Quercetin's Restorative Properties in Male Mice with 3-Nitropropionic Acid-induced Huntington-like Symptoms: Molecular Docking, Behavioral, and Biochemical Assessment.

The neurotoxicity of 3-Nitropropionic acid (3-NP) is well known. Herein, the prophylactic versus therapeutic effects of quercetin (QCT) were investigated against 3-NP-induced behavioral anomalies and oxidative neural damage. Thirty male mice were assigned into five groups; the negative control group, the QCT group (25 mg/kg/day, p.o. for 21 days), the 3-NP group (17 days), the prophylactic group (QCT administration for 14 consecutive days, and then 3-NP was administrated), the therapeutic group (3-NP was administrated and then QCT for 21 days). At the end of the animal treatment, behavioral studies were assessed. Subsequently, the brain sample tissues were assessed for oxidative stress-related parameters and histological evaluation. Moreover, the potential interaction between 3-NP and tumor necrosis factor-alpha (TNF-α) was evaluated by using a molecular docking study. 3-NP markedly led to neurotoxicity which was indicated by behavioral deficits (motor behavior, depression-like behavior, memory dysfunction, and passive avoidance) and oxidative damage. Blind and targeted molecular docking results showed good interaction between 3-NP and TNF-α. However, the prophylactic effects of QCT were superior to the therapeutic effects for attenuating 3-NP-induced neurobehavioral and oxidative neural changes in experimental mice, which histological changes of the brain's striatum region approved our findings. Taken together, the antioxidant activity of QCT remarkably could attenuate 3-NP-induced neurobehavioral deficits and mitochondrial dysfunctions in mice.

Quercetin-loaded nanoemulsions prevent Scopolamine-induced neurotoxicity in male rats.

Quercetin (QCT) is well-known as a neuroprotective agent due to its antioxidant capacities and reinstating mitochondrial functions. Scopolamine is commonly used as a model to induce Alzheimer's disease (AD-like) symptoms. The current study develops QCT-loaded nanoemulsion (QCT-NE) accompanied by evaluating its neuro-therapeutic effectiveness against SCO-induced neurotoxicity in male rats. The QCT-NE was prepared by the spontaneous emulsification technique and characterized by using particle size, zeta potential, drug loading, in vitro drug release behavior, and stability studies. In vivo studies were done on adult Wistar rats by applying the Morris water maze (MWM) test to study spatial memory and learning. The levels of lipid peroxidation and reduced glutathione were quantitatively determined to reveal the potential mechanism of SCO-induced oxidative stress. Finally, histological studies were performed using staining techniques. The QCT-NE particle size, zeta potential, polydispersity index (PDI), and DL were obtained at 172.4 ± 16.8 nm, -29 ± 0.26 mV, 0.3 ± 0.07, and 81.42 ± 9.14 %, respectively. The QCT and more effectively QCT-NE reduced the elevation of neurobehavioral abnormalities in the MWM test in SCO-exposed rats. The results of oxidative status showed that SCO significantly could increase the LPO and decrease the GSH levels in the rat's brain. However, QCT-NE treatment was more effective than free QCT to inhibit oxidative damage and was well correlated with histopathological findings. Taken together, QCT-NE, compared to QCT, was superior in ameliorating SCO-induced AD-like symptoms due to its better neuroprotective activity and can be considered a novel supplementary therapeutic agent in AD management.

Cationic Dextran Stearate (Dex-St-GTMAC): Synthesis and Evaluation as Polymeric Micelles for Indomethacin Corneal Penetration.

Background Indomethacin as a non-steroidal anti-inflammatory drug (NSAID) is commonly used to treat some ocular inflammatory disorders. Unfortunately, indomethacin is a drug that is poorly soluble in water; therefore, it has low efficacy. An attractive approach is the targeted delivery of indomethacin to the cornea using cationic dextran stearate as a polymeric micelle drug carrier. Methods A dextran stearate-glycidyl trimethylammonium chloride (Dex-St-GTMAC) copolymer was prepared through the reaction of GTMAC, stearoyl chloride, and dextran. Then, Dex-St-GTMAC was characterized by Fourier transform infrared (FT-IR) spectroscopy and 1H NMR spectroscopy. Dex-St-GTMAC forms micelles in the presence of indomethacin. The prepared polymeric micelles were characterized for size, ζ-potential, drug loading, particle morphology, critical micelle concentration, and encapsulation efficiency. To study the irritation potential of the indomethacin-loaded Dex-St-GTMAC, Het-Cam and Draize tests have been performed. Prepared cationic micelles were subjected to the in vitro drug release and ex vivotrans-corneal permeation test. Results The dialysis method was used for the preparation of indomethacin-loaded micelles (10, 20, and 30%). Measurement of the particle size showed a mean diameter of 122.1 and 150.9 nm for the drug-loaded micelles. Scanning electron microscopy (SEM) images showed that the morphology of the particles is spherical. 10% formulation was chosen as the best formulation due to more surface charge and reasonable drug loading. ζ-potential measurement for the 10% drug-containing micelles showed a value of +39.1 mV. Drug loading efficiency and the encapsulation efficiency for 10% drug-containing micelles were 6.36 and 63.61%, respectively. The results of the Het-Cam and Draize tests indicated that the indomethacin-loaded Dex-St-GTMAC formulation had no toxicity to eye tissues. Based on our results, the prepared micelles (indomethacin-loaded Dex-St-GTMAC) exhibited a sustained drug release pattern compared to the control group. Indomethacin penetration from the micelles to the excised bovine cornea was 1.75-fold greater than the control (indomethacin 0.1% in phosphate-buffered saline (PBS)). Conclusions Data from the ζ-potential, SEM, drug loading capacity, and in vitro drug release studies indicated that cationic dextran stearate polymeric micelles are an appropriate carrier for the efficient penetration of indomethacin into cornea tissues.

Arsenic and Tau Phosphorylation: a Mechanistic Review.

Arsenic poisoning can affect the peripheral nervous system and cause peripheral neuropathy. Despite different studies on the mechanism of intoxication, the complete process is not explained yet, which can prevent further intoxication and produce effective treatment. In the following paper, we would like to consider the idea that arsenic might cause some diseases via inflammation induction, and tauopathy in neurons. Tau protein, one of the microtubule-associated proteins expressed in neurons, contributes to neuronal microtubules structure. Arsenic may be involved in cellular cascades involved in modulating tau function or hyperphosphorylation of tau protein, which ultimately leads to nerve destruction. For proof of this assumption, some investigations have been planned to measure the association between arsenic and quantities of phosphorylation of tau protein. Additionally, some researchers have investigated the association between microtubule trafficking in neurons and the levels of tau protein phosphorylation. It should be noticed that changing tau phosphorylation in arsenic toxicity may add a new feature to understanding the mechanism of poisonousness and aid in discovering novel therapeutic candidates such as tau phosphorylation inhibitors for drug development.

In silico molecular modeling, neuro-behavioral profile, and toxicity assessment of the essential oil of Ferula gummosa Boiss. as an anti-seizure agent.

ETHNOPHARMACOLOGICAL RELEVANCE: Ferula gummosa Boiss., known in Persian as "Baridje," belongs to the Apiaceae family. All parts of this plant, especially the root, contain galbanum. Galbanum, the oleo-gum resin of F. gummosa, is one of the essential traditional herbal medicines in Iran, which is used as a tonic for epilepsy and chorea, memory enhancement, gastrointestinal diseases, and wound healing. AIM OF THE STUDY: We investigated the toxicity, anticonvulsant effects, and molecular modeling of the essential oil (EO) distilled from the oleo-gum resin of F. gummosa. MATERIALS AND METHODS: Gas chromatography-mass spectrometry was used to identify the EO components. The cytotoxicity of EO on HepG2 cell lines was assessed by the MTT method. Male mice were arranged as follows: negative control groups (sunflower oil (10 ml/kg, i.p.) or saline (10 ml/kg, p.o.)), EO groups (0.5, 1, 1.5, and 2.5 ml/kg, p.o.), and positive control groups (ethosuximide (150 mg/kg, p.o.) or diazepam (1.0 or 2 mg/kg, i.p.)). The motor coordination and neurotoxicity of EO were studied using the rota-rod test. Open-field, novel object recognition, and passive avoidance learning tests were used to investigate the effect of EO on locomotor activity and memory function. An acute pentylenetetrazole-induced seizure model was utilized to evaluate the anticonvulsant properties of the EO. The interaction of the EO main components with the GABAA receptor was investigated by coarse-grained molecular dynamics simulations. RESULTS: ß-pinene, sabinene, α-pinene, and ρ-cymene were the main components of EO. The IC50 of the EO at 24, 48, and 72 h was found to be 59.90, 12.96, and 3.93 µl/ml, respectively. No adverse effects were observed in memory, motor coordination, and locomotor activity in mice treated with EO. Administration of EO (1, 1.5, and 2.5 ml/kg) improved survival rates in mice receiving pentylenetetrazole (PTZ; to induce an epileptic seizure). Sabinene was able to bind to the binding site of benzodiazepines at the GABAA receptor. CONCLUSIONS: Acute treatment with the EO of F. gummosa caused antiepileptic effects and could effectively increase the survival rate in PTZ-treated mice with no significant toxicity.

Analgesic effect of curcumin topical formulation in knee osteoarthritis patients: a clinical trial.

OBJECTIVES: The aim of this study was to recognize the efficacy and safety of curcumin ointment on patients with knee osteoarthritis (OA) compare to diclofenac as standard medication. METHODS: The topical effects of curcumin (10%) and diclofenac (1%) ointments were assessed through the visual analog scale (VAS) and Western Ontario and McMaster Universities Arthritis (WOMAC) index after three times a day administration for two weeks in 60 patients. RESULTS: Desirable effects compared to the pre-treatment period were observed after two weeks of continuous treatment. Based on our results, VAS and WOMAC index were altered after treatment significantly (p<0.0001). CONCLUSIONS: Two-week use of curcumin ointment could ameliorate the pain, stiffness and function disability in patients with OA.

Assessing the Risk of Nephrotoxicity Associated with Aminoglycosides in Brucellosis Patients: A Cross-sectional Study.

OBJECTIVE: The purpose of this study was to investigate renal function in patients with brucellosis before and at the end of gentamicin therapy. To ensure the safety of therapeutic doses of gentamicin, renal functions in brucellosis patients were monitored regarding drug serum levels and check for early detection biomarkers of nephrotoxicity. METHODS: In this cross-sectional study, 41 patients (25 men and 16 women, aged over 15 years) were included, with confirmed acute brucellosis that referred to Brucellosis Research Center in Hamadan, west of Iran between March 2018 to February 2019. At baseline before treatment (first step) and 7 days after gentamicin administration (second step), serum uric acid, blood urea nitrogen (BUN), serum and urine creatinine, erythrocyte sedimentation rate (ESR), quantitative C-reactive protein (CRP) and urinary ß2-microglobulin (ß2M) were measured. Gentamycin serum level due to the highest risk of nephrotoxicity with this drug in aminoglycoside class was also checked by HPLC method. The data were analyzed using SPSS version 22. RESULTS: The mean urinary ß 2M level, serum and urinary creatinine, uric acid, BUN, and quantitative CRP levels in the first step and second step, there were no statistical differences between the two steps. There was a correlation between urinary creatinine and ESR. In addition, a positive correlation was found between urinary ß2M and serum gentamicin level. ESR levels have been significantly reduced in the patients after the treatment compared to before it. CONCLUSION: Our findings confirm that gentamicin is safe at the dose of 5 mg/kg/day for one week intravenously in brucellosis patients.

Rapid determination of ampyra in urine samples using dispersive liquid-liquid microextraction coupled with ion mobility spectrometry.

Ampyra (AMP, 4-Aminopyridine) is a potassium channel blocker that attracts growing research interest due to its adverse effects at high doses. The fast analysis of AMP is challenging because it typically requires complex analytical techniques. In this research, we developed and validated a novel method to assess the fast and quantitative analysis of AMP from real samples. This method combines the strength of ion mobility spectrometry (IMS) for rapid detection and the dispersive liquid-liquid microextraction as a fast and effective preconcentration method for the preconcentration/extraction of AMP. In this method, Ag nanoparticles were used as modifier agents. Moreover, the proposed mechanism for interaction of AMP with AgNPs was investigated based on the quantum theory of atoms in molecules (QTAIM) analysis. Also, the sensitivity of the proposed method was improved through the application of a delay on the carrier gas flow after sample injection. Under the optimum conditions, the developed method detected AMP in the linear range of 0.4-16 µmol L-1 with a detection limit of 0.12 µmol L-1. Finally, the developed method was successfully employed to quantify AMP in urine samples. Method validation was performed by comparing our results with those obtained by HPLC-UV/Vis, confirming the applicability of the proposed method for the AMP analysis in real samples. The proposed method will open up a new door toward developing simple, fast, and effective analytical methods.

Aluminum neurotoxicity and autophagy: a mechanistic view.

It is strongly believed that aluminum is one of the insalubrious agents because of its neurotoxicity effects and influences on amyloid ß (Aß) production and tau protein hyperphosphorylation following oxidative stress, as one of the initial events in neurotoxicity. The autophagy process plays a considerable role in neurons in preserving intracellular homeostasis and recycling organelles and proteins, especially Aß and soluble tau. Thus, autophagy is suggested to ameliorate aluminum neurotoxicity effects, and dysfunction of this process can lead to an increase in detrimental proteins. However, the relationship between aluminum neurotoxicity and autophagy dysregulation in some dimensions remains unclear. In the present review, we want to give an overview of the autophagy roles in aluminum neurotoxicity and how dysregulation of autophagy can affect aluminum neurotoxicity.

A review on nonviral, nonbacterial infectious agents toxicity involved in neurodegenerative diseases.

Neuronal death, decreased activity or dysfunction of neurotransmitters are some of the pathophysiological reasons for neurodegenerative diseases like Alzheimer's, Parkinson's and multiple sclerosis. Also, there is evidence for the role of infections and infectious agents in neurodegenerative diseases and the effect of some metabolites in microorganisms in the pathophysiology of these diseases. In this study, we intend to evaluate the existing studies on the role of infectious agents and their metabolites on the pathophysiology of neurodegenerative diseases. PubMed, Scopus, Google Scholar and Web of Science search engines were searched. Some infectious agents have been observed in neurodegenerative diseases. Also, isolations of some fungi and microalgae have an improving effect on Parkinson's and Alzheimer's.

Phlebotomy-induced iron deficiency attenuates the pulmonary toxicity of paraquat in mice.

Phlebotomy is an effective method in the prevention and treatment of some poisonings, among which iron deficiency is a well-known consequence. Given the role of iron in paraquat (PQ) toxicity, the present study investigated the effectiveness of phlebotomy in PQ pulmonary toxicity. After conducting preliminary studies, the duration time of phlebotomy was set to be seven days. Then, the mice were divided into nine separate groups. Groups 1-3 received a single dose of normal saline, and 5 and 10 mg/kg of PQ, respectively, and phlebotomy was not performed on them (NPG status). The animals in groups 4-6 first underwent phlebotomy for seven days and then received a single dose of normal saline, and 5 and 10 mg/kg of PQ (PBPT status). Groups 7-9 first received a single dose of normal saline, and 5 and 10 mg/kg of PQ and then underwent phlebotomy for seven days (PAPT status). Seven days after acute exposure to PQ, the animals were anesthetized and biochemical biomarkers as well as lung tissue changes were evaluated. The findings showed that phlebotomy before and after PQ toxicity significantly decreased serum iron compared to NPG condition. In the PBPT status, phlebotomy could prevent PQ toxicity by increasing the activity of catalase and superoxide dismutase (SOD) and decreasing the activity of myeloperoxidase (MPO), and the levels of hydroxyproline and lipid peroxidation in the lung tissue. In the PAPT status, a significant improvement was observed in SOD and MPO activities compared to the NPG status. Confirming the biochemical findings, the histological results indicated higher effectiveness of phlebotomy in preventing PQ toxicity (PBPT) compared to its therapeutic effects (PAPT). Considering the role of iron in PQ toxicity, it appears that the reduction of serum iron levels during phlebotomy can be effective in preventing lung injuries caused by PQ and improving the performance of the pulmonary antioxidant system.

Thermally oxidized sunflower oil diet alters leptin/ghrelin balance and lipid profile in rats: Possible role of reactive aldehydes in dyslipidemia.

Sunflower oil is a common edible oil in the world, which is highly prone to oxidative degradation during the frying process. The present study aimed to investigate the effects of products obtained from the thermal oxidation process of sunflower oil on metabolic indices, and the secretion status of leptin and ghrelin in rats. In vivo studies were designed after determining the rate of formation of active aldehydes and peroxide value in sunflower oil following 300°C in a period of 30-240 min. To this end, 36 rats in 6 separate groups were fed with 2 ml of normal saline, fresh sunflower oil, and heated oils at 30, 60, 120, and 240 min for 45 days. Finally, lipid profile changes and leptin/ghrelin secretion were examined, along with histological changes in the liver tissue. The results indicated a significant increase in serum LDL, VLDL and triglycerides, and a decrease in HDL, in the groups treated with heated oils. These changes were associated with a higher accumulation of triglycerides, active aldehydes, and histological changes in the hepatic tissue. Although the serum ghrelin level in the groups receiving heated oil did not change significantly compared to the fresh oil, the serum leptin level increased significantly in the groups receiving heated oil. According to our findings, increasing the time of sunflower oil heating enhanced the formation of active aldehydes, so that daily consumption of such oxidized oils might be associated with the occurrence of dyslipidemia, fatty liver and the development of leptin resistance. PRACTICAL APPLICATIONS: Sunflower oil is highly prone to oxidative degradation during the frying process. Increasing time of sunflower oil heating enhanced the formation of active aldehydes. Daily consumption of oxidized oils might be associated with the occurrence of dyslipidemia, fatty liver and the development of leptin resistance.

Neuroprotective effects of crocin and crocin-loaded niosomes against the paraquat-induced oxidative brain damage in rats.

Paraquat (PQ) is a nonselective herbicide that induces oxidative reactions and multiple-organ failure on exposure. Crocin, a carotenoid obtained from saffron, has demonstrated many therapeutic effects against neural conditions because of its antioxidant properties. In this study, 30 male Wistar rats were divided into 6 groups to evaluate the protective effects of crocin and crocin-loaded niosomes (NC) against PQ in the brain. The levels of total antioxidant capacity (TAC), lipid peroxidation (LPO), total thiol groups (TTG), superoxide dismutase (SOD), and catalase (CAT) activity were measured as the markers of redox status. Histopathological changes in the CA1 region of the hippocampus were evaluated by cresyl violet staining. Results indicated that both crocin and NC were able to attenuate the adverse effects of PQ at the histopathological level, which was following the changes in LPO (P < 0.0001), TAC (P < 0.01), and TTG (P < 0.05) level. The activity of CAT (P < 0.01) and SOD (P < 0.01) could be restored either by crocin or NC. Also, results indicated that nanoformulation of crocin in niosomes appears to be more promising. In conclusion, both crocin and NC showed favourable effects of PQ in the brain of rats, and were determined to be excellent agents to prevent acute toxicities of PQ. Furthermore, these two compounds can be known to provide neuroprotection.

Silibinin-loaded nanostructured lipid carriers (NLCs) ameliorated cognitive deficits and oxidative damages in aluminum chloride-induced neurotoxicity in male mice.

Aluminum chloride (AlCl3) and its accumulation in the brain are associated with neurodegenerative disease. Recent investigations have illustrated that silibinin is known to have neuroprotective properties. The present study investigates the neuroprotective effects of silibinin-loaded nanostructured lipid carriers (Sili-NLCs) against AlCl3-induced neurotoxicity in male mice. Sili-NLCs were prepared using the emulsification-solvent evaporation method and subjected to particle size, zeta potential, and entrapment efficiency (% EE) analysis. Mice were treated with AlCl3 (100 mg/kg/day, p.o.) and with the same concentration of silibinin and Sili-NLCs (50,100, and 200 mg/kg/day, p.o.) for 30 days in different groups. After treating animals, behavioral studies were assessed. Also, the brain tissue samples were collected from all mice to evaluate oxidative damage and histological changes. The particle size, polydispersity index, zeta potential, and entrapment efficiency (% EE) of prepared Sili-NLCs found 239.7 ± 4.04 nm, 0.082 ± 0.003, - 16.33 ± 0.15 mV, and 72.65 ± 2.03 %, respectively. Brain uptake studies showed that Sili-NLCs had a 5.7-fold greater uptake in the mice brain than the free drug. The AlCl3 caused significant cognitive impairment and increased the level of lipid peroxidation accompanied by decreasing antioxidant enzyme activity in the brain tissue. These findings correlated well with the histopathological experiments. Furthermore, treatment with Sili-NLCs significantly improved the AlCl3-induced cognitive impairment, neurochemical anomalies, and histopathological changes. Given these results, silibinin, when delivered using NLCs, is potentially more effective than free silibinin in decreasing AlCl3- induced neurotoxicity.

Comparative efficacy of silibinin and nano-silibinin on lead poisoning in Male Wistar rats.

Lead (Pb) is an environmental neurotoxin that can lead to toxicity. It has shown that tissues can be exposed to oxidative stress in lead poisoning. Since silymarin is a natural agent with antioxidant effects, this study aimed to investigate the antioxidant and chelation effects of silibinin and nano-silibinin on the oxidative stress status in lead-poisoned rats. Sixty male Wistar rats randomly divided into ten groups (n = 6). Control and Pb groups treated with or without silibinin and nano-silibinin for six days. Following measuring of weight and blood lead levels, biochemical antioxidant parameters evaluated. Finally, a histopathological examination of the liver performed. In this experiment, silibinin and more efficiently nano-silibinin prevented weight loss and blood lead level elevation induced by lead. Also, they increased the attenuated levels of superoxide dismutase (SOD) activity, catalase (CAT), total thiol molecules (TTM), glutathione (GSH), and total antioxidant capacity (TAC). Lead-induced elevation of lipid peroxidation products (MDA) and nitric oxide (NO) normalized to the standard level in silibinin and especially nano-silibinin groups. These data suggested that silibinin and especially nano-silibinin can decrease blood lead levels and prevent weight loss and oxidative stress in the lead-poisoned rat's model.

Harnessing the Natural Toxic Metabolites in COVID-19.

SARS-CoV-2 is a novel coronavirus and the cause of the recent pandemic; it is an enveloped ß-coronavirus. SARS-CoV-2 appear in the Wuhan City of China for the first time and outspread worldwide quickly. Due to its person-to-person fast transmission, COVID-19 is becoming a global problem. SARS-CoV-2 enter into cells by using ACE2 receptors that are numerous in the lungs and finally can cause acute respiratory distress syndrome (ARDS). Dry cough, sore throat, fever, body pain, headache, GIT discomfort, diarrhoea, and fatigue are some of the COVID-19 symptoms. There is no definite and certain treatment for disease caused by SARS-CoV-2 till now. Some pharmacological effects of toxins, toxoids, and venoms have been proven, and their effects on some diseases have been evaluated. This study aimed to investigate the role of toxins, toxoids, and venom in the pathophysiology of COVID-19 disease.

Evaluation of serum levels of asprosin and other metabolic profiles in patients with idiopathic tonic-clonic generalized epilepsy on treatment with valproic acid.

BACKGROUND: This cross-sectional research was undertaken to determine the serum levels of asprosin, a novel white adipose tissue-derived glucogenic adipokine, in epileptic patients on valproic acid treatment. METHODS: Sixty-six patients diagnosed with idiopathic tonic-clonic generalized epilepsy were divided into three groups: those treated with valproic acid (n = 22), those treated with lamotrigine (n = 22), and twenty-two newly diagnosed or untreated patients. A control group was twenty-two, healthy volunteers with a similar distribution of gender and age. Body mass index (BMI) and fasting serum levels of asprosin, glucose, glycohemoglobin (HbA1c), insulin, and lipid profile were measured for both patients and control groups. Additionally, homeostasis model assessment for insulin resistance (HOMA-IR) was also calculated for the investigated groups. RESULTS: The mean BMI values and fasting serum levels of glucose, HbA1c, insulin, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglyceride were much higher in subjects treated with valproic acid than those in the other study groups. Furthermore, a higher number of participants in the valproic acid group fulfilled the insulin resistance criterion (defined as HOMA-IR > 2.5) compared with those in other study groups. The mean fasting serum asprosin concentration was also significantly higher in the valproic acid group than in other study groups. This was while the values of the study parameters were comparable in the healthy, un-treated, and lamotrigine groups. CONCLUSIONS: Our finding suggested that elevated asprosin level might be one of the pathological mechanisms involved in the development of obesity, insulin resistance, and metabolic disturbances related to valproic acid treatment.

Clinical Pharmacists' Contribution to Medication Reconciliation in Outpatient Specialty Clinics in Iran.

BACKGROUND: The majority of research in medication reconciliation has focused on the inpatient settings, and little is known about the outpatient settings, particularly in developing countries. As such, we conducted this study to evaluate direct clinical pharmacist involvement in medication reconciliation in outpatient specialty clinics in Iran. METHODS: This prospective interventional study was conducted from September 2019 to February 2020 in a University-affiliated clinic in Iran. For 196 patients over 18 years of age who were scheduled for an appointment with a physician, medication reconciliation intervention was carried out by a clinical pharmacist. The number and type of unintentional discrepancies, their potential harm to the patients, their correlation with the patients' demographic and clinical characteristics, and the number of accepted recommendations upon the unintentional discrepancies by the clinicians were assessed and recorded. Additionally, patients' understanding of any change made to their current medication regimen was also assessed. RESULTS: In total, 57.14% of patients had at least one or more unintentional medication discrepancies, with an overall rate of 1.51 (±0.62) per patient. This is while the patient understanding of their medication changes was inadequate in a significant proportion of the study patients (62.2%). Patients with older ages, lower educational levels, and a higher number of medications and comorbidities were at a higher risk of having unintentional discrepancies. The most common type of unintentional discrepancy was the omission of a drug, and almost half of the reconciliation errors might have had the potential to cause moderate or severe harm to the patient. From 145 recommendations suggested by the clinical pharmacist upon unintentional discrepancies, 131 cases (90.34%) were accepted and implemented by the clinicians. CONCLUSION: These findings further support the need for conducting medication reconciliation in outpatient settings to identify discrepancies and enhance the safety of patient medication use.

Development of the Binary and Ternary Atorvastatin Solid Dispersions: In Vitro and In Vivo Investigations.

The object of this study was to prepare binary and ternary solid dispersions of atorvastatin (ATR) by the melting method using PEGs and poloxamer 188 (P188) as the carriers, singly and in combination with each other. Dissolution behavior, solubility studies, X-ray diffractometry, differential scanning calorimetry, and Fourier transform infrared spectroscopy were studied. Furthermore, antihyperlipidemic activities of formulations were compared to each other by serum lipid analyses in hyperlipidemic rats. Based on the results, the highest dissolution efficiency (DE30 = 83%) was obtained by binary systems consisted of ATR and P188. Also, no additional improvement was observed in dissolution properties of ternary solid dispersion formulations. Solubility studies showed enhancement of ATR phase solubility in water and a buffer solution containing P188 or PEG 10000. Furthermore, saturated solubility of ATR in the buffer solution improved more than twofold in the optimized ternary dispersion system. No crystalline changes occurred in PEG-based formulations; meanwhile, partial amorphization happened in the ATR-P188 combination. Finally, the in vivo study in hyperlipidemic rats exhibited a rapid decrease in the lipid profile of all formulations compared to ATR (after 7 days). Moreover, reduction of serum triglycerides and total cholesterol on the 14th day in the ATR group (p value < 0.01) was less than solid dispersion or physical mixing preparations (p value < 0.001). These findings proved the appropriate influence of using PEG and P188 in solid dispersion systems for the improvement of the therapeutic efficiency of ATR.

Studying the ophthalmic toxicity potential of developed ketoconazole loaded nanoemulsion in situ gel formulation for ophthalmic administration.

Ocular fungal infections are one of the essential reasons for vision loss, especially in developing countries for tropical regions. Ketoconazole (KZ), a broad-spectrum antifungal drug, is a lipophilic compound and practically insoluble in water. Since topical ophthalmic drug delivery confronts low bioavailability, an in situ gel formulation is designed to improve the residence time and consequently the bioavailability. Safety of the developed formulation as a carrier for ophthalmic drug delivery was measured using three different methods: MTT assay for measuring cell viability in which the human retinal pigmentation epithelial cells (RPE) were used, HET-CAM as a borderline method between in vivo and in vitro techniques for investigating the irritation potential of the chosen formulation which was done by adding formulation directly on the CAM surface and visually monitoring the vessels in terms of irritation reactions, and finally the modified Draize test for evaluating tolerability of the selected formulation on eyes. According to our results from the MTT test, cell viability for KZ-NE in situ gel formulation at 0.1% concentration was acceptable. The results obtained from the HET-CAM investigation didn't show any sign of vessel injury on the CAM surface for prepared formulation. Additionally, during 24 hours, the developed formulation was tolerable by rabbit eyes. Regarding our results, KZ-NE in situ gel formulation was non-irritant and non-toxic and can be well-tolerated and presented as an applicable vehicle for ophthalmic delivery of the anti-fungal drug.