Drug Research最新文献

Nightmare disorder is associated with functional impairment, distress, and low quality of life; however, studies on pharmacotherapy of this debilitating disorder yielded mixed results. Prazosin, a non-selective α₁ blocker is reported to be effective in treatment of post-traumatic stress disorder-related nightmares. We aimed at investigating therapeutic effects of tamsulosin which has higher affinity for blocking α_1A and α_1D adrenoceptors in treatment of nightmare disorder. A randomized, double blind, cross-over, placebo-controlled pilot study was conducted. Patients were randomly assigned to receive Tamsulosin 0.4 mg once daily or placebo for period of four weeks. Following a 2-week wash-out period, they were crossed over to the other group and received drug or placebo for duration of 4 additional weeks. Nightmare frequency and intensity measurements were carried out using Disturbing Dreams and Nightmares Severity Index (DDNSI). Blood pressure measurements were also performed. According to per protocol analysis, mean DDNSI scores decreased following administration of tamsulosin and a statistical trend towards significance was reported (p=0.065, d=0.236). Results of intention to treat analysis showed significant difference in DDNSI scores after drug use (p=0.030, d=0.651). Additionally, DDNSI scores dropped significantly following placebo use. However, intention to treat analysis showed no statistically significant difference pre and post placebo period (0.064, d=0.040). Tamsulosin may be effective in treatment of nightmare disorder. However, further larger clinical trials are recommended to clarify the effectiveness of tamsulosin and α₁ subtypes in pharmacotherapy of nightmares.

Parkinson's disease is the highest prevalent neurodegenerative disease in elderly individuals after Alzheimer's disease. The pathological identification for Parkinson's disease is loss of dopaminergic neurons in substantia nigra region of the brain that in turn leads to dopamine deficiency that affects the body's normal physiological and neurological disorder. The important drawback in the modality of treatment is levodopa is only supplying depleted dopamine in the brain, it does not affect neurodegeneration. Even though levodopa manages the disease, an alternative treatment strategy is required to stop or prevent further degeneration of neuron. The compound with neuroprotector activity suits the requirement. Of them, stearic acid plays a vital role in protecting neurons against oxidative stress through a Phosphoinositide 3-kinase-dependent mechanism. Hence, our present study aimed to design, synthesize, and characterize the levodopa stearic acid hydrazide conjugate. Additionally, evaluate the cytotoxicity of synthesized compound in SHSY5Y: cell lines. In brief, levodopa was conjugated to the stearic acid successfully and was confirmed with Fourier-transform infrared spectroscopy, Nuclear magnetic resonance, and Mass Spectroscopy. In vitro cell viability study in SHSY5Y: cell lines showed elevated cell viability in 0.134 µm concentration of Conjugate, and 0.563 µm concentration of levodopa. Showing that the synthesized compound could offer an improved treatment strategy for Parkinson's disease.

Background: Endoplasmic Reticulum (ER) stress and Unfolded Protein Response (UPR) play a key role in cancer progression. The aggregation of incorrectly folded proteins in the ER generates ER stress, which in turn activates the UPR as an adaptive mechanism to fix ER proteostasis. Inositol-requiring enzyme 1 (IRE1) is the most evolutionary conserved ER stress sensor, which plays a pro-tumoral role in various cancers. Targeting its' active sites is one of the most practical approaches for the treatment of cancers.

Objective: In this study, we aimed to use the structure of 4μ8C as a template to produce newly designed compounds as IRE1 inhibitors.

Methods: Various functional groups were added to the 4μ8C, and their binding affinity to the target sites was assessed by conducting a covalent molecular docking study. The potential of the designed compound for further in vitro and in vivo studies was evaluated using ADMET analysis.

Results: Based on the obtained results, the addition of hydroxyl groups to 4μ8C enhanced the binding affinity of the designed compound to the target efficiently. Compound 17, which was constructed by the addition of one hydroxyl group to the structure of 4μ8C, can construct a strong covalent bond with Lys907. The outcomes of ADMET analysis indicated that compound 17 could be considered a drug-like molecule.

Conclusion: Our results revealed that designed compound 17 could inhibit IRE1 activity. Therefore, this designed compound is a remarkable inhibitor of IRE1 and introduces a promising therapeutic strategy for cancer treatment.

Heart failure is a health problem worldwide. There are some drugs for it, including digoxin, spironolactone, captopril, and valsartan, but some of these drugs can produce secondary effects, such as arrhythmia, cough, hyperkalemia, hyponatremia and hypotension. The aim of this research was to evaluate the biological activity of coumarin (2H-chromen-2-one) and its derivatives (3BrAcet-C, 3-4Br-Ph-C, 4-CN-7D-C, 4-Me-7-Ph-C and 6Br-3-D-C) against ischemia/reperfusion injury as a therapeutic alternative for heart failure. In addition, the biological activity of the coumarin derivative 4-Me-7-Ph-C on left ventricular pressure (LVP) was determined in the absence or presence of ouabain and nifedipine at a dose of 1 nM using an isolated rat heart model. The results showed that i) the coumarin derivative 4-Me-7-Ph-C significantly decreased the infarct area (p+=+0.05) compared with 3BrAcet-C, 3-4Br-Ph-C, 4-CN-7D-C, and 6Br-3-D-C; and ii) 4-Me-7-Ph-C increased LVP in a dose-dependent manner, which effect was inhibited by nifedipine. These data suggest that coumarin 4-Me-7-Ph-C may act as a type-L calcium channel activator, so it could be a good agent to treat heart failure.

Parkinson's disease is the loss of dopaminergic neurons in the substantial nigra part of the brain leading to neurodegeneration. Whereas, reactive oxygen species and mitochondrial impairment are considered to be the major pathophysiology of neurodegeneration. The benzylidene-based 2-chloroquinolin derivatives were synthesized and characterized by FT-IR, NMR, and MS spectrometry which were screened using various in-silico approaches. The designed compounds were further assessed using in-vitro cytotoxicity assay by the MTT method, DPPH assay, and Glutathione measurements in the SHSY5Y neuroblastoma cell lines. The compounds JD-7 and JD-4 were found to have a binding affinity of - 7.941 and - 7.633 kcal/mol with an MMGBSA score of - 64.614 and - 62.817 kcal/mol. The compound JD-7 showed the highest % Cell viability of 87.64% at a minimal dose of 125 µg/mL by the MTT method. The neurotoxicity effects were observed at increasing concentrations from 0 to 125, 250, and 500 µg/mL. Further, free radical scavenging activity for the JD-7 was found to be 36.55 at lowest 125 µg/mL concentrations. At 125 µg/mL, GSH % and GSSG % were found to be increasing in rotenone treatment, whereas JD-7 and JD-4 were found in the downregulation of glutathione level in the pre-treated rotenone SHSY5Y neuroblastoma cell lines. The benzylidene-based chloroquinolin derivatives were synthesized, and among the compounds JD-1 to JD-13, the compounds JD-7, and JD-4 were found to have having highest % cell viability, free radical scavenging molecules, and glutathione levels in the SHSY5Y neuroblastoma cell lines and could be used as free radical scavengers in Parkinson's disease.

Clinical trials have revealed that sodium glucose cotransporter 2 (SGLT2) inhibitors suppress the onset of heart failure and cardiovascular death in diabetic patients. On the other hand, few reports have been published concerning such effects of dipeptidyl peptidase-4 (DPP-4) inhibitors. We undertook the present study to evaluate the effects of SGLT2 inhibitors and DPP-4 inhibitors on the advanced glycation end products (AGEs), well known as a risk factor for the development of cardiovascular disorders.Type 2 diabetes mellitus were divided into two groups and treated with either SGLT2 inhibitors or DPP-4 inhibitors for 3 months. Before and after the 3-month treatment period with each drug, the AGEs and diabetes-related parameters were measured. Methylglyoxal-derived hydroimidazolone-1 (MG-H1) was measured as one of the AGEs.In the SGLT2 inhibitor group, both the blood HbA1c and MG-H1 levels decreased significantly after the 3-month treatment period. In the DPP-4 inhibitor group, only the blood HbA1c level decreased significantly, with no significant change of the blood MG-H1 level.SGLT2 inhibitor reduced both the blood levels of HbA1c and AGEs (MG-H1). Considering that the blood levels of AGEs are associated with the risk of heart failure and cardiovascular disorders, the results of the present study suggest that the effect of SGLT2 inhibitors in suppressing cardiovascular death might be mediated by the reduction in the blood levels of AGEs induced by this class of drugs. DPP-4 inhibitors showed no significant effects on the blood levels of AGEs.

Background: To investigate if perioperative parenteral administration of fosfomycin given before or during gastrointestinal surgery could protect against postoperative infectious complications and characterise the administration of fosfomycin and its harms.

Methods: This systematic review included original studies on gastrointestinal surgery where parental administration of fosfomycin was given before or during surgery to≥5 patients. We searched three databases on March 24 2023 and registered the protocol before data extraction (CRD42020201268). Risk of bias was assessed with Cochrane Handbook risk of bias assessment tool or the Newcastle-Ottawa Scale. A narrative description was undertaken. For infectious complications, results from emergency and elective surgery were presented separately.

Results: We included 15 unique studies, reporting on 1,029 patients that received fosfomycin before or during gastrointestinal surgery. Almost half of the studies were conducted in the 1980s to early 1990s, and typically a dose of 4 g fosfomycin was given before surgery co-administered with metronidazole and often repeated postoperatively. The risk of bias across studies was moderate to high. The rates of infectious complications were low after fosfomycin; the surgical site infection rate was 0-1% in emergency surgery and 0-10% in elective surgery. If reported, harms were few and mild and typically related to the gastrointestinal system.

Conclusion: There were few postoperative infectious complications after perioperative parenteral administration of one or more doses of 4 g fosfomycin supplemented with metronidazole in various gastrointestinal procedures. Fosfomycin was associated with few and mild harms.

Hydroxyurea (HU) has shown promise in breast cancer treatment, but its hydrophilic nature limits its efficacy. Therefore, conjugating HU with lipids could increase its liphophilicity and improve its cellular uptake, leading to increased efficacy and reduced toxicity. The PI3K/Akt/mTOR pathway is an attractive therapeutic target in cancer not only because it is the second most frequently altered pathway after p53, but also because it serves as a convergence point for many stimuli. The aim of this study is to design and develop novel hydroxyurea lipid drug conjugates for breast cancer therapy targeting the PI3K/Akt/mTOR pathway using in-silico and in-vitro approaches. The conjugates are designed and docked with the proteins selected for each target like PI3K (PDB ID;2JDO), AKT (PDB ID;3APF), mTOR (PDB ID;4JST). The conjugates with higher docking scores are taken for ADME studies and molecular dynamics. Stearic, lauric, palmitic, myristic and linolenic acids have been used for the conjugation. The conjugates are synthesized and characterized. The HLB calculation and partition coefficient are carried out to find the improvement in liphophilicity of the conjugates compared to hydroxyurea. Finally, the in-vitro cytotoxicity studies are performed with MCF -7 cell lines and the compound HU-MA (hydroxyurea with myristic acid) with low IC₅₀ is considered as the compound having good activity with compound code. These conjugates have been shown to have improved drug solubility and better cellular uptake compared to free hydroxyurea, which can increase drug efficacy.