Inhalable dry powders containing poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) were developed for the delivery of tadalafil (TAD) for treatment of life-treating pulmonary arterial hypertension. Taguchi design was employed to evaluate the effects of different formulation variables on the physicochemical characteristics of PLGA-NPs prepared using emulsion solvent evaporation method. Inhalable PLGA-NPs of TAD were successfully prepared by co-spray drying the PLGA-NPs with inert carriers. Physicochemical characteristics and in vitro deposition of the aerosolized drug were also evaluated. The optimized formulation was prepared using 7.5 mg of PLGA, 2.5 mg of TAD, sonication time of 6 min and 2% polyvinyl alcohol (PVA) as the stabilizer. The optimized aqueous/oil phase ratio for PLGA-NPs preparation was 10:1. Polymer/drug ratio was the most effective parameter on the release efficiency. Encapsulation efficiency, zeta potential and particle size of PLGA-NPs were more affected by aqueous/organic phase ratio. The spray dried powders containing PLGA-NPs had a mass median aerodynamic diameter (MMAD) in the range of 1.4–2.8 μm that was suitable for TAD delivery to the deep region of lung. The presence of L- leucine in mannitol containing formulations decreased the interparticulate forces between particles and increased significantly the process yield and fine particle fraction (FPF). The results indicated that prepared dry powders containing TAD-loaded PLGA-NPs were suitable for inhalation and has the potential for the treatment of pulmonary arterial hypertension.

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Memory impairment is one of the greatest concerns when it comes to long-term CNS-affecting drug administration. Drugs like gabapentin, pregabalin and baclofen are administered in a long-term period in conditions such as epilepsy, neuropathic pain, spasticity associated with spinal cord injury or multiple sclerosis. Despite their wide spread use, few data are available on the effects of these drugs on cognitive functions, such as learning memory. In the present study, the effects of long-term administration of gabapentin, pregabalin and baclofen on memory were investigated in a comparative manner. Male Wistar rats received intraperitoneal (i.p.) injection of gabapentin (30 mg/kg), pregabalin (30 mg/kg), baclofen (3 mg/kg), combination of gabapentin/baclofen (30/3 mg/kg) and combination of pregabalin/baclofen (30/3 mg/kg) once a day for 3 weeks respective to their groups. After the end of treatments, rat memories were assessed using the object-recognition task. The discrimination and recognition indices (RI and DI) in the T2 trials were used as the memory indicating factors. The results showed that daily i.p. administrations of pregabalin but not gabapentin or baclofen significantly decreased DI and RI compared to saline group. In combination groups, either gabapentin or pregabalin impaired discrimination between new and familiar objects. Our findings suggested that pregabalin alone or in combination with baclofen significantly caused cognitive deficits.

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This study aimed to assess the effect of intra-habenular injection of morphine on acute trigeminal pain in rats. Also here, we examined the involvement of raphe nucleus opioid and 5HT₃ receptors on the antinociceptive activity of intra habenular morphine to explore the possibility of existence of descending antinociceptive relay between the habenula and raphe nucleus. The numbers of eye wiping response elicited by applying a drop (40 μL) of NaCl (5 M) solution on the corneal surface were taken as an index of acute trigeminal nociception. Intra habenular microinjection of morphine at a dose of 2 μg was without effect, whereas at doses of 5 and 8 μg significantly produced antinociception. Microinjection of naltrexone (4 μg) and ondansetron (1 μg) into the dorsal raphe nucleus prior to intra-habenular saline did not produce any significant effect on corneal pain perception. Pretreatment of the raphe nucleus with ondansetron but not naltrexone prevented intra habenular morphine (8 μg) induced antinociception. Also, intra habenular injection of lidocaine (2%, 0.5 μL reduced corneal pain response. Moreover, intra-habenular microinjection of L-glutamic acid (1 and 2 μg/site) did not produce any analgesic activity in this model of pain. In conclusion, the present results suggest that the activation of the habenular μ opioid receptor by microinjection of morphine or inhibition of habenular neurons by microinjection of lidocaine produced an analgesic effect in the acute trigeminal model of pain in rats. The analgesic effect of intra habenular morphine was blocked by intra-dorsal raphe injection of serotonin 5-HT₃ antagonist.

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The genetic factors are determinants in required dosage changes of warfarin among which are polymorphisms of CYP2C9 and VKORC1 genes. The present study aimed to determine the allele and genotype frequency of CYP2C9 and VKORC1 genes in Birjand population. This study was conducted on 120 individuals who referred to Imam Reza and Vali-Asr hospitals for PT/INR test. After extracting the genomic DNA, the considered sequences were amplified by PCR, and restriction fragment length polymorphism analysis was done by AvaII and KpnI enzymes to determine allele polymorphisms. Moreover, related sequences of VKORC1, after amplification, were sequenced for determining the genotype. Allelic and genotypic frequencies as well as Hardy-Weinberg equilibrium, observed heterozygosity, expected heterozygosity, and polymorphism information content were calculated by PowerMarker V 3.25 software. Amongst 120 individuals in this study with the mean age of 58.12 ± 12.7 years, 80.8%, 9.1%, and 10% exhibited the alleles of 1, 2, and 3 CYP2C9 gene, respectively. The genotype frequencies of 1/1, 1/2, 2/2, 3/1, 3/2, and 3/3 of this gene were found to be 64.1, 15.8, 0, 17.5, 2.5, and 0 %, respectively. In -1639 G>A region, VKORC1 had normal homozygote genotype (GG) and in 1173 C>T region, heterozygote (CT) with the frequency of 48.7% and 45.9% had the most prevalence. Compared with other populations, there is a considerable difference between the allele frequency of CYP2C9 and VKORC1 genetic variance. Since 35.8% of the selected populations carry an abnormal allele causing sensitivity to warfarin, the specialists at medical centers must be informed about the genotypes of patients before prescribing warfarin.

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In an attempt to identify some new potential leads as anti-breast cancer agents, novel hybrid compounds were designed by molecular hybridization approach. These derivatives were structurally derived from hybrid benzofuran–imidazole and quinazolinone derivatives, which had shown good cytotoxicity against the breast cancer cell line (MCF-7). Since aromatase enzyme (CYP19) is highly expressed in the MCF-7 cell line, the binding of these novel hybrid compounds to aromatase was investigated using the docking method. In this study, due to the positive charge on the imidazole ring of the designed ligands and also, the presence of heme iron in the active site of the enzyme, it was decided to optimize the ligand inside the protein to obtain more realistic atomic charges for it. Quantum mechanical / molecular mechanical (QM/MM) method was used to obtain more accurate atomic charges of ligand for docking calculations by considering the polarization effects of CYP19 on ligands. It was observed that the refitted charge improved the binding energy of the docked compounds. Also, the results showed that these novel hybrid compounds were adopted properly within the aromatase binding site, thereby suggesting that they could be potential inhibitors of aromatase. The main binding modes in these complexes were through hydrophobic and H bond interactions showing agreement with the basic physicochemical features of known anti aromatase compounds. Finally, the complex structures obtained from the docking study were used for single point QM/MM calculations to obtain more accurate electronic interaction energy, considering the electronic polarization of the ligand by its protein environment.

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Phytochemical analysis of the methanolic and dichloromethane extracts of the aerial parts of Scutellaria pinnatifida led to the isolation of a phenylpropanoid, 1-o-feruloyl-ß-D-glucose ^[1], two known flavonoids including luteolin-7-o-glucoside (2) and apigenin-7-o-glucoside (3), three known phenylethanoid glycosides composed of phlomisethanoside (4), syringalide A (5), and verbascoside (6), and oleic acid (7). Isolation and structural elucidation of compounds were accomplished by HPLC and spectroscopic methods (UV, ¹H- NMR, ¹³C-NMR). The extracts were also evaluated for their radical scavenging activity and insecticidal property by 2,2-diphenyl-1-picryl-hydrazyl (DPPH) assay and contact toxicity method, respectively. Among the extracts, the methanol extract showed the most potent free radical scavenging activity with a RC₅₀ value of 0.044 ± 0.350 mg/mL which could be attributed to the presence of the isolated phenolic compounds. In the case of insecticidal activity, the n-hexane extract displayed the most potent activity and caused 10%, 15%, and 40% mortality to Oryzaephilus mercator at the concentration of 5, 10, and 15 mg/mL after 4 h of exposure.

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Liquiritigenin is a chiral flavonoid present in licorice and other medicinal plants. The nature of its biological fate with respect to the individual enantiomers has not been examined. In this study, we characterize, for the first time, the stereoselective pharmacokinetics of liquiritigenin. Liquiritigenin was intravenously (20 mg/kg) and orally (50 mg/kg) administered to male Sprague-Dawley rats (n = 4 per route of administration). Concentrations in serum and urine were characterized via stereospecific reversed-phase, isocratic HPLC method with UV detection. Serum concentrations were quantified but rapidly fell to undetectable levels. S-liquiritigenin showed a short half-life (0.25-0.54 h), while a better estimation of half-life (26-77 h) and other pharmacokinetic parameters was observed using urinary data. The flavonoid is predominantly excreted via non-renal routes (f_e values of 0.16-3.46 %), and undergoes rapid and extensive phase II metabolism. Chiral differences in the chemical structure of the compound result in some pharmacokinetic differences. Serum concentrations rapidly declined, making modeling difficult. S-liquiritigenin showed an increased urinary half-life.

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The objective of the present study was to evaluate the cognitive enhancing of pineapple juice and ethanolic extract in scopolamine-induced cognitive deficit mice. The ethanolic extract of pineapple (Ananas comosus (L.) Merr.) was prepared by maceration method and its juice was obtained by a homogenizer. Object recognition task was used to evaluate the mice memory. Exploration time in the first and second trial was recorded. The differences in exploration time between a familiar and a novel object in the second trial were taken as a memory index. Animals were randomly assigned into 15 groups of 6 each including: control group (normal saline + vehicle), positive control group (scopolamine + rivastigmine), seven experimental groups (received scopolamine alone or scopolamine + ethanolic extract of pineapple in different doses), six other experimental groups were treated by ethanolic extract or juice of pineapple in different doses. Scopolamine (100 μL, 1 mg/kg, i.p.) and pineapple juice or extract (50, 75 and 100 mg/kg, i.p.) were administered 40 and 30 min before starting the second trial in the experimental groups. Object discrimination was impaired after scopolamine administration. Results showed that juice and ethanolic extract of pineapple significantly restored object recognition ability in mice treated with scopolamine. These finding suggested that pineapple had a protective role against scopolamine-induced amnesia, indicating its ability in management of cognitive disorders.

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Hydroalcoholic extract and essential oil of aerial parts of Pycnocycla caespitosa have spasmolytic activity on rat ileum contractions. The objective of this research was to separate fractions of total hydroalcoholic extract of P. caespitosa guided by their spasmolytic activity on rat uterus. Aerial parts of P. caespitosa were extracted with ethanol. The concentrated extract was subjected to column chromatography and thin layer chromatography (TLC) for isolation fractions, then one of the bioactive fractions was subjected to further isolation to find its active components. Five fractions were obtained (Fr.1-Fr.5) and their anti-spasmodic activities were examined on uterus contraction induced by KCl (80 mM) and compared with ritodrine. In addition, spasmolytic effect of Fr.4 (one of the bioactive fractions) was determined on rat uterus induced by oxytocin (0.0005 IU/mL) and compared with ritodrine. Hydroalcoholic extract of P. caespitosa (0.032-2 mg/mL) reduced the responses to KCl but the inhibitory effect was not complete with 2 mg/mL extract in the bath. Four fractions (Fr.1, Fr.2, Fr.3 and Fr.4) (32-500 μg/mL) inhibited rat uterus contractions on the uterus while Fr.4 was slightly more active than others (IC₅₀ = 146 ± 23 μg/mL). Falcarindiol and isoacetovanillone were identified from Fr.4 using phytochemical methods including high-performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR) and TLC. In conclusion, in this research bioactivity guided technique was successfully used for separation of active fraction of P. caespitosa. Falcarindiol and isoacetovanillone were identified from the active fraction which inhibited both tonic and rhythmic contractile responses in rat isolated uterus.

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PIM-1 protein kinase inhibitor belongs to a novel class of serine/threonine kinases. As PIM-1 is overexpressed in cancer cells and possesses oncogenic functions, its inhibition provides a new option in cancer therapy. In this study, in vitro inhibitory effects of seven analogues of 1, 2-dihydropyridine-3- carbonitrile derivatives Ia-c, IIa-d on the activity of recombinant PIM-1 were evaluated using dimethylthiazol diphenyltetrazolium bromide (MTT) assay. The PIM-1 protein kinase inhibitory potencies and the cytotoxicity effects of tested compounds were respectively as follows: Ic > IIa > Ia > IIb > Ib > IId > IIc and IIb > IIa > Ia > IIc > Ic > Ib > IId, respectively. The compound Ic with methylthio imidazole substituent at C-3 position and benzodioxole substituent at C-6 position of 2-imino-1, 2-dihydropyridine-3- carbonitrile structure showed the strongest PIM-1 inhibitory effect (IC₅₀ = 111.01 nM), while the compound IIc with methythio imidazole substituent at C-3 position and benzodioxole substituent at C-6 position of 2-oxo-1, 2-dihydropyridine-3- carbonitrile structure exhibited the least inhibition activity (IC₅₀ = 433.71 nM). The docking results showed that all tested compounds localized appropriately in the middle of binding cavity after docking procedure, demonstrating suitable interactions between ligands and protein. This study demonstrated that the PIM-1 inhibitory potencies of newly synthesized compounds were in submicromolar concentrations (IC₅₀ < 150 nM) while they exhibited low cytotoxicity on HT-29 cell line (IC₅₀> 130 μM). Altogether, our data indicated that compounds Ic, IIa, Ia could be considered as new potent non-toxic PIM-1 inhibitors which could be used in combination with routine anti-proliferative drugs.

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