Antibody Conjugated Nano-Enabled Drug Delivery Systems Against Brain Tumors.

The use of antibody-conjugated nanoparticles for brain tumor treatment has gained significant attention in recent years. Nanoparticles functionalized with anti-transferrin receptor antibodies have shown promising results in facilitating nanoparticle uptake by endothelial cells of brain capillaries and post-capillary venules. This approach offers a potential alternative to the direct conjugation of biologics to antibodies. Furthermore, studies have demonstrated the potential of antibody-conjugated nanoparticles in targeting brain tumors, as evidenced by the specific binding of these nanoparticles to brain cancer cells. Additionally, the development of targeted nanoparticles designed to transcytoses the blood-brain barrier (BBB) to deliver small molecule drugs and therapeutic antibodies to brain metastases holds promise for brain tumor treatment. While the use of nanoparticles as a delivery method for brain cancer treatment has faced challenges, including the successful delivery of nanoparticles to malignant brain tumors due to the presence of the BBB and infiltrating cancer cells in the normal brain, recent advancements in nanoparticle-mediated drug delivery systems have shown potential for enhancing the efficacy of brain cancer therapy. Moreover, the development of brain-penetrating nanoparticles capable of distributing over clinically relevant volumes when administered via convection-enhanced delivery presents a promising strategy for improving drug delivery to brain tumors. In conclusion, the use of antibody-conjugated nanoparticles for brain tumor treatment shows great promise in overcoming the challenges associated with drug delivery to the brain. By leveraging the specific targeting capabilities of these nanoparticles, researchers are making significant strides in developing effective and targeted therapies for brain tumors.

Celecoxib Nanoformulations with Enhanced Solubility, Dissolution Rate, and Oral Bioavailability: Experimental Approaches over In Vitro/In Vivo Evaluation.

Celecoxib (CXB) is a Biopharmaceutical Classification System (BCS) Class II molecule with high permeability that is practically insoluble in water. Because of the poor water solubility, there is a wide range of absorption and limited bioavailability following oral administration. These unfavorable properties can be improved using dry co-milling technology, which is an industrial applicable technology. The purpose of this study was to develop and optimize CXB nanoformulations prepared by dry co-milling technology, with a quality by design approach to maintain enhanced solubility, dissolution rate, and oral bioavailability. The resulting co-milled CXB composition using povidone (PVP), mannitol (MAN) and sodium lauryl sulfate (SLS) showed the maximum solubility and dissolution rate in physiologically relevant media. Potential risk factors were determined with an Ishikawa diagram, important risk factors were selected with Plackett-Burman experimental design, and CXB compositions were optimized with Central Composite design (CCD) and Bayesian optimization (BO). Physical characterization, intrinsic dissolution rate, solubility, and stability experiments were used to evaluate the optimized co-milled CXB compositions. Dissolution and permeability studies were carried out for the resulting CXB nanoformulation. Oral pharmacokinetic studies of the CXB nanoformulation and reference product were performed in rats. The results of in vitro and in vivo studies show that the CXB nanoformulations have enhanced solubility (over 4.8-fold (8.6 ± 1.06 µg/mL vs. 1.8 ± 0.33 µg/mL) in water when compared with celecoxib pure powder), and dissolution rate (at least 85% of celecoxib is dissolved in 20 min), and improved oral pharmacokinetic profile (the relative bioavailability was 145.2%, compared to that of Celebrex®, and faster tmax 3.80 ± 2.28 h vs. 6.00 ± 3.67 h, indicating a more rapid absorption rate).

Current status of micro/nanomotors in drug delivery.

Synthetic micro/nanomotors (MNMs) are novel, self-propelled nano or microscale devices that are widely used in drug transport, cell stimulation and isolation, bio-imaging, diagnostic and monitoring, sensing, photocatalysis and environmental remediation. Various preparation methods and propulsion mechanisms make MNMs "tailormade" nanosystems for the intended purpose or use. As the one of the newest members of nano carriers, MNMs open a new perspective especially for rapid drug transport and gene delivery. Although there exists limited number of in-vivo studies for drug delivery purposes, existence of in-vitro supportive data strongly encourages researchers to move on in this field and benefit from the manoeuvre capability of these novel systems. In this article, we reviewed the preparation and propulsion mechanisms of nanomotors in various fields with special attention to drug delivery systems.

Assessment of Dose Proportionality of Rivaroxaban Nanocrystals.

Rivaroxaban (RXB) is a class II drug, according to the Biopharmaceutics Classification System. Since its bioavailability is low at high doses, dose proportionality is not achieved for pharmacokinetic parameters. However, when taken with food, its bioavailability increases at high doses. In this study, nanocrystal technology was used to increase the solubility and, hence, the bioavailability of RXB. Pluronic F127, pharmacoat 603, and PVP K-30 were used as stabilizers to prepare RXB nanosuspension, combining ball mill and high pressure homogenization methods. Particle sizes of RXB in nanosuspension (formulation A:348 nm; formulation B:403 nm) and nanocrystal formulations (formulation A:1167 nm; formulation B:606 nm) were significantly reduced (p < 0.05) compared to those of bulk RXB. In both formulations, 80% of the drug dissolved in 30 min. For dose proportionality evaluation, 3, 10, and 15 mg/kg of RXB nanosuspensions (formulation B) were administered to rabbits. The dose proportionality for AUC and Cmax of RXB nanocrystals was assessed by the power model, variance analysis of pharmacokinetic parameters, linear regression, and equivalence criterion methods. Dose proportionality for AUC was achieved at doses between 10-15 and 3-15 mg/kg. In conclusion, the preparation of a nanocrystal formulation of RXB improved its dissolution rate and pharmacokinetic profile.

Neuroprotective Efficiency of Cyclosporine After Traumatic Brain Injury in Rats.

AIM: To evaluate the possible neuroprotective effects of systemic administration of cyclosporine (Cyclosporin A) after traumatic brain injury in rats. MATERIAL AND METHODS: The modified Feeney method was used as the trauma model in male Sprague Dawley rats. After the trauma, 20 mg/kg of cyclosporine was administered to the one group of the rats (n=12) intraperitoneally. Twenty-four hours after injury, the subjects were sacrificed, and brain samples were removed. The level of brain edema was evaluated through the wet-dry weight method, the lipid peroxidation ratio, and histological examination by transmission electron microscopy. RESULTS: The level of brain edema and lipid peroxidation ratio significantly decreased in the rats that received cyclosporine. Ultrastructural neurodestruction was graded, and a comparison of the scores between the experimental groups revealed significant neuroprotective effects of cyclosporine. CONCLUSION: The results demonstrated that systemic administration of cyclosporine produces a statistically significant decrease in both the level of brain edema and lipid peroxidation ratio when compared with "no treatment". Cyclosporine, which is regularly used as an immunosuppressant agent, is also known to prevent opening of the mitochondrial permeability transition pore by unbinding mitochondrial matrix cyclophilin. Regulation of transition pore for mitochondrial permeability by cyclosporine implies that mitochondrial dysfunction following traumatic brain injury is an important event in the progressive loss of neuronal tissue.

Composite nanofibers incorporating alpha lipoic acid and atorvastatin provide neuroprotection after peripheral nerve injury in rats.

Despite the new treatment strategies within the last 30 years, peripheral nerve injury (PNI) is still a worldwide clinical problem. The incidence rate of PNIs is 1 in 1000 individuals per year. In this study, we designed a composite nanoplatform for dual therapy in peripheral nerve injury and investigated the in-vivo efficacy in rat sciatic nerve crush injury model. Alpha-lipoic acid (ALA) was loaded into poly lactic-co-glycolic acid (PLGA) electrospun nanofibers which would release the drug in a faster manner and atorvastatin (ATR) loaded chitosan (CH) nanoparticles were embedded into PLGA nanofibers to provide sustained release. Sciatic nerve crush was generated via Yasargil aneurism clip with a holding force of 50 g/cm2. Nanofiber formulations were administered to the injured nerve immediately after trauma. Functional recovery of operated rat hind limb was evaluated using the sciatic functional index (SFI), extensor postural thrust (EPT), withdrawal reflex latency (WRL) and Basso, Beattie, and Bresnahan (BBB) test up to one month in the post-operative period at different time intervals. In addition to functional recovery assessments, ultrastructural and biochemical analyses were carried out on regenerated nerve fibers. L-929 mouse fibroblast cell line and B35 neuroblastoma cell line were used to investigate the cytotoxicity of nanofibers before in-vivo experiments. The neuroprotection potential of these novel nanocomposite fiber formulations has been demonstrated after local implantation of composite nanofiber sheets incorporating ALA and ATR, which contributed to the recovery of the motor and sensory function and nerve regeneration in a rat sciatic nerve crush injury model.

Development and characterization of metformin hydrochloride- and glyburide-containing orally disintegrating tablets.

Diabetes is characterized by chronic hyperglycemia. Although metformin hydrochloride (MHCl)- and glyburide (GLB)-containing conventional tablets are available in the market and used to treat diabetes, orally disintegrating tablets (ODTs) containing the combination of these drugs are not commercially available. Therefore, the aim of this study was to prepare ODTs containing MHCl and GLB by direct-compression (DC-ODTs) and freeze-drying (FD-ODTs) methods. Physical properties of the powder mixture of DC-ODT formulation were determined (Angle of repose: 37.18 ± 1.27°; compressibility index: 20.31 ± 1.06%; Hausner ratio: 1.25 ± 0.03). Its moisture content was 0.3 ± 0.09%. The hardness values and the disintegration times for DC-ODTs and FD-ODTs were 221.60 ± 40.82 and 66.54 ± 2.68 N, and 80 and 30 s, respectively. Friability values were 0.24% for DC-ODTs and 0.38% for FD-ODTs. In uniformity-of-mass for single-dose-preparations test, the average weight was 684.38 ± 1.97 mg for DC-ODTs and 342.93 ± 2.4 mg for FD-ODTs, with less than 5% deviation for all 20 tablets. Water-absorption ratio for DC-ODTs was 1.30 ± 0.05. More than 90% of MHCl and GLB were dissolved within 5 min in both DC-ODTs and FD-ODTs. Although Caco-2 permeability of MHCl was influenced by the ODTs, GLB permeability was not. These results indicated that MHCl- and GLB-containing ODTs may be used as promising formulations for the treatment of diabetes.

Development and validation of an HPLC method for determination of rofecoxib in bovine serum albumin microspheres.

A simple and reliable HPLC method was developed and validated for determination of rofecoxib in bovine serum albumin microsphere. The analyses were performed on a C18 column (150 x 4.6 mm, 5 µm particle size) at room temperature with UV detection at 272 nm. The mobile phase was composed of acetonitrile-0.1% o-phosphoric acid solution in water (1:1, v/v) mixture, and flow rate was set to 1 mL/min. The method was validated according to the international guidelines with respect to stability, linearity range, limit of quantitation and detection, precision, accuracy, specificity, and robustness. The detection and quantification limit of the method were 1.0 µg/mL and 2.5 µg/mL, respectively. The method was linear in the range of 2.5-25 µg/mL with excellent determination coefficients (R2 >0.99). Intra-day and inter-day precision (<1.76% RSD) and accuracy (<0.55 % Bias) values of the method also fulfilled the required limits. It was concluded that the developed method was accurate, sensitive, precise, and reproducible according to the evaluation of the validation parameters. The applicability of the method was confirmed for in vitro quantification of rofecoxib in bovine serum albumin microspheres.

A Snapshot on the Current Status of Alzheimer's Disease, Treatment Perspectives, in-Vitro and in-Vivo Research Studies and Future Opportunities.

Alzheimer's Disease (AD) is one of the most challenging diseases faced by humankind. AD is still not classified as curable because of the complex structure of pathologies underlying it. As the mean life expectancy of the world population constantly increases, the prevalence of AD and treatment costs for AD also grow rapidly. Current state of the art for AD treatment mainly consists of palliative therapy aimed at providing symptomatic relief and improving the standard of living in patients with AD. However, different research groups are working on more effective and safe drug delivery options aimed at both symptomatic relief and treatment of the underlying mechanisms. In this review, the current prevalence of AD, health costs, pathologies, and available treatment options including the ones in the market and/or under trial have been reviewed. Data in the existing literature have been presented, and future opportunities have been discussed. It is our belief that these nanotechnological products provide the required efficacy and safety profiles to enable these formulations go through phase studies and enter the market after regulatory authority approval, as with cancer. Last, but not the least the metabolomic studies will be providing useful informative data on the early diagnosis of AD, thus may be clinical implications might be delayed with the administration of therapeutic agents at the initial state of the disease.

Cyber-physical-based PAT (CPbPAT) framework for Pharma 4.0.

Industry 4.0 aims to integrate manufacturing operations into a seamless digital whole by incorporating flexibility, agility, re-configurability, and sustainability. The result of this integration is a "smart factory" that is more lean, agile, and flexible in operations. There are valid reasons, and perhaps requirements, for pharmaceutical industries to embrace smart factory and to "borrow" the concept of Industry 4.0 to give rise to "Pharma 4.0" (i.e., the pharmaceutical version of Industry 4.0). This paper proposes a cyber-physical-based PAT framework called CPbPAT for implementing smart manufacturing systems in the pharmaceutical industry. The framework has been developed using an agent-based system and is presented by a standard system modeling language called the Unified Modeling Language (UML). The pharmaceutical manufacturing system shown in "Quality by Design for ANDAs" is used as a case study to illustrate the application of the proposed framework.

Dry powders for the inhalation of ciprofloxacin or levofloxacin combined with a mucolytic agent for cystic fibrosis patients.

OBJECTIVE: This study aimed to design and characterize an inhalable dry powder of ciprofloxacin or levofloxacin combined with the mucolytics acetylcysteine and dornase alfa for the management of pulmonary infections in patients with cystic fibrosis. METHODS: Ball milling, homogenization in isopropyl alcohol and spray drying processes were used to prepare dry powders for inhalation. Physico-chemical characteristics of the dry powders were assessed via thermogravimetric analysis, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), X-ray diffractometry and scanning electron microscopy. The particle size distribution, dissolution rate and permeability across Calu-3 cell monolayers were analyzed. The aerodynamic parameters of dry powders were determined using the Andersen cascade impactor (ACI). RESULTS: After the micronization process, the particle sizes of the raw materials significantly decreased. X-ray and DSC results indicated that although ciprofloxacin showed no changes in its crystal structure, the structure of levofloxacin became amorphous after the micronization process. FT-IR spectra exhibited the characteristic peaks for ciprofloxacin and levofloxacin in all formulations. The dissolution rates of micro-homogenized and spray-dried ciprofloxacin were higher than that of untreated ciprofloxacin. ACI results showed that all formulations had a mass median aerodynamic diameter less than 5 µm; however, levofloxacin microparticles showed higher respirability than ciprofloxacin powders did. The permeability of levofloxacin was higher than those of the ciprofloxacin formulations. CONCLUSION: Together, our study showed that these methods could suitably characterize antibiotic and mucolytic-containing dry powder inhalers.

Localized delivery of methylprednisolone sodium succinate with polymeric nanoparticles in experimental injured spinal cord model.

With important social and economic consequences, spinal cord injuries (SCIs) still exist among major health problems. Although many therapeutic agents and methods investigated for the treatment of acute SCI, only high dose methylprednisolone (MP) is being used currently in practice. Due to the serious side effects, high dose systemic MP administration after SCI is a critical issue that is mostly considered controversial. In our study, it is aimed to develop a nanoparticle-gel combined drug delivery system for localization of MP on trauma site and eliminating dose-dependent side effects by lowering the administered dose. For this purpose, methyl prednisolone sodium succinate (MPSS) loaded polycaprolactone based nanoparticles were developed and embedded in an implantable fibrin gel. The effects of MPSS delivery system are evaluated on an acute SCI rat model, by quantification the levels of three inflammatory cytokines (interleukin-1ß, interleukin-6 and caspase-3) and assessment of the damage on ultrastructural level by transmission electron microscopy. Developed NP-gel system showed very similar results with systemic high dose of MPSS. It is believed that developed system may be used as a tool for the safe and effective localized delivery of several other therapeutic molecules on injured spinal cord cases.

Design and optimization of novel paclitaxel-loaded folate-conjugated amphiphilic cyclodextrin nanoparticles.

As nanomedicines are gaining momentum in the therapy of cancer, new biomaterials emerge as alternative platforms for the delivery of anticancer drugs with bioavailability problems. In this study, two novel amphiphilic cyclodextrins (FCD-1 and FCD-2) conjugated with folate group to enable active targeting to folate positive breast tumors were introduced. The objective of this study was to develop and characterize new folated-CD nanoparticles via 3(2) factorial design for optimal final parameters. Full physicochemical characterization studies were performed. Blank and paclitaxel loaded FCD-1 and FCD-2 nanoparticles remained within the range of 70-275nm and 125-185nm, respectively. Zeta potential values were neutral and -20mV for FCD-1 and FCD-2 nanoparticles, respectively. Drug release studies showed initial burst release followed by a longer sustained release. Blank nanoparticles had no cytotoxicity against L929 cells. T-47D and ZR-75-1 human breast cancer cells with different levels of folate receptor expression were used to assess anti-cancer efficacy. Through targeting the folate receptor, these nanoparticles were efficiently engulfed by the breast cancer cells. Additionally, breast cancer cells became more sensitive to cytotoxic and/or cytostatic effects of PCX delivered by FCD-1 and FCD-2. In conclusion, these novel folate-conjugated cyclodextrin nanoparticles can therefore be considered as promising alternative systems for safe and effective delivery of paclitaxel with a folate-dependent mechanism.

Preparation and characterization of nimesulide containing nanocrystal formulations.

The aim of this study was to develop and characterize nanocrystal formulation containing nimesulide. Physical mixture of drug and excipient (nimesulide:pluronic F127, 1:0.5) was also prepared to compare the efficiency of formulations. The physicochemical characteristics of the formulations were determined by means of Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), and X-ray diffractometry. Particle size, saturation solubilities as a function of pH, and permeability across Caco-2 monolayers were determined for nimesulide in powder, physical mixture, and nanocrystal formulations. In FT-IR analysis, the characteristic peaks that belong to nimesulide were seen in all formulations. X-ray diffractograms displayed that crystalline structure of nimesulide was conserved in the nanocrystal formulation. The interaction between nimesulide and pluronic F127 was demonstrated by DSC analysis. In all conditions, the average particle size of the nanocrystal formulations decreased significantly (p < 0.05) as compared with nimesulide and physical mixture. The solubility of nimesulide in nanocrystal formulation was higher than those of nimesulide in powder and physical mixture. Permeability studies revealed that nimesulide is a highly permeable compound whether in powder form or in physical mixture and nanocrystal formulation. All these results clearly demonstrate that aqueous solubility of poorly water-soluble compounds can be improved by preparing nanocrystal formulations.

Systematic development of pH-independent controlled release tablets of carvedilol using central composite design and artificial neural networks.

The purpose of this study was to apply the optimization method incorporating artificial neural network (ANN) using pH-independent release of weakly basic drug, carvedilol from HPMC-based matrix formulation. Because of weakly basic nature of carvedilol, drug shows pH-dependent solubility. The enteric polymer EUDRAGIT L100 was added formulations to overcome pH-dependent solubility of carvedilol. Effects of the Hydroxypropylmethyl cellulose (HPMC) K4M and EUDRAGIT L100 amount on drug release were investigated. For this purpose 13 kinds of formulations were prepared at three different levels of each variables. The optimization of the formulation was evaluated by using ANN method. Two formulation parameters, the amounts of HPMC K4M and Eudragit L100 at three levels (-1, 0, 1) were selected as independent/input variables. In-vitro dissolution sampling times at twelve different time points were selected as dependent/output variables. By using experimental dissolution results and amount of HPMC K4M and EUDRAGIT L100, percentage of dissolved carvedilol was predicted by ANN. Similarity factor (f2) between predicted and experimentally observed profile was calculated and f2 value was found 76.33. This value showed that there was no difference between predicted and experimentally observed drug release profile. As a result of these experiments, it was found that ANNs can be successfully used to optimize controlled release drug delivery systems.

Preparation and in vitro/in vivo evaluation of microparticle formulations containing meloxicam.

In this study, we have formulated chitosan-coated sodium alginate microparticles containing meloxicam (MLX) and aimed to investigate the correlation between in vitro release and in vivo absorbed percentages of meloxicam. The microparticle formulations were prepared by orifice ionic gelation method with two different sodium alginate concentrations, as 1% and 2% (w/v), in order to provide different release rates. Additionally, an oral solution containing 15 mg of meloxicam was administered as the reference solution for evaluation of in vitro/in vivo correlation (ivivc). Following in vitro characterization, plasma levels of MLX and pharmacokinetic parameters [elimination half-life (t(1/2)), maximum plasma concentration (C(max)), time for C(max) (t(max))] after oral administration to New Zealand rabbits were determined. Area under plasma concentration-time curve (AUC(0-∞)) was calculated by using trapezoidal method. A linear regression was investigated between released% (in vitro) and absorbed% (in vivo) with a model-independent deconvolution approach. As a result, increase in sodium alginate content lengthened in vitro release time and in vivo t(max) value. In addition, for ivivc, linear regression equations with r(2) values of 0.8563 and 0.9402 were obtained for microparticles containing 1% and 2% (w/v) sodium alginate, respectively. Lower prediction error for 2% sodium alginate formulations (7.419 ± 4.068) compared to 1% sodium alginate formulations (9.458 ± 5.106) indicated a more precise ivivc for 2% sodium alginate formulation.

Design and characterization of nanocrystal formulations containing ezetimibe.

Ezetimibe is a lipid-lowering compound that selectively inhibits the absorption of cholesterol and related phytosterols from the intestine. As ezetimibe is almost insoluble in water, its bioavailability is too low to be detected. Thus, the objective of this study was to improve the solubility and dissolution rate of ezetimibe by preparing drug nanocrystals utilizing ball milling, high speed homogenization techniques. Pluronic F127 was chosen as a surface modifier to stabilize the nanocrystal formulations. Nanocrystal formulations of ezetimibe were prepared by using ball milling and high speed homogenization techniques. Additionally, the physicochemical characteristics of ezetimibe and nanocrystal formulations were determined by Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), X-ray analysis and particle size analysis. Tablets were prepared containing ezetimibe nanocrystals formed by high speed homogenization (ultrasonic) and ball milling according to the results of particle size measurements and in vitro dissolution rates of the nanocrystal formulations. As a result of these experiments, it was found that the dissolution rate of the nanocrystal formulations increased and although tablet formulations which did not contain any solubilizing agent like sodium lauryl sulfate (SDS), the dissolution profile of these formulations were found similar to the commercial product.

A quadruped study on chitosan microspheres containing atorvastatin calcium: preparation, characterization, quantification and in-vivo application.

Atorvastatin is commonly used as a cholesterol lowering agent in patients. Recently, the neuroprotective effects of atorvastatin became the focus of many research studies. In this study, we have formulated chitosan microspheres containing atorvastatin calcium. In-vitro characterization of chitosan microspheres and quantification of atorvastatin calcium from formulations were also evaluated. The neuroprotective efficiency of atorvastatin calcium was investigated by an experimental spinal cord injury model. Atorvastatin calcium microspheres were implanted at the laminectomy area (1 mg/kg) immediately after trauma. Twenty-four hours after injury, motor functions of animals were scored according to modified Tarlov Scale. In spinal cord tissues tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6 and lipid peroxidation levels were quantified and ultrastructural changes have been investigated. The results of all parameters indicate that microspheres containing atorvastatin calcium were capable of improving functional outcome, attenuating the expression of TNF-alpha, IL-1beta and IL-6; lowering lipid peroxidation levels and maintaining the preservation of the cellular uniformity.

Local administration of chitosan microspheres after traumatic brain injury in rats: a new challenge for cyclosporine--a delivery.

The major aim of this study was to evaluate the efficiency of chitosan microspheres containing cyclosporine-A (Cs-A) on mitochondrial damage in traumatic brain injury (TBI) animal model. Trauma was introduced to male Sprague-Dawley (SD) rats similar to that of modified Feeney Method. Briefly, after craniectomy in the left parietal region (5 mm). Trauma was performed by dropping 24 g metal sterile rods through a teflon guide tube (9.3 cm) on a foot plate placed over the duramater. Just after the trauma, 20 mg/kg Cs-A (Sandimmune) has been administered to the traumatised SD rats intraperitoneally (i.p.). On the other hand, only chitosan microspheres containing 10 mg/kg was implanted at the craniectomy area locally after trauma in Group E. A small piece of surgicell was placed over the craniectomy hole and the scalp incision was sutured. 24 h after injury and the brain tissues were removed intact. The results were evaluated through lipid peroxidation ratio and ultrastructural grading system. The statistical comparisons were evaluated by using Mann Whitney- U test at the significance level p = 0.05. The lipid peroxidation ratios of sham (78.4 +/- 6.0 nmol/g tissue) and vehicle (80.2 +/- 10.6 nmol/g tissue) were significantly increased 24 h after TBI. However, for treatment groups (i.p. Cs-A; 20 mg/kg) and (10 mg/kg Cs-A in microspheres), statistically significant lower lipid peroxidation ratios were determined as 53.5 +/- 9.7 and 47.9 +/- 8.1 nmol/g tissue, respectively (p < 0.05). The mitochondrial damage scores of the treatment groups were recorded as 21.7 +/-2.6 and 19.4 +/- 3.9 for Group D and Group E, respectively. Both of these scores of the treatment groups were found as significantly different from the sham and vehicle groups' scores individually. The implantation of microsphere formulation has provided a better efficiency in keeping the uniformity of mitochondrial structure in this complex cascade of events after TBI.

Atorvastatin efficiency after traumatic brain injury in rats.

BACKGROUND: The neuroprotective effects of statins possibly depend on their pleiotropic effect such as antioxidative and anti-inflammatory properties. In this study, we have evaluated the efficiency of atorvastatin on brain edema, lipid peroxidation, and ultrastructural changes in TBI animal model. METHODS: Modified Feeney method has been used for the trauma model in rats. Only craniectomy for group A and trauma after craniectomy for group B was the procedure for animals. For the trauma, rods weighing 24 g were dropped on a foot plate just over the dura. Atorvastatin (1 mg/kg, IP) was administered to the animals in group C after craniectomy and trauma; but on the other hand, animals in group D received only 0.5 mL PEG as the vehicle. Brains were harvested 24 hours after the trauma for the assays of wet-dry weight, lipid peroxidation level, and ultrastructural investigations. Lipid peroxidation levels, TEM, and UNGS were the investigated parameters. The statistical comparisons between the groups were investigated by 1-way ANOVA and post hoc analysis by Duncan and Dunnett T3 test within the groups at the significance level P = .05. RESULTS: Trauma increased water contents of the brain tissues and lipid peroxidation levels in groups B and D. When compared with the results of group B (brain edema, 84.694% +/- 1.510%; lipid peroxidation, 74.932 +/- 2.491 nmol/g tissue), atorvastatin (1 mg/kg) significantly decreased brain edema (77.362% +/- 1.448%), lipid peroxidation level (58.335 +/- 3.980 nmol/g tissue), and UNGS scores in group C (P < 0.05). CONCLUSION: In this descriptive study, the remarkable improvements of atorvastatin on brain edema, lipid peroxidation, and ultrastructural investigations encouraged us for a further dose optimization study.