Modulation of Hematopoietic Injury by a Promising Radioprotector, Gamma-Tocotrienol, in Rhesus Macaques Exposed to Partial-Body Radiation.

Currently, no radioprotectors have been approved to mitigate hematopoietic injury after exposure to ionizing radiation. Acute ionizing radiation results in damage to both hematopoietic and immune system cells. Pre-exposure prophylactic agents are needed for first responders and military personnel. In this study, the ability of gamma-tocotrienol (GT3), a promising radioprotector and antioxidant, to ameliorate partial-body radiation-induced damage to the hematopoietic compartment was evaluated in a nonhuman primate (NHP) model. A total of 15 rhesus NHPs were divided into two groups, and were administered either GT3 or vehicle 24 h prior to 4 or 5.8 Gy partial-body irradiation (PBI), with 5% bone marrow (BM) sparing. Each group consisted of four NHPs, apart from the vehicle-treated group exposed to 5.8 Gy, which had only three NHPs. BM samples were collected 8 days prior to irradiation in addition to 2, 7, 14, and 30 days postirradiation. To assess the clonogenic ability of hematopoietic stem and progenitor cells (HSPCs), colony forming unit (CFU) assays were performed, and lymphoid cells were immunophenotyped using flow cytometry. As a result of GT3 treatment, an increase in HSPC function was evident by an increased recovery of CFU-granulocyte macrophages (CFU-GM). Additionally, GT3 treatment was shown to increase the percentage of CD34+ cells, including T and NK-cell subsets. Our data further affirm GT3's role in hematopoietic recovery and suggest the need for its further development as a prophylactic radiation medical countermeasure.

A prospective study to determine the risk factors associated with post traumatic seizures: A single institution experience.

Background: Post traumatic seizures (PTS) are a known sequel of traumatic brain injury (TBI). Incidence of PTS is dependent on many factors including study design and characteristics of the study population. As incidence of TBI increases and death due to TBI decreases, more individuals will be at risk of developing and living with chronic complications. The objective of the present study was to determine the frequency and risk factors for PTS following TBI. Methods: A prospective study was conducted on patients admitted with TBI from April 1, 2019, to May 31, 2020, to determine the frequency, time to event, and risk factors for PTS following TBI. We classified the severity of head injury using a standard criterion, into mild, moderate and severe injury. Follow-up of 3 months was undertaken for all patients. Variables include age, sex, trauma severity, Glasgow coma scale, onset of PTS, and neuroradiological finding. Results: We enrolled 450 post traumatic subjects, out of which 36 (8%) developed seizures. Of the total of 36 patients detected to have hemorrhagic contusion on computerized tomography scan, 12 patients developed seizures. We found that the independent risk factors associated with occurrence of PTS were frontal- temporal lobar contusion and severity of head injury. All these findings were statistically significant. Conclusion: We found that the independent risk factors associated with occurrence of PTS were frontal-temporal lobar contusion and severity of head injury. Type of management (Operative vs. Non operative) does not affect the outcome of PTS.

Gamma-Tocotrienol Modulates Total-Body Irradiation-Induced Hematopoietic Injury in a Nonhuman Primate Model.

Radiation exposure causes acute damage to hematopoietic and immune cells. To date, there are no radioprotectors available to mitigate hematopoietic injury after radiation exposure. Gamma-tocotrienol (GT3) has demonstrated promising radioprotective efficacy in the mouse and nonhuman primate (NHP) models. We determined GT3-mediated hematopoietic recovery in total-body irradiated (TBI) NHPs. Sixteen rhesus macaques divided into two groups received either vehicle or GT3, 24 h prior to TBI. Four animals in each treatment group were exposed to either 4 or 5.8 Gy TBI. Flow cytometry was used to immunophenotype the bone marrow (BM) lymphoid cell populations, while clonogenic ability of hematopoietic stem cells (HSCs) was assessed by colony forming unit (CFU) assays on day 8 prior to irradiation and days 2, 7, 14, and 30 post-irradiation. Both radiation doses showed significant changes in the frequencies of B and T-cell subsets, including the self-renewable capacity of HSCs. Importantly, GT3 accelerated the recovery in CD34+ cells, increased HSC function as shown by improved recovery of CFU-granulocyte macrophages (CFU-GM) and burst-forming units erythroid (B-FUE), and aided the recovery of circulating neutrophils and platelets. These data elucidate the role of GT3 in hematopoietic recovery, which should be explored as a potential medical countermeasure to mitigate radiation-induced injury to the hematopoietic system.

Effects of Gamma-Tocotrienol on Partial-Body Irradiation-Induced Intestinal Injury in a Nonhuman Primate Model.

Exposure to high doses of radiation, accidental or therapeutic, often results in gastrointestinal (GI) injury. To date, there are no therapies available to mitigate GI injury after radiation exposure. Gamma-tocotrienol (GT3) is a promising radioprotector under investigation in nonhuman primates (NHP). We have shown that GT3 has radioprotective function in intestinal epithelial and crypt cells in NHPs exposed to 12 Gy total-body irradiation (TBI). Here, we determined GT3 potential in accelerating the GI recovery in partial-body irradiated (PBI) NHPs using X-rays, sparing 5% bone marrow. Sixteen rhesus macaques were treated with either vehicle or GT3 24 h prior to 12 Gy PBI. Structural injuries and crypt survival were examined in proximal jejunum on days 4 and 7. Plasma citrulline was assessed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Crypt cell proliferation and apoptotic cell death were evaluated using Ki-67 and TUNEL staining. PBI significantly decreased mucosal surface area and reduced villous height. Interestingly, GT3 increased crypt survival and enhanced stem cell proliferation at day 4; however, the effects seemed to be minimized by day 7. GT3 did not ameliorate a radiation-induced decrease in citrulline levels. These data suggest that X-rays induce severe intestinal injury post-PBI and that GT3 has minimal radioprotective effect in this novel model.

CST6 suppresses osteolytic bone disease in multiple myeloma by blocking osteoclast differentiation.

Osteolytic bone disease is a hallmark of multiple myeloma (MM). A significant fraction (~20%) of MM patients do not develop osteolytic lesions (OLs). The molecular basis for the absence of bone disease in MM is not understood. We combined PET-CT and gene expression profiling (GEP) of purified BM CD138+ MM cells from 512 newly diagnosed MM patients to reveal that elevated expression of cystatin M/E (CST6) was significantly associated with the absence of OL in MM. An enzyme-linked immunosorbent assay revealed a strong correlation between CST6 levels in BM serum/plasma and CST6 mRNA expression. Both recombinant CST6 protein and BM serum from patients with high CST6 significantly inhibited the activity of the osteoclast-specific protease cathepsin K and blocked osteoclast differentiation and function. Recombinant CST6 inhibited bone destruction in ex vivo and in vivo myeloma models. Single-cell RNA-Seq showed that CST6 attenuates polarization of monocytes to osteoclast precursors. Furthermore, CST6 protein blocks osteoclast differentiation by suppressing cathepsin-mediated cleavage of NF-κB/p100 and TRAF3 following RANKL stimulation. Secretion by MM cells of CST6, an inhibitor of osteoclast differentiation and function, suppresses osteolytic bone disease in MM and probably other diseases associated with osteoclast-mediated bone loss.

Effects of Gamma-Tocotrienol on Intestinal Injury in a GI-Specific Acute Radiation Syndrome Model in Nonhuman Primate.

The gastrointestinal (GI) system is highly susceptible to irradiation. Currently, there is no Food and Drug Administration (FDA)-approved medical countermeasures for GI radiation injury. The vitamin E analog gamma-tocotrienol (GT3) is a promising radioprotector in mice and nonhuman primates (NHP). We evaluated GT3-mediated GI recovery in total-body irradiated (TBI) NHPs. Sixteen rhesus macaques were divided into two groups; eight received vehicle and eight GT3 24 h prior to 12 Gy TBI. Proximal jejunum was assessed for structural injuries and crypt survival on day 4 and 7. Apoptotic cell death and crypt cell proliferation were assessed with TUNEL and Ki-67 immunostaining. Irradiation induced significant shortening of the villi and reduced mucosal surface area. GT3 induced an increase in crypt depth at day 7, suggesting that more stem cells survived and proliferated after irradiation. GT3 did not influence crypt survival after irradiation. GT3 treatment caused a significant decline in TUNEL-positive cells at both day 4 (p < 0.03) and 7 (p < 0.0003). Importantly, GT3 induced a significant increase in Ki-67-positive cells at day 7 (p < 0.05). These data suggest that GT3 has radioprotective function in intestinal epithelial and crypt cells. GT3 should be further explored as a prophylactic medical countermeasure for radiation-induced GI injury.

Comparative Study of Subgaleal and Subdural Closed Drain in Surgically Treated Cases of Chronic Subdural Hematoma.

BACKGROUND: Chronic subdural hematoma (CSDH) is seen most common in geriatric patients, and trauma is the most important reason for CSDH. Operative treatment of CSDH in symptomatic patients is yet the gold standard of therapy because it allows decompression of the subdural space and aids improvement in neurological status. Burr-hole craniostomy is the most common accepted treatment for CSDH. There is still controversy regarding which type of drain placement is best in the outcome: subdural or subgaleal drain. AIM: The aim of the study was to compare the outcome of subgaleal versus subdural drain in surgically treated patients of CSDH. MATERIALS AND METHODS: Patients were assigned by simple random sampling in two groups. The study was conducted from February 2016 to July 2017. A total of 70 patients were enrolled into the study and were divided in two groups (Group 1 - Subgaleal drain; Group 2 - Subdural drain). Statistical analysis was done using Chi-square and t-test. Outcome was assessed at the end of hospital stay by modified Rankin scale. Postoperative computed tomography scan was done after 24 h of surgery. RESULTS: This study concluded that both types of drains are equally effective for the treatment of CSDH. There is a statistically significant difference in the occurrence of seizure in both the groups as there was no seizure in subgaleal drain group compared to 5 (14.3%) patients who had seizures postoperatively in subdural drain group (P = 0.020). There was insignificant difference with respect to preoperative Glasgow Coma Scale/sex/preoperative hematoma volume/postoperative hematoma volume/preoperative midline shift. CONCLUSION: Subgaleal drain is safe and technically easy, as subgaleal drain has no direct contact with brain parenchyma, thus less chances of brain laceration, intracerebral hematoma formation, and seizures.

Current Trends in Self-Emulsifying Drug Delivery Systems (SEDDSs) to Enhance the Bioavailability of Poorly Water-Soluble Drugs.

The main object of the self-emulsifying drug-delivery system (SEDDS) is oral bioavailability (BA) enhancement of a poorly water-soluble drug. Low aqueous solubility and low oral BA are major concerns for formulation scientists. As many drugs are lipophilic in nature, their lower solubility and dissolution are major drawbacks for their successful formulation into oral dosage forms. More than 60% of drugs have a lipophilic nature and exhibit poor aqueous solubility. Various strategies are reported in the literature to improve the solubility and enhance BA of lipophilic drugs, including the formation of a cyclodextrin complex, solid dispersions, and micronization. SEDDSs are ideally isotropic mixtures of drug, oil, surfactant, and/or cosurfactant. SEDDSs have gained increasing attention for enhancing oral BA and reducing drug dose. SEDDSs also provide an effective and excellent solution to the various issues related to the formulation of hydrophobic drugs that have limited solubility in gastrointestinal fluid. Our major focus of this review is to highlight the importance of SEDDSs in oral BA enhancement of poorly water-soluble drugs.

Chemotherapeutic Evaluation of Guar Gum Coated Chitosan Nanoparticle Against Experimental Tuberculosis.

The major goal of the current research was to develop and evaluate the therapeutic potential of anti-tubercular drugs (ATDs) loaded natural polysaccharide comprising of galacto mannan subunit in experimental tuberculosis (TB). Experimental formulations were prepared by ionotropic gelation technique followed by spray drying. Morphological analysis suggested that optimized nanoparticles were found to be discrete and spherical in nature with a particle size distribution range from 230 ± 4.5 nm to 310 ± 6.2 nm. The in-vitro drug release behavior indicated the biphasic pattern comprising of initial burst followed by a sustained release pattern. Guar gum coated chitosan nanoparticles (CGNPs) among the leading formulation exhibited the highest cell uptake potential confirmed by FACS analysis. Challenge study also supports the in-vivo bio-distribution illustrated by the significant reduction in CFU count in experimental TB in mice. Histopathology study demonstrated that none of the treated group shows any evidence of lung tissue abnormality. Hence, the study marked the fact that CGNPs could be a promising carrier for selective delivery of ATDs to alveolar macrophages for efficient management of TB with the interception of minimal side effects.

Development of transferosomal gel for trans-dermal delivery of insulin using iodine complex.

The main object of this current research was to examine transferosomes as a transdermal delivery system for insulin, to overwhelm the difficulties related with its subcutaneous delivery. Transferosomal gel formulations were prepared by rotary evaporation sonication technique. The result revealed that insulin was successfully entrapped (78%) in optimized formulations (2.5 I.U. of the drug and 25% of sodium cholate) with cumulative percent drug release (83.11 ± 3.782). The glucose lowering study revealed that the transferosomal gel with chemical penetration enhancer showed better glucose lowering effect as compared to the control gel. Consequently, this study authenticated that the transferosomal gel can be used as a possible substitute to the conventional formulations of insulin with progressive permeation characteristics for transdermal application.

Advances in nanotechnology-based carrier systems for targeted delivery of bioactive drug molecules with special emphasis on immunotherapy in drug resistant tuberculosis - a critical review.

From the early sixteenth and seventeenth centuries to the present day of life, tuberculosis (TB) still is a global health threat with some new emergence of resistance. This type of emergence poses a vital challenge to control TB cases across the world. Mortality and morbidity rates are high due to this new face of TB. The newer nanotechnology-based drug-delivery approaches involving micro-metric and nano-metric carriers are much needed at this stage. These delivery systems would provide more advantages over conventional systems of treatment by producing enhanced therapeutic efficacy, uniform distribution of drug molecule to the target site, sustained and controlled release of drug molecules and lesser side effects. The main aim to develop these novel drug-delivery systems is to improve the patient compliance and reduce therapy time. This article reviews and elaborates the new concepts and drug-delivery approaches for the treatment of TB involving solid-lipid particulate drug-delivery systems (solid-lipid micro- and nanoparticles, nanostructured lipid carriers), vesicular drug-delivery systems (liposomes, niosomes and liposphere), emulsion-based drug-delivery systems (micro and nanoemulsion) and some other novel drug-delivery systems for the effective treatment of tuberculosis and role of immunomodulators as an adjuvant therapy for management of MDR-TB and XDR-TB.

Development, optimization, and characterization of polymeric electrospun nanofiber: a new attempt in sublingual delivery of nicorandil for the management of angina pectoris.

The objective of the current investigation was to develop a novel biocomposite polymeric nanofiber for sublingual delivery of nicorandil in an attempt to reduce mucosal ulceration and to improve drug bioavailability. Polymeric nanofibers were achieved using vitamin B12 and a blend of hyaluronic acid and polyvinyl alcohol as polymeric constituents. The electrospinning method was used to prepare drug (nicorandil)-loaded nanofibers. The resulting nanofibers were characterized for morphology, drug loading, XRD, DSC, in vitro drug release, degree of swelling, and pharmacokinetic behavior. The prepared nanofibers were found to be uniform, non-beaded, and non-woven, with fiber diameter ranging from 200-450 nm. In vitro drug release substantiated the controlled release behavior of the developed formulation. Histopathology studies demonstrated no evidence of mucosal ulceration at the site of application. Pharmacokinetic studies established the preclinical safety and showed the maintenance of an effective therapeutic level for a prolonged period. The present investigation gives inputs showing that the biocomposite nanofiber assists as a perfect carrier system for sublingual delivery of anti-anginal drugs.

Collagen nanofiber containing silver nanoparticles for improved wound-healing applications.

Electrospun nanofibers showing great promise for fabricating nanostructured materials might help to improve the quality of wound care. The present study aimed to investigate the wound-healing potential of collagen nanofiber mats containing silver nanoparticles. Silver nanoparticles (AgNPs) synthesized by the chemical reduction method were incorporated in collagen nanofibers during the electrospinning process. Characterization of electrospun nanofiber mats revealed a mean fiber diameters in the range of 300-700 nm with a sustained release of silver ions shown to follow pseudo-order kinetics. MIC of AgNPs against Staphylococcus aureus and Pseudomonas aeruginosa were evaluated using micro-dilution assay and further antimicrobial activity of fabricated nanofibers was performed. Finally, in vivo studies were performed to demonstrate the wound-healing efficacy of composite nanofibers. In vitro results confirmed the potential antimicrobial efficacy provided by AgNPs and AgNPs composite nanofibers, essential to provide an aseptic environment at the wound site. In vivo study revealed that the rate of wound healing of the composite nanofiber mats was found to be accelerated compared with plain collagen nanofibers. Histology analysis revealed an accelerated re-epithelization, collagen production, and better wound contraction with AgNPs composite collagen nanofibers.

Development and characterization of cefazolin loaded zinc oxide nanoparticles composite gelatin nanofiber mats for postoperative surgical wounds.

Systemic antibiotic therapy in post-operative wound care remain controversial leading to escalation in levels of multi-resistant bacteria with unwanted morbidity and mortality. Recently zinc (Zn) because of multiple biophysiological functions, gain considerable interest for wound care. Based on our current understanding, the present study was designed with an intent to produce improve therapeutic approaches for post-operative wound management using composite multi-functional antibiotic carrier. The study involved the fabrication, characterization and pre-clinical evaluation of cefazolin nanofiber mats loaded with zinc oxide (ZnO) and comparing co-formulated mats with individual component, enable a side by side comparison of the benefits of our intervention. Minimum inhibitory concentration (MIC) of the drug, ZnO nanoparticles (ZnONPs) and drug-ZnONP mixture against Staphylococcus aureus was determined using micro dilution assay. The fabricated nanofibers were then evaluated for in-vitro antimicrobial activity and the mechanism of inhibition was predicted by scanning electron microscopy (SEM). Further these nanofiber mats were evaluated in-vivo for wound healing efficacy in Wistar rats. Study revealed that the average diameter of the nanofibers is around 200-900 nm with high entrapment efficiency and display sustained drug release behavior. The combination of ZnO and cefazolin in 1:1 weight ratio showed higher anti-bacterial activity of 1.9 ± 0.2 µg/ml. Transmission electron microscopy of bacterial cells taken from the zone of inhibition revealed the phenomenon of cell lysis in tested combination related to cell wall disruption. Further composite medicated nanofiber mats showed an accelerated wound healing as compared to plain cefazolin and ZnONP loaded mats. Macroscopical and histological evaluations demonstrated that ZnONP hybrid cefazolin nanofiber showed enhanced cell adhesion, epithelial migration, leading to faster and more efficient collagen synthesis. Hence the fabricated composite nanofiber mats have the potential to be used as a postoperative antimicrobial wound dressings.

Fabrication and characterization of cefazolin-loaded nanofibrous mats for the recovery of post-surgical wound.

The aim of the present study was to evaluate the wound healing performance of cefazolin-loaded gelatin nanofiber mats in post-operative wound. The obtained nanofibers were smooth, non-beaded and having diameter ranging from 620-680 nm. Nanofiber mats that are prepared exhibit high drug entrapment, excellent oxygen permeability and sustained drug release behavior. Further, medicated nanofiber mats showed an accelerated wound healing as compared to plain cefazolin. Macroscopical and histological evaluations demonstrated that cefazolin-loaded gelatin nanofiber showed increased epithelialization rate and collagen deposition. The results indicated that therapeutic strategies offer new prospects in the management of post-operative wound repair.

Spray-dried particles as pulmonary delivery system of anti-tubercular drugs: design, optimization, in vitro and in vivo evaluation.

Currently, one-third of the world's population is infected with tuberculosis (TB) mainly spread by inhalation of the tubercle bacilli, Mycobacterium tuberculosis. Patient non-compliance is the major reason for failure of anti-tubercular drugs (ATDs) chemotherapy due to multidrug administration for longer duration of time period. The main aim of current research study was to develop and characterize inhalable spray-dried particles for pulmonary delivery of ATDs, i.e., rifampicin (RIF) and isoniazid (INH). ATDs-loaded alginate particles were prepared by ionotropic gelation technique followed by spray drying and characterized on the basis of various evaluation parameters. Results showed that the optimized spray-dried particles were found to be spherical in shape with excellent flow properties. The drug release showed the biphasic pattern of release, i.e., initial burst (30-40% up to 4 h) followed by a sustained release pattern (90% up to 60 h). Optimized formulations exhibited lower cytotoxicity and excellent lung uptake up to 8 h. Optimized formulation also showed higher rate and extent of drug uptake by lungs due to preferential phagocytosis be macrophage. In future, alginate particles could be a promising carrier for targeted delivery of ATDs to alveolar macrophages for efficient management of TB.

Development and evaluation of a sublingual film of the antiemetic granisetron hydrochloride.

The objective of this study was to develop an oral transmucosal formulation of an antiemetic drug that can not only serve in the active form but also provide a controlled release profile. In this study, sublingual films based on the biodegradable and water-soluble polymers, that is HPMCK-4M and PVPK-30, were developed by the solvent casting method, and were loaded with the antiemetic drug granisetron hydrochloride (granisetron HCl). The entrapment efficiency of the developed formulation was found to be 86%. The in vitro profile showed an instant release of the drug from the sublingual film, in a pattern following the first order kinetics array. The in vivo studies showed that granisetron HCl was delivered in its active state and showed effective results, as compared to its activity in the marketed formulation.

Recent advancements in the cardiovascular drug carriers.

Cardiovascular disease is the disease that affects the cardiovascular system, vascular diseases of the brain and kidney, and peripheral arterial disease. Despite of all advances in pharmacological and clinical treatment, heart failure is a leading cause of morbidness and mortality worldwide. Many new therapeutic advance strategies, including cell transplantation, gene delivery or therapy, and cytokines or other small molecules, have been research to treat heart failure. The main aim of this review article is to focus on nano carriers advancement and addressing the problems associated with old and modern therapeutics such as nonspecific effects and poor stability.

Nanogel--an advanced drug delivery tool: Current and future.

Nanogels are robust nanoparticles that could be used to deliver active drug compounds in controlled drug delivery applications. Nanogels drug delivery system is more effective and safer for both hydrophilic and hydrophobic drugs due to their chemical composition and formulations that are inappropriate for other formulations. Nanogels have enabled enlargement of functionalized nanoparticles, which act as a drug carriers that can be loaded with drugs and other active material to be released in a controlled manner at specific site. This review aims at providing general introduction on nanogels, recent synthesis methodology and their novel application in different fields.

Herbal and polymeric approaches for liver-targeting drug delivery: novel strategies and their significance.

The liver is a vital organ present in vertebrates, which performs many functions including detoxification, protein synthesis and production of various bio-chemicals which are very important for digestion. A large number of serious liver disorders affect millions of people worldwide which are very difficult to treat properly despite many efforts. There are several factors which are responsible for liver injuries, include plants (Crotalaria Senecio Heliotropium Symphytum officinale), drugs (analgesic and antibiotics), industrial toxins (mercury and lead), water, alcohol and so on. Herbal medicinal preparations can be used for the treatment of a large number of human liver disorders like cirrhosis, hepatitis, carcinomas, etc. Indian Medicinal Practitioner's Co-operative pharmacy and Stores (IMPCPS) approved herbal-based systems (Unani, Siddha and Ayurveda) for the treatment of various chronic liver disorders. Different types of the receptors are found on the surface of hepatocytes, Kupffer cell, hepatic stellate cell and sinusoidal endothelial cells, etc., which can be used for achieving liver targeting. These receptors bind to different types of ligands (galactosylated, lactobionic acid, asialofetuin, etc.) which can be used in the formulation to achieve targeted delivery of the drug. Various novel particulate approaches (liposomes, niosomes, nanoparticles, micelles, nanosuspensions, etc.) can be used to enhance the targeting efficiency of systems to receptors found on the surface of different cells present in the liver. In this review, we focused on the status of liver targeting via herbal and nanotechnology inspired formulation approaches.