Screening of Cyclodextrins in the Processing of Buserelin Dry Powders for Inhalation Prepared by Spray Freeze-Drying.

Purpose: In this study, we prepared inhalable buserelin microparticles using the spray freeze-drying (SFD) method for pulmonary drug delivery. Raffinose as a cryoprotectant carrier was combined with two levels of five different cyclodextrins (CDs) and then processed by SFD. Methods: Dry powder diameters were evaluated by laser light scattering and morphology was determined by scanning electron microscopy (SEM). Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analysis were utilized for the determination of crystalline structures. The aerodynamic properties of the spray freeze-dried powders were evaluated by twin stage impinger (TSI) and the stability of prepared samples was assessed under normal and accelerated conditions. Results: The prepared powders were mostly porous spheres and the size of microparticles ranged from 9.08 to 13.53 µm, which are suitable as spray-freeze dried particles. All formulations showed amorphous structure confirmed by DSC and XRD. The aerosolization performance of the formulation containing buserelin, raffinose and 5% beta-cyclodextrin (ß-CD), was the highest and its fine particle fraction (FPF) was 69.38%. The more circular and separated structures were observed in higher concentrations of CDs, which were compatible with FPFs. The highest stability was obtained in the formulation containing hydroxypropyl beta-cyclodextrin (HP-ß-16. CD) 5%. On the contrary, sulfobutylether beta-cyclodextrin (SBE-ß-CD) 5% bearing particles showed the least stability. Conclusion: By adjusting the type and ratio of CDs in the presence of raffinose, the prepared formulations could effectively enhance the aerosolization and stability of buserelin. Therefore, they can be proposed as a suitable career for lung drug delivery.

Engineered PLGA microspheres for extended-release of naltrexone: in vitro, in vivo, and IVIVR.

Poly(lactide-co-glycolide) (PLGA)-based formulation is one of the most often used parenteral extended-release forms to deliver various therapeutics. VIVITROL® as a commercialized PLGA microsphere formulation encapsulates naltrexone, a narcotic antagonist for opioid addiction and alcohol dependency. However, no U.S. Food and Drug Administration-approved generic product of naltrexone PLGA microsphere formulation has entered the market. The availability of generic naltrexone PLGA microspheres in low-income countries will broaden patients' accessibility to the safe, effective, and more affordable drug. A major challenge in developing such generic forms is the sensitivity of the drug-loaded microspheres' critical characteristics to the small manufacturing changes, even in formulations with the same compositions as the reference product. In this study, we evaluated the different key manufacturing parameters on the physicochemical, in vitro and in vivo release characteristics of naltrexone microspheres to develop a generic form of naltrexone PLGA microspheres. The selected formulations demonstrated a significant similarity in physicochemical characteristics and release profiles (f2 > 50) to the reference product, VIVITROL®. A strong relationship was observed between in vitro release profile of naltrexone as against its corresponding in vivo profile. It helped to roughly predict the in vivo release behavior of the different manufactured formulations by their corresponding in vitro release profiles.

Pharmacokinetic study of high-dose oral rifampicin in critically Ill patients with multidrug-resistant Acinetobacter baumannii infection.

PURPOSE: Although rifampicin (RIF) is used as a synergistic agent for multidrug-resistant Acinetobacter baumannii (MDR-AB) infection, the optimal pharmacokinetic (PK) indices of this medication have not been studied in the intensive care unit (ICU) settings. This study aimed to evaluate the PK of high dose oral RIF following fasting versus fed conditions in terms of achieving the therapeutic goals in critically ill patients with MDR-AB infections. METHODS: 29 critically ill patients were included in this study. Under fasting and non-fasting conditions, RIF was given at 1200 mg once daily through a nasogastric tube. Blood samples were obtained at seven time points: exactly before administration of the drug, and at 1, 2, 4, 8, 12, and 24 h after RIF ingestion. To quantify RIF in serum samples, high-performance liquid chromatography (HPLC) was used. The MONOLIX Software and the Monte Carlo simulations were employed to estimate the PK parameters and describe the population PK model. RESULTS: The mean area under the curve over the last 24-h (AUC0-24) value and accuracy (mean ± standard deviation) in the fasting and fed states were 220.24 ± 119.15 and 290.55 ± 276.20 µg × h/mL, respectively. There was no significant difference among AUCs following fasting and non-fasting conditions (P > 0.05). The probability of reaching the therapeutic goals at the minimum inhibitory concentration (MIC) of 4 mg/L, was only 1.6%. CONCLUSION: In critically ill patients with MDR-AB infections, neither fasting nor non-fasting administrations of high-dose oral RIF achieve the therapeutic aims. More research is needed in larger populations and with measuring the amount of protein-unbound RIF levels.

Evaluation of amikacin dosing schedule in critically ill elderly patients with different stages of renal dysfunction.

OBJECTIVES: Amikacin is still a widely used aminoglycoside for the treatment of life-threatening infections. The pharmacokinetic parameters of this antibiotic may be altered in critically ill conditions. Moreover, in the elderly population, pathophysiological changes affect these pharmacokinetic variables, making it difficult to predict the appropriate dose and dosing schedule for amikacin. This study aimed to characterise the pharmacokinetics of amikacin in critically ill elderly patients with renal dysfunction, and to evaluate if the available dose adjustment schedules dependent on renal function would be appropriate for empirical dosing. METHODS: Critically ill patients aged >60 years with a creatinine clearance of >20 mL/min in need of treatment with amikacin were randomly enrolled. All the patients received approximately 25 mg/kg amikacin. The patients were then divided into three groups according to the stages of their renal dysfunction based on creatinine clearance, and the optimum time to re-dosing was calculated for each group. The pharmacokinetic parameters of the patients were calculated and estimated as population pharmacokinetic data. RESULTS: Of 30 patients, only 20% attained the target peak levels of amikacin of >64 mg/L. In addition, the mean volume of distribution was 0.47 L/kg. There was a poor correlation between amikacin clearance and creatinine clearance. The difference in amikacin half-life was not statistically significant among any of the stages of renal impairment. CONCLUSIONS: The initial dosing of amikacin in critically ill elderly patients should not be reduced, even in the context of renal impairment. Regarding the dose adjustment in renal impairment, dosing intervals estimation, no decision can be made based on the creatinine clearance and the first dose individualisation method in terms of the two-sample measurements may be considered as an appropriate strategy.

Efficacy assessments of tretinoin-loaded nano lipid carriers in acne vulgaris: a double blind, split-face randomized clinical study.

Here, we assessed the efficacy and safety of Nano lipid carrier (NLC) drug delivery system containing tretinoin (NLC-TRE) in comparison with the conventional 0.05% tretinoin cream (TRE cream) in mild to moderate acne vulgaris. A stable and appropriate NLC-TRE formulation was prepared using a high-pressure homogenizer and particle characterization and physicochemical properties were evaluated under accelerated conditions. Efficacy assessment was performed via a split-face clinical study, by comparing the number of acne lesions, porphyrin production and skin biophysical parameters in both sides of the face randomly treated with NLC-TRE and TRE cream. Plasma concentration of tretinoin after topical application of NLC-TRE was measured for primary safety evaluation. We acquired a stable, spherical nanoparticles with particle size of 118.5 nm, PI equal to 0.485 and ZP of - 44.7 mV. The rate of decrease of acne lesions was significantly higher in NLC- TRE side (p value < 0.001). The size and intensity of porphyrin production in pilosebaceous follicles were significantly reduced only on NLC-TRE side (p value < 0.01). The plasma concentration of the tretinoin, after 8 weeks' application remained lower than the toxic levels. The NLC-TRE formula provides better efficiency and good loading capacity of TRE in the drug delivery system.

Relationship between amikacin pharmacokinetics and biological parameters associated with organ dysfunction: a case series study of critically ill patients with intra-abdominal sepsis.

OBJECTIVES: This study aimed to evaluate the relationship between amikacin pharmacokinetics and the biomarkers associated with organ dysfunction in critically ill patients with intra-abdominal sepsis. METHODS: A case series involving critically ill patients with intra-abdominal sepsis who received an amikacin loading dose of 20-25 mg/kg intravenous infusion was studied. The 1-, 2-, 4-, 6- and 24-hour amikacin serum concentrations were measured to calculate the pharmacokinetic parameters. The Sequential Organ Failure Assessment (SOFA) score, white blood cells, neutrophil to lymphocyte ratio, platelet count, serum creatinine, creatinine clearance, bilirubin, partial pressure of oxygen to fraction of inspired oxygen ratio, serum albumin, procalcitonin, lactate level, erythrocyte sedimentation rate (ESR) and C-reactive protein were recorded. A linear regression analysis was performed to examine the relationship between the amikacin pharmacokinetics and the biological parameters. RESULTS: Twenty-one patients were studied. A significant correlation was found between the volume of distribution and ESR (p<0.05, r=0.844). Moreover, drug clearance had a significant inverse correlation with serum lactate (p<0.05, r=-0.603). No other significant correlations were found. CONCLUSIONS: ESR and serum lactate were identified as useful predictors of amikacin pharmacokinetics in critically ill patients with intra-abdominal sepsis and may help guide the selection of appropriate empirical dosing.

Evaluation of changes in cytochrome P450 2C19 activity in type 2 diabetic rats before and after treatment, by using isolated perfused liver model.

OBJECTIVES: Alteration in drug metabolism is very likely in diabetes mellitus. This study assessed changes in CYP2C19 enzymatic activity in the liver using omeprazole as a probe in the animal model of type II diabetes (T2DM) before and after treatment with metformin and cinnamon. MATERIALS AND METHODS: Twenty-eight male Wistar rats were randomly divided into seven groups. Fourteen days after induction of type 2 diabetic mellitus (T2DM), rats in the test group received metformin, cinnamon, and metformin plus cinnamon daily for 14 days. On day 28, rats were subjected to liver perfusion by Krebs-Henseleit buffer containing omeprazole as a CYP2C19 probe. Perfusate samples were analyzed by HPLC-UV to evaluate the activity of CYP2C19. RESULTS: Mean metabolic ratio of omeprazole was changed from 0.091±0.005 in the control group to 0.054±0.005 in the untreated-diabetic rats. This average was increased inordinately to 0.218±0.036 in the treated rats with metformin. Interestingly, the administration of cinnamon in combination with metformin in diabetic rats caused the enzyme activity to return to (0.085±0.002) approximately the observed levels in the control group (0.091±0.005). CONCLUSION: Results showed that despite the suppression of the CYP2C19 enzyme activity in T2DM rats, metformin treatment could increase the enzyme activity. Simultaneous application of cinnamon and metformin can modulate the function of CYP2C19 to the observed level in the control group and make it more predictable to treat diabetes mellitus and fate of drugs that are metabolized by this enzyme.

Assessment of tramadol pharmacokinetics in correlation with CYP2D6 and clinical symptoms.

Objectives Due to lack of adequate data on tramadol kinetic in relevance of CYP2D6 toxicity, this study was designed to investigate the effect of CYP2D6 phenotype in tramadol poisoning. The saliva, urine and blood samples were taken at the admission time. Consequently, concentration of tramadol and its major metabolites were measured. Methods A pharmacokinetic and metabolic study was developed in cases of tramadol poisoned (n=96). Cases of tramadol poisoned evidenced seizure, hypertension, dizziness, nausea and vomiting symptoms participated. Results Female cases showed higher N-desmethyltramadol (M2) tramadol concentrations than male cases: in urine (40.12 ± 124.53 vs. 7.3 ± 7.13), saliva (16.91 ± 26.03 vs. 5.89 ± 7.02), and blood (1.11 ± 1.56 vs. 0.3 ± 0.38) samples. Significant correlation between blood, saliva, and urine concentrations were found (r = 0.5). Based on the metabolic ratio of O-desmethyltramadol (M1) of male (0.53 ± 0.22) and female (0.43 ± 0.26), poisoning and severe symptoms like seizure in female occurs statistically fewer (13.04%) than in male (50.6%). Assessment of CYP2D6 phenotype showed all of the participants were extensive metabolizers (EM) and their phenotype was associated with clinical symptoms. Conclusions According to our results, M1 as a high potent metabolite has an important role in toxicity and the likelihood of poisoning in people with EM phenotype. Finally, tramadol metabolic ratio may justify the cause of various symptoms in human tramadol poisoning.

Assessment of tramadol pharmacokinetics in correlation with CYP2D6 and clinical symptoms.

Objectives Due to lack of adequate data on tramadol kinetic in relevance of CYP2D6 toxicity, this study was designed to investigate the effect of CYP2D6 phenotype in tramadol poisoning. The saliva, urine and blood samples were taken at the admission time. Consequently, concentration of tramadol and its major metabolites were measured. Methods A pharmacokinetic and metabolic study was developed in cases of tramadol poisoned (n=96). Cases of tramadol poisoned evidenced seizure, hypertension, dizziness, nausea and vomiting symptoms participated. Results Female cases showed higher N-desmethyltramadol (M2) tramadol concentrations than male cases: in urine (40.12 ± 124.53 vs. 7.3 ± 7.13), saliva (16.91 ± 26.03 vs. 5.89 ± 7.02), and blood (1.11 ± 1.56 vs. 0.3 ± 0.38) samples. Significant correlation between blood, saliva, and urine concentrations were found (r = 0.5). Based on the metabolic ratio of O-desmethyltramadol (M1) of male (0.53 ± 0.22) and female (0.43 ± 0.26), poisoning and severe symptoms like seizure in female occurs statistically fewer (13.04%) than in male (50.6%). Assessment of CYP2D6 phenotype showed all of the participants were extensive metabolizers (EM) and their phenotype was associated with clinical symptoms. Conclusions According to our results, M1 as a high potent metabolite has an important role in toxicity and the likelihood of poisoning in people with EM phenotype. Finally, tramadol metabolic ratio may justify the cause of various symptoms in human tramadol poisoning.

Bucladesine Attenuates Spatial Learning and Hippocampal Mitochondrial Impairments Induced by 3, 4-Methylenedioxymethamphetamine (MDMA).

Neurotoxic effects of systemic administration of 3, 4- methylenedioxymethamphetamine (MDMA) has been attributed to MDMA and its metabolites. However, the role of the parent compound in MDMA-induced mitochondrial and memory impairment has not yet been investigated. Moreover, it is not yet studied that analogs of 3', 5'-cyclic adenosine monophosphate (cAMP) could decrease these neurotoxic effects of MDMA. We wished to investigate the effects of the central administration of MDMA on spatial memory and mitochondrial function as well as the effects of bucladesine, a membrane-permeable analog of cAMP, on these effects of MDMA. We assessed the effects of pre-training bilateral intrahippocampal infusion of MDMA (0.01, 0.1, 0.5, and 1 µg/side), bucladesine (10 and 100 µM) or combination of them on spatial memory, and different parameters of hippocampal mitochondrial function including the level of reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), mitochondrial swelling, mitochondrial outer membrane damage, the amount of cytochrome c release as well as hippocampal ADP/ATP ratio. The results showed that MDMA caused spatial memory impairments as well as mitochondrial dysfunction as evidenced by the marked increase in hippocampal ADP/ATP ratio, ROS level, the collapse of MMP, mitochondrial swelling, and mitochondrial outer membrane damage leading to cytochrome c release from the mitochondria. The current study also found that bucladesine markedly reduced the destructive effects of MDMA. These results provide evidence of the role of the parent compound (MDMA) in MDMA-induced memory impairments through mitochondrial dysfunction. This study highlights the role of cAMP/PKA signaling in MDMA-induced memory and mitochondrial defects.

Evaluation of Amikacin Pharmacokinetics in Critically Ill Patients with Intra-abdominal Sepsis.

Purpose: Although the current widespread use of amikacin is in intra-abdominal sepsis treatment, its pharmacokinetic changes in the present setting are not yet well known. This study was aimed to evaluate the amikacin pharmacokinetic profile in critically ill patients with intraabdominal sepsis compared to pneumosepsis. Methods: Adult septic patients received amikacin therapy were studied. Patients with intraabdominal sepsis were enrolled in group 1 (n=16), and patients with pneumosepsis were enrolled in group 2 (n=13). The amikacin serum concentrations were evaluated in the first, second, fourth and sixth hours after initiating 30-minute infusion. The pharmacokinetic parameters were calculated for each patient. Results: There was no significant difference in the volume of distribution between the two groups (0.33±0.08 vs. 0.28±0.10 L/kg, P=0.193). The amikacin clearance was significantly lower in group 1 compared to group 2 (58.5±21.7 vs. 83.9±37.0 mL/min, P=0.029). There was no significant correlation between amikacin clearance and creatinine clearance estimated by Cockcroft-Gault formula in all patients (P=0.206). The half-life was significantly longer in group 1 compared to group 2 (5.3±2.8 vs. 3.4±3.2 hours, P=0.015). Conclusion: Pathophysiologic changes following intra-abdominal sepsis can affect amikacin pharmacokinetics behavior. The clearance and half-life may change, but the alteration of the volume of distribution is not significantly different in comparison with pneumosepsis. Further studies are required to evaluate the pharmacokinetic variables of amikacin in critically ill patients with intra-abdominal sepsis.

Improving the in-vivo biological activity of fingolimod loaded PHBV nanoparticles by using hydrophobically modified alginate.

Uncontrolled distribution of nanoparticles (NPs) within the body can significantly decrease the efficiency of drug therapy and is considered among the main restrictions of NPs application. The aim of this study was to develop a depot combination delivery system (CDS) containing fingolimod loaded poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) NPs dispersed into a matrix of oleic acid-grafted-aminated alginate (OA-g-AAlg) to minimize the nonspecific biodistribution (BD) of PHBV NPs. OA-g-AAlg was synthesized in two step; First, Alg was aminated by using adipic dihydrazide (ADH). The degree of hyrazide group substitution of Alg was determined by trinitro-benzene-sulfonic acid (TNBS) assay. Second, OA was attached to AAlg through formation of an amide bond. Chemical structure of OA-g-AAlg was confirmed with FTIR and HNMR spectroscopy. Furthermore, rheological properties of OA-g-AAlg with different grafting ratios were evaluated. In-vitro release studies indicated that 47% of fingolimod was released from the CDS within 28 days. Blood and tissue samples were analyzed using liquid chromatography/tandem mass spectrometry following subcutaneous (SC) injection of fingolimod-CDS into Wistar rats. The elimination phase half-life of CDS-fingolimod was significantly higher than that of fingolimod (∼32 d vs. ∼20 h). To investigate the therapeutic efficacy, lymphocyte count was assessed over a 40 day period in Wistar rats. Peripheral blood lymphocyte count decreased from baseline by 27 ± 8% in 2 days after injection. Overall, the designed CDS represented promising results in improving the pharmacokinetic properties of fingolimod. Therefore, we believe that this sustained release formulation has a great potential to be applied to delivery of various therapeutics.

Area under the Curve-Based Dosing of Vancomycin in Critically Ill Patients Using 6-Hour Urine Creatinine Clearance Measurement.

BACKGROUND: The area under the curve- (AUC-) guided vancomycin dosing is the best strategy for individualized therapy in critical illnesses. Since AUC can be calculated directly using drug clearance (CLvan), any parameter estimating CLvan will be able to achieve the goal of 24-hour AUC (AUC24 h). The present study was aimed to determine CLvan based on 6-hour urine creatinine clearance measurement in critically ill patients with normal renal function. METHOD: 23 adult critically ill patients with an estimated glomerular filtration rate (eGFR) ≥60 mL/min who received vancomycin infusion were enrolled in this pilot study. Vancomycin pharmacokinetic parameters were determined for each patient using serum concentration data and a one-compartment model provided by MONOLIX software using stochastic approximation expectation-maximization (SAEM) algorithm. Correlation of CLvan with the measured creatinine clearance in 6-hour urine collection (CL6 h) and estimated creatinine clearance by the Cockcroft-Gault formula (CLCG) was investigated. RESULTS: Data analysis revealed that CL6 h had a stronger correlation with CLvan rather than CLCG (r = 0.823 vs. 0.594; p < 0.001 vs. 0.003). The relationship between CLvan and CL6 h was utilized to develop the following equation for estimating CLvan: CLvan (mL/min) = ─137.4 + CL6 h (mL/min) + 2.5 IBW (kg) (R 2 = 0.826, p < 0.001). Regarding the described model, the following equation can be used to calculate the empirical dose of vancomycin for achieving the therapeutic goals in critically ill patients without renal impairment: total daily dose of vancomycin (mg) = (─137.4CL6-h (mL/min) + 2.5 IBW (kg)) × 0.06 AUC24 h (mg.hr/L). CONCLUSION: For AUC estimation, CLvan can be obtained by collecting urine in a 6-hour period with good approximation in critically ill patients with normal renal function.

Evaluation of Epithelial Lining Fluid Concentration of Amikacin in Critically Ill Patients With Ventilator-Associated Pneumonia.

INTRODUCTION: Classically, aminoglycosides are known to have low penetration into the lung tissue. So far, no study has been conducted on human adult patients to evaluate amikacin concentration in epithelial lining fluid (ELF) of the alveoli. Therefore, convincing data are not available from the perspective of pharmacokinetics to support the fact that a dosage of 20 mg/kg of amikacin is sufficient to treat patients with ventilator-associated pneumonia (VAP). METHOD: This was a pilot study of amikacin concentration measurement in the alveolar site of action in critically ill adult patients with VAP who required aminoglycoside therapy. A dose of 20 mg/kg of amikacin was administered over a 30-minute infusion. The serum concentrations of amikacin were evaluated in the first, second, fourth, and sixth hours. However, the ELF concentration of amikacin was evaluated in the second hour with the help of bronchoalveolar lavage sampling technique. RESULTS: A total number of 8 patients was included in the study. The mean (SD) administered dose was 20 (0.9) mg/kg. The mean (SD) peak plasma concentration of amikacin was 59.6 (23) mg/L, with the volume of distribution of 0.36 (0.13)L/kg. The amikacin concentration in ELF was successfully measured in 7 patients (6.3) mg/L. The lung tissue penetration of the drug was described as alveolar percentage, proportional to both the first- and second-hour plasma concentrations, with a mean (SD) of 10.1% (8.4%) and 18% (16.7%), respectively. CONCLUSION: To our knowledge, the current study is the first that investigates whether standard doses of amikacin may lead to sufficient alveolar concentration of the drug. The results show that administration of amikacin in doses of 20 mg/kg in critically ill patients with VAP may not provide sufficient concentrations in ELF.

Pharmacokinetics and Bioequivalence Studies of Teriflunomide in Healthy Iranian Volunteers.

Multiple sclerosis, which is characterized by inflammation and neurodegeneration, is considered a chronic disease of the central nervous system. Given the lack of pharmacokinetic evaluation of teriflunomide in the Iranian context, the present 2-way crossover study aimed to assess the pharmacokinetic properties and bioequivalence of 2 teriflunomide formulations. To this end, 2 single-dose generic and branded teriflunomide formulations were orally administered to 14 healthy Iranian male volunteers. A washout period of 21 days was allowed between the treatments. The plasma samples containing teriflunomide were analyzed by a simple and sensitive high-performance liquid chromatography method using standard ultraviolet detection. In addition, the pharmacokinetic parameters were calculated for bioequivalence evaluation. The peak area ratio between the teriflunomide and the internal standard was the source of calibration curves, which were linear over the range of 20-40,000 ng/mL (R2 = 0.9994). The results indicated that the 2 formulations had similar pharmacokinetics. Further, the 90%CI of the mean ratios of the test versus the reference formulations of log-transformed area under the concentration-time curve over 72 hours (93% to 107%) and peak concentration (92% to 108%) were within the acceptable range of 80% to 125%. Based on the obtained results, the test formulation of teriflunomide could be similar to that of the reference formulation.

The effect of surface treatment on the brain delivery of curcumin nanosuspension: in vitro and in vivo studies.

Background: Curcumin, a bioactive component with multiple characteristics, has been shown to have many therapeutic effects. However, there are several limitations regarding the use of curcumin such as instability, low solubility, poor bioavailability, and rapid elimination. Different approaches have been used to solve these problems. Materials and methods: In this study, surface-modified nanosuspension (NS) is investigated as a novel brain delivery system. Two different methods were used for the preparation of nanosuspensions with two different stabilizers. The surface of the nanosuspensions was coated with D-α-tocopheryl polyethylene glycol 1,000 succinate (TPGS) and Tween 80 using physical adsorption. Curcumin NSs were prepared using two different top-down techniques by high-pressure homogenizer and probe sonicator. A validated sensitive and selective high-performance liquid chromatography method using fluorescence detection was used for the determination and quantification of curcumin. Pharmacokinetics and biodistribution of curcumin NSs and solutions after intravenous administration in rats were studied. Results: Higher levels of curcumin in the brain were detected when Tween 80-coated NS was used compared with the curcumin solution and TPGS coated NS (TPGS-NS) (P-value<0.05). Absorption of ApoE and/or B by Tween 80-coated nanoparticles (NPs) from the blood were caused transferring of these NPs into the brain using receptor-mediated endocytosis. Distribution of TPGS-NS in the brain compared with the curcumin solution was higher (P-value<0.05). Higher levels of curcumin concentration in the liver, spleen, and lung were also observed with TPGS-NS. Conclusion: The results of this study indicate that the surface-coating of NSs by Tween 80 may be used to improve the biodistribution of curcumin in the brain.

A randomized controlled trial on the efficacy, safety, and pharmacokinetics of metformin in severe traumatic brain injury.

OBJECTIVE: Traumatic brain injury (TBI) is a leading cause of morbidity and mortality worldwide. Metformin is reported to have pleiotropic neuroprotective effects through anti-inflammatory, antioxidative, and anti-ischemic activity, and improvements in vascular hemodynamics and endothelial function. The aim of this study is to examine the efficacy and safety of metformin therapy in severe TBI patients. METHODS: This single-blind, parallel-group, randomized controlled trial enrolled adult TBI patients. Of 158 trauma patients assessed, 30 met the eligibility criteria and were randomly allocated in a one-to-one ratio to receive 1 g metformin every 12 h for five consecutive days (intervention group) or to usual management only (control group). For efficacy analysis, temporal profiles of serum levels of S100b, neutrophil to lymphocyte ratio (NLR), and glial fibrillary acidic protein (GFAP) were assessed. For pharmacokinetic analysis, serum concentrations of metformin were evaluated in the intervention group. RESULTS: The two study groups were similar in terms of demographics, baseline clinical characteristics, and on-admission biomarkers' serum levels. Longitudinal analysis of S100b and NLR levels showed statistically significant declines in values toward normal levels in the intervention group (p values of < 0.001 and 0.030, respectively), different from the profiles of the control group (p values of 0.074 and 0.645, respectively). Pharmacokinetic analysis demonstrated that metformin absorption is delayed in TBI patients. No events of hypoglycemia and lactic acidosis occurred. CONCLUSIONS: Metformin could potentially be an effective and safe therapeutic intervention in patients with severe TBI. Large-scale, multicentre studies are needed to confirm our encouraging results.

Pharmacokinetic changes of tramadol in rats with hepatotoxicity induced by ethanol and acetaminophen in perfused rat liver model.

Tramadol is an opioid agonist with activation monoaminergic properties. It can be administered orally, rectally, intravenously, or intramuscularly as a centrally acting analgesic. Liver injury can lead to changes in the metabolism of tramadol. In this study, the rate of tramadol metabolism in rats with damaged liver induced by ethanol and acetaminophen was assessed in a recirculation perfusion system. Acetaminophen is a mild analgesic and antipyretic agent, which can cause centrilobular hepatic necrosis in toxic doses, whereas alcohol causes death due to liver diseases. Alcoholic liver disease (ALD), such as alcoholic fatty liver, alcoholic hepatitis, and alcoholic fibrosis, is the most common liver disease. The aim of this study was to investigate the alteration in tramadol metabolism in different hepatotoxicity conditions in animal models. Male rats were randomly assigned to three groups. The control group received normal saline, group 2 received acetaminophen at the dose of 250 mg/kg/day, and group 3 received ethanol at the beginning dose of 3 g/kg/day, which was slowly increased to 6 g/kg/day. Tramadol was added to the perfusion solution at the concentration of 500 ng/mL. Samples were collected during 180 min, and analyte concentrations were determined by the High-Performance Liquid Chromatography (HPLC) method. The concentration of tramadol and its three main metabolites, O-desmethyltramadol (M1), N-desmethyltramadol (M2), and N,O-didesmethyltramadol (M5), were determined in perfusate samples. Ethanol and acetaminophen significantly affected the pattern of weight gain and liver weights before perfusion and caused a significant increase in enzyme activities. Moreover, histopathologic examination revealed that ethanol and acetaminophen caused liver damage. An increase in the elimination half-life and reduced clearance rate of tramadol were seen in the acetaminophen and ethanol groups, in comparison to the control group. Additionally, significant reductions in the Area Under the Curve (AUC) of metabolites of tramadol (M1, M2, and M5) were observed in the acetaminophen and ethanol groups in the perfused rat liver model. Liver damage caused by ethanol and acetaminophen during 45 days in animals leads to a significant reduction in the level of tramadol metabolites. Therefore, in patients with liver damage caused by ethanol and acetaminophen, caution needs to be considered when prescribing tramadol.

Prevalence of candidemia and associated candida subtypes following severe sepsis in non-neutropenic critically ill patients.

BACKGROUND: Invasive candidiasis management through the rapid initiation of appropriate antifungal therapy has been shown to be associated with the better prognosis, improved clinical outcome and reduced mortality in critically ill patients. Therefore, selection of  an appropriate antifungal therapy should be based on the distribution of candida species and the pattern of antifungal resistance. This study aimed to assess the prevalence of candidemia and associated subtypes following severe sepsis in non-neutropenic critically ill patients. METHODS: This study was a cross-sectional study that was conducted on severe sepsis patients stayed at least seven days in intensive care unit. Patients less than 18 years old, pregnant and breastfeeding patients, immunocompromised patients, neutropenic patients, patients with concurrent use of antifungal medicines and cytotoxic agents were excluded.To asses the candidemia, one mililiter of patients' blood sample was collected. Sample analysis was performed by Real-Time PCR and high resolution melting curve analysis method. RESULTS: Thirty-one critically ill patients were recruited in this study over 12-month period. Candidemia with a detection limit of 100 pg per 0.2 ml blood sample was not recognized in any of the included patients. CONCLUSION: The present result indicates low incidence of candidemia in the targeted intensive care units, but other factors such as small sample size, exclusion of patients with compromised immune system and the low fungal load at the time of sampling may also account for our observation.