Iranian Journal of Pharmaceutical Research最新文献

Background: Developing a potent and safe scaffold is challenging in anti-cancer drug discovery.

Objectives: The study focused on developing novel series of compounds based on the inhibition of epidermal growth factor receptor tyrosine kinase (EGFR-TK) as one of the most promising compounds in cancer therapy.

Methods: In this study, a novel series of quinazoline-2,4,6-triamine derivatives were designed and synthesized through intramolecular C-H activation reaction of para-nitro aniline, trichloroacetonitrile, and isocyanides employing a one-pot reaction.

Results: The in-vitro antitumor activities of the compounds which showed acceptable inhibitory effects were investigated against breast (MCF-7), lung (A-549), and colon (HT-29) cancer cell lines by employing MTT assay. All compounds had the most negligible cytotoxicity toward normal fibroblast human cell lines. Based on structural and thermodynamics analysis results, it was found that Met 769 is a key residue in interaction with all inhibitors through the formation of hydrogen bonds with high occupancies with the amine group on the quinazoline ring of inhibitors. Also, there was a good consistency between calculated ΔG binding and experimental IC₅₀ values of compounds 10d, 10e, and erlotinib.

Conclusions: Compound 10e had an extensive range of antitumor activity on three diverse cell lines comparable with erlotinib and doxorubicin reference drugs. Also, compound 10d showed selective cytotoxicity against cancerous lung cells (A-549). On the other side, computational studies confirmed that Met 769 is a crucial residue in interaction with all inhibitors.

The current study aimed to evaluate the safety profile and efficacy of a cannabis-based sublingual spray, CBDEX10^® (containing 100 µg cannabidiol and 10 µg Δ⁹-tetrahydrocannabinol per puff; CBD/Δ⁹-THC 10:1), in improving lipid profile and glycemic state of the diabetic patients. Fifty diabetic patients were randomly allocated to the treatment (n = 25; receiving two puffs of CBDEX10^® twice daily) or the control groups (n = 25; receiving two puffs of placebo). The primary endpoint of the study was to evaluate the efficacy of the CBDEX10^® adjunctive therapy in improving the lipid profile and glycemic state of diabetic patients; the secondary endpoint was to assess the safety profile and tolerability of the spray. A statistically significant decline in total cholesterol [estimated treatment difference (ETD) = -19.73 mg/dL; P < 0.05], triglyceride (ETD = -27.84 mg/dL; P < 0.01), LDL-C (ETD = -5.37 mg/dL; P < 0.01), FBS (ETD = -12 mg/dL; P < 0.01), Hb A1C (ETD = -0.21 mg/dL; P < 0.01) and insulin secretion (ETD = -5.21 mIU/L; P < 0.01) was observable in the patients treated with CBDEX10^® at the end of the 8-week treatment period. Regarding safety, the mentioned adjunctive regimen was well, and there were no serious or severe adverse effects. Overall, CBDEX1^® sublingual spray could be a new therapeutic agent for lipid and glycemic control in diabetic patients.

Background: Postoperative peritoneal adhesions are among common challenging problems in surgery. The availability of limited efficient strategies to prevent intra-abdominal adhesion reinforces the need to explore new methods. Given the favorable prolonged drug release characteristics of polycaprolactone (PCL) films and their ability to act as a biodegradable physical barrier implant, along with the anti-inflammatory and anti-adhesion properties of indomethacin and phospholipids, this study hypothesized that indomethacin sustained-release membrane composed of phosphatidylcholine (PC) and PCL blend could efficiently prevent abdominal adhesion formation.

Methods: Different polymeric and polymeric/lipidic hybrid formulations with three feeding materials to drug weight ratios were prepared, and their physicochemical characteristics and drug release kinetics were evaluated and compared. Abdominal adhesions were induced in 48 rats by the abrasion of the cecum and excision of a section of the opposite abdominal wall. Adhesion formation was evaluated by macroscopic scoring, histological, scanning electron microscopy, and polymerase chain reaction analyses.

Results: Both PCL and PCL-PC films exhibited sustained indomethacin release profiles. The X-ray diffraction and Fourier-transform infrared spectroscopy studies confirmed indomethacin incorporation in formulations in molecular dispersion form without any interaction. The films showed smooth surfaces and good mechanical properties. The treatment with indomethacin PCL-PC membrane significantly reduced the expression levels of tumor necrosis factor-alpha, transforming growth factor-beta, interleukin-1, interleukin-6, and fibrinogen in the adhesion tissues. The separation of the injured peritoneum, very low adhesion scores, and complete mesothelial cell regeneration were also achieved.

Conclusions: This study suggests that indomethacin-eluting PCL-PC membrane acting through the combination of physical barrier, anti-inflammatory agents, and controlled drug delivery warrants an effective approach to prevent intra-abdominal adhesion.

Background: Although no authorization is available for antibiotics to treat bee diseases, some veterinary compounds are used by beekeepers, and each country sets its own thresholds. Inappropriate and excessive use of these drugs can cause allergic reactions and antibiotic resistance in humans who consume the remaining antibiotic residues in honey and its products. It is, therefore, relevant to monitor the presence of antibiotic residues in this matrix.

Objectives: A rapid method for the simultaneous screening of nitrofuran metabolite residues in honey was validated according to Commission Decision 2002/657/EC (C.D 657) and the European guideline for the validation of screening methods for veterinary medicines.

Methods: This multi-analytical screening method enables the simultaneous determination of four nitrofuran metabolites [3-amino-2-oxazolidone (AOZ), 3-amino-5-morpholinomethyl-2-oxazolidinone (AMOZ), 1-Aminohydantoin HCl (ADH), and semicarbazide (SEC)] from a single honey sample. Thirty-five honey samples were collected randomly as real samples for screening from Tehran, IR Iran, Germany, and the Netherlands in 2018.

Results: For all four antibiotic residues, the positivity threshold T was higher than the cut-off value Fm, and no false-positive results were obtained for three antibiotics (AOZ, AMOZ, and SEC). Detection capabilities (CCβ) of all compounds were under the minimum required performance limit (MRPL) authorized by the European Commission (currently 1 μg/kg). The screening results of 15 domestic and 20 imported honey samples showed that the levels of AOZ in 6.66% and 10% of the samples, the level of AMOZ in 13.33% and 0% of the samples, and the level of SEC in 33.33% and 40% of the samples were less than the cut-off ([in relative light units (RLUs)], respectively.

Conclusions: This study found that this technique is valid for detecting and quantifying three antibiotic residues in honey samples at the measured validation levels. This method was simple, rapid, and capable of simultaneously screening three nitrofuran metabolites from a single honey sample.

Background: Postoperative cognitive dysfunction (POCD) can be described as a clinical phenomenon characterized by cognitive impairment in patients, particularly elderly patients, after anesthesia and surgery. Researchers have focused on the probable effect of general anesthesia drugs on cognitive functioning status in older adults. Melatonin is an indole-type neuroendocrine hormone with broad biological activity and potent anti-inflammatory, anti-apoptotic, and neuroprotective effects. This study investigated the effects of melatonin on cognitive behavior in aged mice anesthetized with sevoflurane. In addition, melatonin's molecular mechanism was determined.

Objectives: This study aimed to investigate the mechanisms of melatonin against sevoflurane-induced neurotoxicity.

Methods: A total of 94 aged C57BL/6J mice were categorized into different groups, namely control (control + melatonin (10 mg/kg)), sevoflurane (sevoflurane + melatonin (10 mg/kg)), sevoflurane + melatonin (10 mg/kg) + phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) inhibitor LY294002 (30 mg/kg), and sevoflurane + melatonin (10 mg/kg) + mammalian target of rapamycin (mTOR) inhibitor (10 mg/kg). The open field and Morris water maze tests were utilized to assess the neuroprotective effects of melatonin on sevoflurane-induced cognitive impairment in aged mice. The expression levels of the apoptosis-linked proteins, PI3K/Akt/mTOR signaling pathway, and pro-inflammatory cytokines in the brain's hippocampus region were determined using the Western blotting technique. The apoptosis of the hippocampal neurons was observed using the hematoxylin and eosin staining technique.

Results: Neurological deficits in aged, sevoflurane-exposed mice were significantly decreased after melatonin treatment. Mechanistically, melatonin treatment restored sevoflurane-induced down-regulated PI3K/Akt/mTOR expression and significantly attenuated sevoflurane-induced apoptotic cells and neuroinflammation.

Conclusions: The findings of this study have highlighted the neuroprotective effect of melatonin on sevoflurane-induced cognitive impairment via regulating the PI3K/Akt/mTOR pathway, which might be effective in the clinical treatment of elderly patients with anesthesia-induced POCD.

Background: As a widely used therapeutic protein, recombinant human erythropoietin (rhEPO) is currently one of the most effective biopharmaceuticals on the market for the treatment of anemia in patients with chronic renal disease. Increasing in vivo rhEPO half-life and its bioactivity is a significant challenge. It was hypothesized that the application of self-assembly PEGylation retaining activity, named supramolecular (SPRA) technology, could prolong the protein half-life without a significant loss of bioactivity.

Objectives: This study aimed to assess the stability of rhEPO during synthetic reactions, including the conjugation with adamantane and the formation of the SPRA complex. To do this, the secondary structure of the protein was also evaluated.

Methods: FTIR, ATR-FTIR, Far-UV-CD, and SDS-PAGE methods were employed. Thermal stability studies of SPRA-rhEPO complex and rhEPO were investigated at 37°C for ten days using a nanodrop spectrophotometer.

Results: The secondary structure of lyophilized rhEPO, AD-rhEPO, and rhEPO (pH 8) was compared to rhEPO. Results showed that the secondary structure of the protein was unaffected by lyophilization, pH change, and the formation of covalent bonds in conjugation reaction. SPRA-rhEPO complex was also stable for seven days in phosphate buffer (pH 7.4) at 37°C.

Conclusions: It was concluded that the stability of rhEPO could increase by complexation using SPRA technology.

Background: The symptoms of pulmonary sarcoidosis may lead to fatigue, excessive daytime sleepiness, poor sleep quality, and a decrease in quality of life in these patients.

Objectives: This study was designed to evaluate the effects of oral melatonin on sleep disorders of patients with pulmonary sarcoidosis.

Methods: A randomized, single-blinded clinical trial was conducted on patients with pulmonary sarcoidosis. Eligible patients were randomly allocated into melatonin and control groups. Patients in the melatonin group were given 3 mg melatonin one hour before bedtime for three months. Sleep quality, daytime sleepiness, fatigue status, and quality of life were assessed applying General Sleep Disturbance Scale (GSDS), Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), Fatigue Assessment Scale (FAS), and the Patient-Reported Outcomes Measurement Information System (PROMIS), respectively, as well as the 12-item Short Form Survey (SF-12) scores at the baseline and three months after treatment.

Results: There was a significant change in the GSDS (P < 0.001), PSQI (P < 0.001), ESS (P = 0.002), and FAS (P < 0.001) scores, which were decreased, compared to those of the control group. After intervention¸ global physical health and global mental health raw scores were improved comparing to the control group (P = 0.006, P = 0.02, respectively). The 12-item Short Form Survey evaluation showed that there was a significant difference between the melatonin (3.38 ± 4.61) and control (0.55 ± 7.25) groups in PCS-12 score after three months of therapy (P = 0.02).

Conclusions: Our findings showed that supplemental melatonin could significantly improve sleep problems, quality of life, and excessive daytime sleepiness in sarcoidosis patients.

Background: Daurisoline can suppress the development of liver and lung cancers, but its effect on bladder cancer has not been investigated.

Objectives: This study probed into the mechanism underlying the effects of daurisoline on angiogenesis and epithelial-mesenchymal transition (EMT) in bladder cancer.

Methods: Tissue samples were taken from 40 patients with bladder cancer to analyze the expression of HAKAI and the relationship between HAKAI expression and patient survival. After the gain of function of HAKAI and/or treatment with daurisoline or heat shock protein 90 (HSP90) inhibitor geldanamycin, bladder cancer cells were collected for western blot detection of EMT-related proteins and transwell invasion assay. Tube formation assay assessed the angiogenesis of human umbilical vein endothelial cells (HUVECs) cultured in a conditioned medium of bladder cancer cells. The relationships between daurisoline, HSP90, HAKAI, and E-cadherin (E-cad) were analyzed using drug affinity responsive target stability (DARTS) assay and co-immunoprecipitation (co-IP) method. The effect and action mechanism of daurisoline were validated in nude mice.

Results: HAKAI was up-regulated 1.26-fold in bladder cancer tissues (P = 0.004) and correlated with poor prognosis. Daurisoline or geldanamycin inhibited EMT of bladder cancer cells and HUVEC angiogenesis. HAKAI overexpression reversed the suppression by daurisoline or geldanamycin. HAKAI was a client protein of HSP90, which could be directly targeted by daurisoline. HAKAI could target E-cad. Daurisoline also counteracted the promotive effects of overexpressed HAKAI on bladder carcinoma growth in nude mice.

Conclusions: Daurisoline suppresses EMT and angiogenesis in bladder cancer by targeting HSP90 and disrupting the stability of HAKAI protein to up-regulate the expression of E-cad.

Background: According to reports, icariin (ICA) is a bone anabolic agent able to prevent osteoporosis in both ovariectomized rats and postmenopausal women. However, its effect on osteoblast proliferation remains to be determined, and the underlying mechanism remains to be elucidated.

Methods: Icariin-bovine serum albumin (BSA) conjugates were purified by Sephadex G-25 gel chromatography technology. Primary osteoblasts from neonatal rats were used to evaluate the effects of ICA, ICA-BSA, ICA-BSA + ICI182780, and ICA-BSA + PD98059. 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and propidium iodide (PI)-staining assays were used to detect the proliferation of osteoblasts after drug exposure. The intracellular calcium ions were detected using a confocal microscope with Fluo-3/AM as the fluorescent indicator. Western blot was capitalized on to measure the relative content of phospho-extracellular signal-regulated kinase (p-ERK).

Results: Primary osteoblasts in culture were detected by histochemical staining of alkaline phosphatase, and calcified nodules were obtained by sequential digestion. Icariin and bovine serum albumin could form conjugate, which could be purified by Sephadex G-25 gel chromatography technology. MTT and flow cytometry results show that ICA-BSA conjugate significantly facilitated the proliferation of osteoblasts (P < 0.05). The intracellular calcium ions also ascended vastly in the cells treated with ICA-BSA conjugate (P < 0.01). Icariin-bovine serum albumin exposure rapidly activated the extracellular signal-regulated kinase (ERK) signaling. Furthermore, ICA- and ICA-BSA-mediated actions on osteoblasts were signally alleviated after dealing with ERK inhibitor PD98059 or estrogen receptor (ER) antagonist ICI182780, which might have a relation to the repression of ERK phosphorylation.

Conclusions: Icariin could serve as estrogen in osteoblast cells by the rapid nongenomic ER signaling pathway independent of ligand and estrogen response element (ERE) and mediated by mitogen-activated protein kinase (MAPK).

The use of nuclear magnetic resonance (NMR) spectroscopy as a tool for determining pharmaceutical molecules in bulk drugs and their dosage forms is growing. New advancements in benchtop NMR spectrometers with cryogen-free magnets have made this technique more appealing and accessible. Herein, we developed a method using a benchtop NMR spectrometer to quantify phenytoin (PhT) and phenobarbital (PhB) in bulk and combined dosage forms. The results were compared to those obtained by high performance liquid chromatography (HPLC) as a well-characterized procedure. This method is simple, low cost, relatively fast, and non-inferior to HPLC in terms of figures of merit.