilize the joint pharmacophore space (JPS) model to design a new molecule [AC0107] incorporating structural characteristics of known Aβ inhibitors, blood-brain barrier permeability, and limited toxicity. To test the molecule’s efficacy experimentally, we employed ion mobility mass spectrometry (IM-MS) to discover [AC0107] inhibits the formation of the toxic Aβ42 dodecamer at both high (1:10) and equimolar concentrations of inhibitor. Atomic force microscopy (AFM) experiments reveal that [AC0107] prevents further aggregation of Aβ42, destabilizes preformed fibrils, and reverses Aβ42 aggregation. This trend continues for long-term interaction times of 2 days until only small aggregates remain with virtually no fibrils or higher order oligomers surviving. Pairing JPS with IM-MS and AFM presents a powerful and effective first step for AD drug development. .
62 RADIOLOGY AND NUCLEAR MEDICINE↗
An unsteady flow of magnetic nanoparticles as drug carrier suspended in micropolar fluid through a porous tapered arterial stenosis under non-uniform magnetic field and periodic body acceleration
A mathematical model has been developed for pulsatile flow of blood through a tapered arterial stenosis in a porous medium under the influence of non-uniform magnetic field and periodic body acceleration treating blood as micropolar fluid carrying iron oxide nanoparticles. The governing equations of the system are solved numerically using finite difference schemes. The effects of stenotic height, taper angle, micropolar parameters, magnetic field, porosity, pulsatility, and magnetic nanoparticles on the flow of blood are analysed, and the results are represented graphically. It is significant to note that the flow parameters such as wall shear stress and flow resistance increase with increase in stenotic height, tapering parameter, magnetic field, pulsatile Reynolds number, time period, particle concentration, and particle mass parameters. Wall shear stress decreases with the increasing values of coupling number and it shows opposite behaviour in the case of flow resistance. Also increase in Darcy number leads to decrease in wall shear stress and flow resistance. The significance of treating blood as micropolar fluid is that the rotation of particles is taken into account. Cardiovascular diseases occur mainly due to abnormal blood flow in the arteries. To normalize the blood flow in the arteries, analysis of parameters involved in the study is essential. Hence, the present study has various applications in biomedical sciences. The effects of nanoparticles on blood flow analysed in the study have significant applications in delivery of drugs for treating cancer.
62 RADIOLOGY AND NUCLEAR MEDICINE↗
Antibiotic drug tigecycline inhibited cell proliferation and induced autophagy in gastric cancer cells
Highlights: • Tigecycline inhibited cell growth and proliferation in human gastric cancer cells. • Tigecycline induced autophagy not apoptosis in human gastric cancer cells. • AMPK/mTOR/p70S6K pathway was activated after tigecycline treatment. • Tigecycline inhibited tumor growth in xenograft model of human gastric cancer cells. - Abstract: Tigecycline acts as a glycylcycline class bacteriostatic agent, and actively resists a series of bacteria, specifically drug fast bacteria. However, accumulating evidence showed that tetracycline and their derivatives such as doxycycline and minocycline have anti-cancer properties, which are out of their broader antimicrobial activity. We found that tigecycline dramatically inhibited gastric cancer cell proliferation and provided an evidence that tigecycline induced autophagy but not apoptosis in human gastric cancer cells. Further experiments demonstrated that AMPK pathway was activated accompanied with the suppression of its downstream targets including mTOR and p70S6K, and ultimately induced cell autophagy and inhibited cell growth. So our data suggested that tigecycline might act as a candidate agent for pre-clinical evaluation in treatment of patients suffering from gastric cancer.
60 APPLIED LIFE SCIENCES↗