The DHFR inhibitors 17 (IC50 0.01μM) and 28 (IC50 0.4μM)
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•Synthesis of 2-mercapto-quinazolin-4-one analogues.•Compound 17 the most active DHFR inhibitor with IC50 value of 0.01μM, ...eight fold more active than methotrexate (MTX).•Compounds 16 showed antitumor activity against human Caco2 colon (IC50 25.4μg/ml).•Compounds 24 showed antitumor activity against MCF-7 breast tumor (IC50 9.5μg/ml).•Compound 17 shared a similar molecular docking mode with MTX.
A new series of 2-mercapto-quinazolin-4-one analogues was designed, synthesized and evaluated for their in vitro DHFR inhibition, antitumor and antimicrobial activity. Compound 17 proved to be the most active DHFR inhibitor with IC50 value of 0.01μM, eight fold more active than methotrexate (MTX). Compounds 16 and 24 showed antitumor activity against human Caco2 colon and MCF-7 breast tumor cell lines with IC50 values of 25.4 and 9.5μg/ml, respectively. Compounds 15, 20, 21 and 30 showed considerable activity against the Gram-positive bacteria Staphylococcus aureus while 24 and 30 proved active against Bacillus subtilis with a magnitude of potency comparable to the broad spectrum antibiotic Ciprofloxacin. Strong activity was observed for 13, 14, 19, 20 and 24 against Candida albicans and Aspergillus flavus. Compound 17 shared a similar molecular docking mode with MTX and made a critical hydrogen bond and arene-arene interactions via Ala9 and Phe34 amino acid residues, respectively.
Controlling psoriasis with various systemic treatments, including methotrexate, may significantly decrease associated cardiovascular risk problems.
To assess the value of vitamin D supplementation on ...clinical response as well as changes in cardiovascular risk parameters in psoriasis patients treated with methotrexate.
This prospective randomized comparative study included 30 patients with moderate to severe psoriasis divided randomly to receive either methotrexate alone (Mtx) or methotrexate plus intramuscular vitamin D (MtxD) for 3 months. Lipid profile, HsCRP, carotid intima-media thickness (CIMT) and blood pressure (BP) measurements were recorded before and after the therapy.
At end of study period, significant clinical improvement in both groups was observed. CIMT and systolic BP decreased in both groups but only statistically significant in Mtx group. HsCRP decreased in both groups but didn't reach statistical significance. We also observed, an increase in triglycerides and cholesterol levels in the Mtx group with the latter decreasing in the combined Mtx and vitamin D therapy group.
Treating psoriasis with methotrexate may decrease cardiovascular disease risk factors. Adding vitamin D supplementation to methotrexate may protect lipid homeostasis, specifically cholesterol and triglycerides.
Introduction
Asthma is a heterogenous disease with various phenotypes that is characterized by airway limitation due to bronchospasm and airway inflammation associated with excessive mucus secretion. ...Eosinophilic asthma subtype is described as a late onset asthma that presents with more severe respiratory symptoms, and with sputum eosinophilia ≥ 3%. In the current study, we aimed to identify the difference in the clinical and demographic characteristics between eosinophilic and non-eosinophilic asthma subtypes and to determine predictors of eosinophilic asthma.
Materials and methods
One hundred bronchial asthma patients with age ≥ 18 years were divided into two groups according to sputum eosinophilia. All patients were subjected to medical history, Asthma Control Test (ACT), spirometry, serum IgE level, skin prick testing (SPT), and nasal endoscopy to detect nasal polyposis and allergic signs.
Results
No statistical difference was found between eosinophilic and non-eosinophilic asthma patients regarding age, gender, and body mass index. Patients with sputum eosinophilia had more severe obstruction by spirometry, and positive SPT to food allergens, pollens, and latex with statistical significance (
p
values 0.001, 0.016, and 0.017 respectively). Additionally, patients with sputum eosinophilia had lower ACT score, higher serum IgE level and higher serum eosinophil count. Total IgE had the highest diagnostic accuracy for discrimination of sputum eosinophilia among asthma patients. Pollen allergy and the severity of airway obstruction by spirometry were independent predictors of eosinophilic asthma.
Conclusion
Patients with eosinophilic asthma had more severe airway obstruction, lower ACT scores, higher serum IgE level, and serum eosinophil count. Pollen allergy and obstructive pattern by spirometry were independent predictors of eosinophilic asthma.
In an effort to increase the oral bioavailability of Amphotericin B (AmB), a pH-sensitive drug carrier composed of Tragacanth (Trag) and acrylic acid (AAc) was prepared using γ-irradiation. The ...swelling behavior of (Trag/AAc) hydrogels was characterized as a function of pH and ionic strength of the swelling medium. The obtained swelling indices revealed the ability of the prepared hydrogel to protect a loaded drug in stomach-simulated medium (Fickian behavior) and to release such drug in intestinal-simulated medium (non-Fickian behavior). In vitro release studies of the antifungal (AmB) were performed to evaluate the hydrogel potential as a drug carrier. The antifungal activity of the prepared oral formulation was investigated in a mouse model of systemic candidiasis. Data revealed that (Trag/AAc)-AmB has a potent antifungal efficacy as demonstrated by prolonging the survival time and reducing the tissue fungal burden, serum antibody titers, as well as inflammatory cytokines in kidney and liver tissues. Furthermore, in vivo toxicity of (Trag/AAc)-AmB was assessed via measuring kidney and liver functions, and results displayed the safety of this novel AmB formulation which was confirmed by histopathological examination. Overall, results indicated that the prepared (Trag/AAc)-AmB is an effective oral delivery system for AmB with better bioavailability and minimal toxicity and could represent a promising approach for improving the therapeutic index of the drug.
Pregabalin is widely used as a treatment for multiple neurological disorders; however, it has been reported to have the potential for misuse. Due to a lack of safety studies in pregnancy, pregabalin ...is considered the last treatment option for various neurological diseases, such as neuropathic pain. Therefore, pregabalin abuse in pregnant women, even at therapeutic doses, may impair fetal development. We used primary mouse embryonic neurons to investigate whether exposure to pregabalin can impair the morphogenesis and differentiation of ventral midbrain neurons. This study focused on ventral midbrain dopaminergic neurons, as they are responsible for cognition, movement, and behavior. The results showed that pregabalin exposure during early brain development induced upregulation of the dopaminergic progenitor genes
and
and the mature dopaminergic gene
. Interestingly, pregabalin had different effects on the morphogenesis of non-dopaminergic ventral midbrain neurons. Importantly, our findings illustrated that a therapeutic dose of pregabalin (10 μM) did not affect the viability of neurons. However, it caused a decrease in ATP release in ventral midbrain neurons. We demonstrated that exposure to pregabalin during early brain development could interfere with the neurogenesis and morphogenesis of ventral midbrain dopaminergic neurons. These findings are crucial for clinical consideration of the use of pregabalin during pregnancy.
Reflex tachycardia that occurs during nitroglycerin-induced hypotensive anesthesia in functional endoscopic sinus surgery (FESS) increases both the risk of intraoperative bleeding and the duration of ...surgery. Our clinical trial aimed to compare the effect of oral ivabradine versus oral propranolol as a premedication before nitroglycerin-induced hypotensive anesthesia on the reduction of reflex tachycardia in FESS.
In this clinical, comparative, prospective, randomized, controlled, double-blinded study, 40 patients were divided into two equal groups (20 each); group P received oral propranolol (10 mg tablet) and group I received oral ivabradine (5 mg tablet) in the evening before the surgery and 1 hour before the induction of anesthesia.
The reduction in heart rate (HR) was statistically significantly higher in group I than in group P. Conversely, the reduction in mean blood pressure (MAP) was statistically significantly higher in group P than in group I at baseline (pre-induction). However, after that, MAP reduction was statistically non-significant between both groups. Meanwhile, there was no statistically significant difference between both groups as regards duration of surgery, duration of deliberate hypotension, intraoperative NTG infusion doses, and the amount of bleeding.
Premedication with oral propranolol 10 mg or oral ivabradine 5 mg before FESS proved to be safe and effective in the reduction of reflex tachycardia that occurs during controlled nitroglycerin induced hypotensive anesthesia in FESS. However, ivabradine was more effective with higher safety profile than propranolol.
Background and aim Crocin is a pharmacologically active chemical found in the spice saffron from Crocus sativus L. It possesses antioxidant and anti-radical properties that can minimize the hepatic ...phospholipidosis triggered using the tricyclic antidepressant desipramine. The aim of this study was to examine the effect of crocin on desipramine-induced hepatic phospholipidosis targeting the oxidative stress-related PI3K/Akt/mTOR signaling pathways.
Forty adult male rats were divided into 4 groups (n =10): control group, a group receiving intraperitoneal (IP) crocin (50 mg/kg/day), a group receiving IP desipramine (10 mg/kg/day), and a group receiving both IP crocin and desipramine.
After 3 weeks of treatment, the combined treatment group showed diminished desipramine-induced hepatic phospholipidosis, along with significant reductions in total oxidant status (TOS) , the levels of inflammatory markers including interleukin 6 (IL6) and tumor necrosis factor α (TNF-α) and apoptotic markers including caspase3 and Bcl2 (B-cell lymphoma 2) while other markers including total antioxidant capacity (TAC), superoxide dismutase (SOD), phosphoinositide 3-kinases (PI3K), and mammalian target of rapamycin (mTOR) were increased. The gene expression of lysosomal enzymes including ELOVL6, SCD1 and HMGR was notably downregulated, while AP1S1 was upregulated in the combined treatment group compared to the desipramine group. No ultrastructural signs of hepatic phospholipidosis, in the form of multilamellar bodies, were apparent in the combined treatment group.
These data collectively suggest that crocin has a protective effect against desipramine-induced phospholipidosis. (www.actabiomedica.it).
The gold-standard approach for diagnosing and confirming Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2) infection is reverse transcription-polymerase chain reaction (RT-PCR). This ...method, however, is inefficient in detecting previous or dormant viral infections. The presence of antigen-specific antibodies is the fingerprint and cardinal sign for diagnosis and determination of exposure to infectious agents including Corona virus disease-2019 (COVID-19). This cross-sectional study examined the presence of SARS-CoV-2 spike-specific immunoglobulin G (IgG) among asymptomatic blood donors in Makkah region. A total of 4368 asymptomatic blood donors were enrolled. They were screened for spike-specific IgG using ELISA and COVID-19 RNA by real-time PCR. COVID-19 IgG was detected among 2248 subjects (51.5%) while COVID-19-RNA was detected among 473 (10.8%) subjects. The IgG frequency was significantly higher among males and non-Saudi residents (p < 0.001 each) with no significant variation in IgG positivity among blood donors with different blood groups. In addition, COVID-19 RNA frequency was significantly higher among donors below 40-years old (p = 0.047, χ2 = 3.95), and non-Saudi residents (p = 0.001, χ2 = 304.5). The COVID-19 IgG levels were significantly higher among the RNA-positive donors (p = 001), and non-Saudi residents (p = 0.041), with no variations with age or blood group (p > 0.05). This study reveals a very high prevalence of COVID-19 IgG and RNA among asymptomatic blood donors in Makkah, Saudi Arabia indicating a high exposure rate of the general population to COVID-19; particularly foreign residents. It sheds light on the spread on COVID-19 among apparently healthy individuals at the beginning of the pandemic and could help in designing various control measures to minimize viral spread.
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