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A simple and reliable method was developed using LC-MS/MS to quantify alprazolam, bromazepam, clonazepam, diazepam, and flunitrazepam in clinical samples. This method was validated for the simultaneous determination of alprazolam, bromazepam, clonazepam, diazepam, and flunitrazepam. It was applied to human urine samples collected from people suspected of drug abuse in the Kuwaiti region. Formic acid in water and acetonitrile was used in mobile phase with a gradient mode of elution using C18 reverse-phase column. The instrument was operated in a positive mode with an electrospray ionization source using multiple reaction monitoring. For sample extraction, the liquid-liquid extraction technique was used. The method was validated for limit of detection, limit of quantitation, selectivity, linearity, accuracy, and precision. The concentration for limit of quantitation was 6.0 ng/mL, the linearity ranged from 2.0 to 300 ng/mL for each of the analytes, and the r2 values were ≥0.99. The accuracy was found to be within a range of 80–120% and precision had a %RSD of ≤15% for each of the analytes. The method was applied to 48 urine samples collected from those suspected of drug abuse by the Toxicology Department of the General Department of Criminal Evidence, Kuwait, and alprazolam, bromazepam, clonazepam, diazepam and flunitrazepam were identified commonly in the samples. The overall drug positivity rate obtained considering 48 samples was 93.75%. Based on these results and successful determination of alprazolam, bromazepam, clonazepam, diazepam and flunitrazepam in human urine samples from those suspected of drug abuse, this method is deemed to be suitable for its routine analysis.

Electrospun drug‐loaded polymers are used to make formulations that slowly release medication. This study creates ciprofloxacin (Cip)‐loaded fiber mats by melt electrospinning using polycaprolactone (PCL) and PEG4000 for controlled release of Cip. The increase in Cip concentration and PEG4000 percentages increases the mat thickness resulting in uniform morphology. The tensile strength of the PCL mat is significantly improved by adding higher concentrations of Cip while PEG inclusion reduced the tensile strength significantly. Differential Scanning Calorimetry (DSC) curves of PCL and PEG 4000 either as free components of after melt electrospinning are identical and both components shows a single endothermic peak at 63 and 61 °C respectively. Fourier transform infrared spectroscopy confirms the chemical stability of the raw materials, while X‐ray diffraction shows the conversion of PEG and Cip from crystalline to amorphous structure following melt electrospinning. Cip is released gradually over 72 h, and the release is increased in the presence of PEG with a maximum Cip release ≈25% after 72 h. The study provides new insights into the development of controlled release fiber mats loaded with antibacterial agents. This can help to develop formulations for wound dressings that improve the clinical outcomes.

Trypanosomiasis is a protozoan disease transmitted via Trypanosoma brucei. This study aimed to examine the metabolic profile and anti-trypanosomal effect of methanol extract of Thunbergia grandifolia leaves. The liquid chromatography-high resolution electrospray ionisation mass spectrometry (LC-HRESIMS) revealed the identification of fifteen compounds of iridoid, flavonoid, lignan, phenolic acid, and alkaloid classes. The extract displayed a promising inhibitory activity against T. brucei TC 221 with MIC value of 1.90 μg/mL within 72 h. A subsequent in silico analysis of the dereplicated compounds (i.e. inverse docking, molecular dynamic simulation, and absolute binding free energy) suggested both rhodesain and farnesyl diphosphate synthase as probable targets for two compounds among those dereplicated ones in the plant extract (i.e. diphyllin and avacennone B). The absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling of diphyllin and avacennone were calculated accordingly, where both compounds showed acceptable drug-like properties. This study highlighted the antiparasitic potential of T. grandifolia leaves.

Conflicting evidence exists about the effect of angiotensin‐converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) on COVID‐19 clinical outcomes. We aimed to provide a comprehensive/updated evaluation of the effect of ACEIs/ARBs on COVID‐19‐related clinical outcomes, including exploration of interclass differences between ACEIs and ARBs, using a systematic review/meta‐analysis approach conducted in Medline (OVID), Embase, Scopus, Cochrane library, and medRxiv from inception to 22 May 2020. English studies that evaluated the effect of ACEIs/ARBs among patients with COVID‐19 were included. Studies’ quality was appraised using the Newcastle‐Ottawa Scale. Data were analyzed using the random‐effects modeling stratified by exposure (ACEIs/ARBs, ACEIs, and ARBs). Heterogeneiity was assessed using I2 statistic. Several subgroup analyses were conducted to explore the impact of potential confounders. Overall, 27 studies were eligible. The pooled analyses showed nonsignificant associations between ACEIs/ARBs and death (OR:0.97, 95%CI:0.75,1.27), ICU admission (OR:1.09;95%CI:0.65,1.81), death/ICU admission (OR:0.67; 95%CI:0.52,0.86), risk of COVID‐19 infection (OR:1.01; 95%CI:0.93,1.10), severe infection (OR:0.78; 95%CI:0.53,1.15), and hospitalization (OR:1.15; 95%CI:0.81,1.65). However, the subgroup analyses indicated significant association between ACEIs/ARBs and hospitalization among USA studies (OR:1.59; 95%CI:1.03,2.44), peer‐reviewed (OR:1.93, 95%CI:1.38,2.71), good quality and studies which reported adjusted measure of effect (OR:1.30, 95%CI:1.10,1.50). Significant differences were found between ACEIs and ARBs with the latter being significantly associated with lower risk of acquiring COVID‐19 infection (OR:0.24; 95%CI: 0.17,0.34). In conclusion, high‐quality evidence exists for the effect of ACEIs/ARBs on some COVID‐19 clinical outcomes. For the first time, we provided evidence, albeit of low quality, on interclass differences between ACEIs and ARBs for some of the reported clinical outcomes.

Amorphous solid dispersion is one of the techniques used for enhancing dissolution rate of drugs with low aqueous solubility. The physical stability of the amorphous solid dispersion is the main challenge for their formulation development and commercialisation by pharmaceutical industry. The aims of the project were to prepare amorphous solid solution of a poorly aqueous soluble drug using different molecular weight mixtures of PEG and PEG mixed with other polymers such as PVP and poloxamers, the formulations were prepared using melt method, solvent evaporation and quench cooled from melt method. Also, to find a system with controlled instability to study the impact of various features on the stability of the formulation. A series of physicochemical characterisation techniques were used to evaluate the different formulations such as XRPD, VT XRPD, DSC, dissolution and microscopy. The cooling temperature of the formulation from melt has a great impact on forming amorphous CBZ in PEG mixture. PEG 300 did show the ability to reduce the crystallinity in the other PEG used and to reduce the enthalpy of CBZ recrystallisation which indicates that less crystals been formed. The higher the PEG concentration in the formulation, the more stable the CBZ amorphous form. The best performing formulations in terms of controlling the recrystallisation of the CBZ from melt were the PEG 4000 and 6000 mixed with PEG 300, but their dissolution profile was not as good as the formulations with one PEG. The substitution of just5% of PEG weight with PVP did show an increase in CBZ amorphous form stability. The quench cooling method did not show any decomposition of CBZ and that was proven by the HPLC method used. CBZ amorphous solid solution can be achieved by formulating the drug with PEG using melt method and the addition of secondary polymer such as PVP to the formulation at low concentration can inhibit the CBZ recrystallisation from the glassy/liquid state and increases CBZ physical stability.

uncover potential anticancer therapeutic targets. However, most SL screens have utilized knockout or knockdown approaches that do not accurately mimic chemical inhibition of a target protein. Here, we test whether missense mutations can be utilized as a model for a type of protein inhibition that creates a dominant gain-of-function cytotoxicity. We expressed missense mutations in the FEN1 endonuclease and the replication-associated helicase, CHL1, that inhibited enzymatic activity but retained substrate binding, and found that these mutations elicited a dominant SL phenotype consistent with the generation of cytotoxic protein–DNA or protein–protein intermediates. Genetic screens with nuclease-defective hFEN1 and helicase-deficient yCHL1 captured dominant SL interactions, in which ectopic expression of the mutant form, in the presence of the wild-type form, caused SL in specific mutant backgrounds. Expression of nuclease-defective hFEN1 in yeast elicited DNA binding-dependent dominant SL with homologous recombination mutants. In contrast, dominant SL interactions with helicase-deficient yCHL1 were observed in spindle-associated, Ctf18-alternative replication factor C (Ctf18-RFC) clamp loader complex, and cohesin mutant backgrounds. These results highlight the different mechanisms underlying SL interactions that occur in the presence of an inhibited form of the target protein and point to the utility of modeling trapping mutations in pursuit of more clinically relevant SL interactions.

The association between polymorphisms in the p53 tumor suppressor gene and breast cancer risk has been studied in many human populations with conflicting conclusions. However, similar studies in Arab women are not available, and the status of these polymorphisms in this ethnic population is not known. We investigated the status of four known p53 gene polymorphisms and their possible role in breast cancer risk in Arab women. Genotyping was performed for 288 breast cancer women and 188 controls to determine Pro47Ser, Arg72Pro, Intron 3 Ins16 bp and intron 6 (G > C) polymorphisms. The p53 variant Pro47Ser was detected only in one Kuwaiti breast cancer patient and was not detected in any of the control subjects. Frequency of Arg/Arg at codon 72 was 26.6% in controls and 28.1% in patients, Arg/Pro frequency was 59.6% in controls and 69.4% in patients, the Pro/Pro genotype was 13.8% in controls and 2.4% in patients. We observed that women with Pro/Pro genotype have decreased risk for developing breast cancer (OR = 0.166, 95% CI = 0.067–0.411, p  < 0.001). The intron 3 genotypes were A1/A1 (48.9%), A1/A2 (40.6%) and A2/A2 (10.5%) in controls and A1/A1(42.4%), A1/A2 (52.8%) and A2/A2 (4.8%) in cases. The intron 6 genotypes were 92.4% (GG), 7.6% (GC) and 0% (CC) in controls and 96.5% (GG), 3.5% (GC) and 0% (CC) in cases. No statistically significant differences between patients and controls were observed for intron 3 and intron 6 polymorphisms. Our data show that proline homozygosity at p53 codon 72 is associated with decreased breast cancer risk in Arab women.