Tadalafil versus tamsulosin as combination therapy with 5-alpha reductase inhibitors in benign prostatic hyperplasia, urinary and sexual outcomes.

PURPOSE: To compare the urological and sexual outcomes of using either tamsulosin/finateride or tadalafil/finasteride as combination therapies in patients with large prostate. PATIENTS AND METHODS: Selection criteria included prostate volume > 40 ml and IPSS > 7. Patients with severe erectile dysfunction (IIEF-erectile functions ≤ 10) were excluded. Patients were randomized into group I (tamsulosin/finasteride) and group II (tadalafil/finasteride). The primary endpoint was to define urinary and sexual function changes (IPSS, IPSS-quality of life, urinary flow rates and IIEF domains) within each group. The secondary endpoint was to compare the treatment induced changes between both groups. RESULTS: At 4th and 12th weeks, 131 and 127 patients were available in both groups, respectively. Both groups showed significant LUTS improvement (IPSS changes: - 4.9 ± 2.7 and - 4.3 ± 2.9 at 4th week and - 6.1 ± 3 and - 5.4 ± 2.8 points by the 12th week in both groups, respectively). Group I had better average flow rates at both follow-up visits. Meanwhile, maximum flow rates were comparable in both groups at 12th week (13.5 ± 3.9vs. 12.6 ± 3.7, p > 0.05). In group I, all IIEF domains were significantly lowered at both visits (p < 0.05). Group II showed significant increase in IIEF-erectile function scores (1.3 ± 1.1 and 1.8 ± 1.2 at the 4th and 12th weeks) with a transient significant reduction of IIEF-orgasm and sexual desire noted only by the 4th week (- 0.8 ± 0.4 and - 0.6 ± 0.4, respectively). CONCLUSION: Within three months, both combinations are comparably effective in improving BPH related LUTS. Tamsulosin/finasteride provided significantly better Qmax only at 4th week. Tadalafil/finasteride had the advantage of improving sexual performance over the other combination.

Rational design, synthesis, molecular modeling, biological activity, and mechanism of action of polypharmacological norfloxacin hydroxamic acid derivatives.

Fluoroquinolones are broad-spectrum antibiotics that target gyrase and topoisomerase IV, involved in DNA compaction and segregation. We synthesized 28 novel norfloxacin hydroxamic acid derivatives with additional metal-chelating and hydrophobic pharmacophores, designed to enable interactions with additional drug targets. Several compounds showed equal or better activity than norfloxacin against Gram-positive, Gram-negative, and mycobacteria, with MICs as low as 0.18 µM. The most interesting derivatives were selected for in silico, in vitro, and in vivo mode of action studies. Molecular docking, enzyme inhibition, and bacterial cytological profiling confirmed inhibition of gyrase and topoisomerase IV for all except two tested derivatives (10f and 11f). Further phenotypic analysis revealed polypharmacological effects on peptidoglycan synthesis for four derivatives (16a, 17a, 17b, 20b). Interestingly, compounds 17a, 17b, and 20b, showed never seen before effects on cell wall synthetic enzymes, including MreB, MurG, and PonA, suggesting a novel mechanism of action, possibly impairing the lipid II cycle.

N4-Substituted Piperazinyl Norfloxacin Derivatives with Broad-Spectrum Activity and Multiple Mechanisms on Gyrase, Topoisomerase IV, and Bacterial Cell Wall Synthesis.

Fluoroquinolones are an important class of antibiotics with broad-spectrum antibacterial and antitubercular activity. Here, we describe the design and synthesis of a series of 38 N4-substituted piperazinyl norfloxacin derivatives. Their activity and mechanism of action were characterized using in silico, in vitro, and in vivo approaches. Several compounds displayed interesting activities against both Gram-negative and Gram-positive bacteria, and few displayed antimycobacterial activity, whereby some were as potent as norfloxacin and ciprofloxacin. Molecular docking experiments suggested that the new derivatives inhibit both DNA gyrase and DNA topoisomerase IV in a similar manner as norfloxacin. Selecting the most promising candidates for experimental mode of action analysis, we confirmed DNA gyrase and topoisomerase IV as targets of all tested compounds using enzymatic in vitro assays. Phenotypic analysis of both Escherichia coli and Bacillus subtilis confirmed a typical gyrase inhibition phenotype for all of the tested compounds. Assessment of possible additional targets revealed three compounds with unique effects on the B. subtilis cell wall synthesis machinery, suggesting that they may have an additional target in this pathway. Comparison with known cell wall synthesis inhibitors showed that the new compounds elicit a distinct and, so far, unique phenotype, suggesting that they act differently from known cell wall synthesis inhibitors. Interestingly, our phenotypic analysis revealed that both norfloxacin and ciprofloxacin displayed additional cellular effects as well, which may be indicative of the so far unknown additional mechanisms of fluoroquinolones.

Design, Synthesis, Molecular Modeling, Biological Activity, and Mechanism of Action of Novel Amino Acid Derivatives of Norfloxacin.

Two series of N4-substituted piperazinyl amino acid derivatives of norfloxacin (24 new compounds) were designed and synthesized to attain structural surrogates with additional binding sites and enhanced antibacterial activity. Synthesized derivatives showed increased antibacterial and antimycobacterial activity compared to their lead structure, norfloxacin. Molecular modeling studies supported the notion that the derivatives can establish additional bonds with the target enzymes gyrase and topoisomerase IV. In vitro enzyme inhibition assays confirmed that the tested compounds were significant inhibitors of these enzymes. Inhibition of gyrase and topoisomerase IV was then confirmed in living bacterial cells using bacterial cytological profiling of both Gram-negative Escherichia coli and Gram-positive Bacillus subtilis, revealing a typical topoisomerase inhibition phenotype characterized by severe nucleoid packing defects. Several derivatives exhibited additional effects on the Gram-positive cell wall synthesis machinery and/or the cytoplasmic membrane, which likely contributed to their increased antibacterial activity. While we could not identify specific cell wall or membrane targets, membrane depolarization was not observed. Our experiments further suggest that cell wall synthesis inhibition most likely occurs outside the membrane-bound lipid II cycle.

A diselenide additive enables photocatalytic hydroalkoxylation of gem-difluoroalkenes.

A photocatalytic hydroalkoxylation reaction enables the coupling of aliphatic alcohols with gem-difluoroalkenes, expanding the scope of accessible α,α-difluorinated ethers, a desirable substructure for medicinal and agricultural chemists. This reaction exploits an uncommon diselenide co-catalyst to facilitate the net hydrofunctionalization process, which contrasts alternate single-electron reactions that deliver dioxidation products. Future use of this co-catalyst might enable other currently unknown photocatalytic reactions.

General Co-catalytic Hydrothiolation of gem-Difluoroalkenes.

Regioselective functionalization of gem-difluoroalkenes enables convergent late-stage access to fluorinated functional groups, though most functionalization reactions proceed through defluorinative functionalization processes that deliver mono-fluorovinyl products. In contrast, fewer reactions undergo net hydrofunctionalization to generate difluorinated products. Herein, we report a photocatalytic hydrothiolation of gem-difluoroalkenes that enables access to a broad spectrum of α,α-difluoroalkylthioethers. Notably, the reaction successfully couples nonactivated substrates, which expands the scope of accessible molecules relative to previously reported reactions involving organo- or photocatalytic strategies. Further, this reaction successfully couples biologically relevant molecules under aqueous conditions, highlighting potential applications in both late-stage and biorthogonal functionalizations.

Design, Synthesis, Molecular Modeling, and Anticancer Evaluation of New VEGFR-2 Inhibitors Based on the Indolin-2-One Scaffold.

A new series of indoline-2-one derivatives was designed and synthesized based on the essential pharmacophoric features of VEGFR-2 inhibitors. Anti-proliferative activities were assessed for all derivatives against breast (MCF-7) and liver (HepG2) cancer cell lines, using sunitinib as a reference agent. The most potent anti-proliferative derivatives were evaluated for their VEGFR-2 inhibition activity. The effects of the most potent inhibitor, 17a, on cell cycle, apoptosis, and expression of apoptotic markers (caspase-3&-9, BAX, and Bcl-2) were studied. Molecular modeling studies, such as docking simulations, physicochemical properties prediction, and pharmacokinetic profiling were performed. The results revealed that derivatives 5b, 10e, 10g, 15a, and 17a exhibited potent anticancer activities with IC50 values from 0.74-4.62 µM against MCF-7 cell line (sunitinib IC50 = 4.77 µM) and from 1.13-8.81 µM against HepG2 cell line (sunitinib IC50 = 2.23 µM). Furthermore, these compounds displayed potent VEGFR-2 inhibitory activities with IC50 values of 0.160, 0.358, 0.087, 0.180, and 0.078 µM, respectively (sunitinib IC50 = 0.139 µM). Cell cycle analysis demonstrated the ability of 17a to induce a cell cycle arrest of the HepG2 cells at the S phase and increase the total apoptosis by 3.5-fold. Moreover, 17a upregulated the expression levels of apoptotic markers caspase-3 and -9 by 6.9-fold and 3.7-fold, respectively. In addition, 17a increased the expression level of BAX by 2.7-fold while decreasing the expression level of Bcl-2 by 1.9-fold. The molecular docking simulations displayed enhanced binding interactions and similar placement as sunitinib inside the active pocket of VEGFR-2. The molecular modeling calculations showed that all the test compounds were in accordance with Lipinski and Veber rules for oral bioavailability and had promising drug-likeness behavior.

Refractory Hyperammonemic encephalopathy in Fibrolamellar hepatocellular carcinoma, a case report and literature review.

Fibrolamellar hepatocellular carcinoma is a rare type of hepatocellular carcinoma with unclear etiology. Its prevalence ranges from 0.6%-5%. One of the rare manifestations of FHCC includes hyperammonemic hepatic encephalopathy (HAE). Data regarding HAE in FHCC is limited to case reports, and much is unknown, including its precipitating factors, clinical course, and management. We have reported one such case of FHCC associated HAE and presented an extensive literature review on the topic. We report the case of a 26-year-old Pakistani male who was diagnosed with fibrolamellar hepatocellular carcinoma. On day five after the first chemotherapy, he presented with nausea, vomiting, and confusion. His serum ammonia level was raised, and he was treated with lactulose and rifaximin. The patient continued chemotherapy and had recurrent admissions with HAE. A detailed workup revealed acquired ornithine transcarbamylase deficiency. Ammonia level peaked at 694 umol/L during the clinical course of his disease. He received treatment with multiple ammonia scavengers, including sodium benzoate + phenylacetate, with relief of symptoms and reduction in ammonia level. The patient was eventually lost to follow-up. HAE presents as a paraneoplastic manifestation of FHCC. Patients have laboratory features suggestive of acquired ornithine transcarbamylase deficiency. There is a variable frequency of episodes reported in the literature. Most patients respond well to ammonia scavenger therapies rather than conventional HE management with lactulose or rifaxmin.

Smart wearable devices in cardiovascular care: where we are and how to move forward.

Technological innovations reach deeply into our daily lives and an emerging trend supports the use of commercial smart wearable devices to manage health. In the era of remote, decentralized and increasingly personalized patient care, catalysed by the COVID-19 pandemic, the cardiovascular community must familiarize itself with the wearable technologies on the market and their wide range of clinical applications. In this Review, we highlight the basic engineering principles of common wearable sensors and where they can be error-prone. We also examine the role of these devices in the remote screening and diagnosis of common cardiovascular diseases, such as arrhythmias, and in the management of patients with established cardiovascular conditions, for example, heart failure. To date, challenges such as device accuracy, clinical validity, a lack of standardized regulatory policies and concerns for patient privacy are still hindering the widespread adoption of smart wearable technologies in clinical practice. We present several recommendations to navigate these challenges and propose a simple and practical 'ABCD' guide for clinicians, personalized to their specific practice needs, to accelerate the integration of these devices into the clinical workflow for optimal patient care.

Fatal temozolomide induced aplastic anemia in a female with Glioblastoma multiforme : A case report and literature review.

When seeing patients on Temozolomide with pancytopenia, aplastic anemia secondary to the drug should be considered early in the differentials to avoid permanent hematological suppression.

Microwave pre-treatment of canola seeds and flaked seeds for increased hot expeller oil yield.

Microwave (MW) pre-treatment of canola seeds or flaked seeds was found to be a superior alternative to the conventional thermal pre-treatment (steam). Flaked seeds were "cooked" (heat-treated) with steam or using microwave treatments in the temperature range of 62-130 °C prior to expeller pressing. Microwave cooking at 100 °C resulted in the highest increase in the pressed oil yield, which is an increase of 3.7% (w/w) on a pressed oil basis or 9.0% (oil in seed basis) compared with steam cooking. Whole canola seeds conditioning was conducted with microwaves or steam, in the temperature range of 40-75 °C, followed by microwave or steam cooking at 100 °C to evaluate the effect of MW treatment during conditioning on the expeller oil yield. The use of a continuous microwave process for combined conditioning of whole seeds at 55 °C and subsequent cooking of flaked seeds at 100 °C resulted in a 4.0% increase in expeller oil yield, compared with steam conditioning and cooking. The influence of dry basis (db %) moisture contents of 5%, 11.5%, and 16.5% on oil yield after steam or MW treatments of seeds and flaked seeds was also studied. The moisture content of 11.5% (db %) yielded the highest net oil yield for both MW and steam at best conditioning and cooking temperatures of 55 °C and 100 °C, respectively. No significant impact of MW cooking was seen on oil quality compared with conventional steam cooking.

Cardiac Biomarkers and Cardiovascular Outcome in Children with Chronic Kidney Disease.

INTRODUCTION: Myocardial dysfunction is a leading cause of mortality in chronic kidney disease (CKD) children specially those on regular hemodialysis. Cardiac biomarkers play a key role for early detection of myocardial injury. We aim to clarify the prognostic role of circulating cardiac biomarkers, heart type fatty acid binding protein (H-FABP) and pregnancy associated plasma protein-A (PAPP-A) in CKD children on regular hemodialysis. MATERIAL AND METHODS: This is a prospective case control study over 2 years duration. Initial assessment included 20 CKD children on regular hemodialysis and 20 age- and sex- matched healthy children as a control group. Serum level of H-FABP and PAPP-A were measured and correlated to conventional echocardiographic findings and cardiovascular outcome in CKD children. RESULTS: 60% of CKD children developed cardiovascular comorbidities. H-FABP and PAPP-A levels were significantly elevated especially in those with worse cardiovascular outcome. H-FABP and PASP-A levels were positively correlated with LVM index. At cut off point > 17.65 pg/mL, H-FABP has 91% sensitivity and 87.5% specificity for prediction of cardiac morbidity. Elevated H-FABP (OR = 33; CI 95%: 2.455 - 443.591), LVM indexed to body surface area (OR = 21; CI 95%: 1.777 - 248.103), LVM indexed to lean body mass (OR = 15; CI 95%: 1.652 -136.172), elevated PAPP-A (OR = 9.8; CI 95%: 0.898 - 106.845) and Hypertension (OR = 8.333; CI 95%: 1.034 - 67.142) are the main risk factors for cardiac morbidities in CKD children. CONCLUSIONS: Elevated H-FABP and PAPP-A are valuable prognostic markers for cardiovascular outcome in CKD children on regular hemodialysis.

Immunohistochemical Expression of Caspase-3 in Psoriasis.

INTRODUCTION: Psoriasis is a persistent chronic immune-mediated, relapsing, inflammatory and hyper proliferative skin disorder with genetic predisposition. Psoriasis can be considered as a T-cell mediated disease, with a complex role for a variety of cytokine interaction between keratinocytes and T-lymphocytes. Caspase-3 is an enzyme that plays a key role in apoptosis; it is a member of the family of cysteinyle aspartate specific proteases. AIM: To evaluate the expression of caspase-3 in Egyptian psoriasis patients and its role in apoptosis of keratinocytes. Also, to correlate this expression with the clinicopathological parameters in order to identify the possible hypothesized role of caspase-3 in the pathogenesis of psoriasis. MATERIALS AND METHODS: This was a case-control study conducted on patients suffering from chronic plaque psoriasis. A total of 20 psoriasis patients and 10 controls were selected from outpatient clinic of Dermatology, Menoufia University Hospital, between the period of October 2014 and January 2016. From each patient and control, a punch biopsy was taken. Evaluation of H&E stained sections and caspase-3 expression was done using standard immunohi-stochemical techniques. Non-parametric chi-square test, Mann-Whitney U test, Kruskal Wallis test and Spearman's coefficient test were the statistical tests used. RESULTS: High caspase-3 H score was significantly in favour of psoriatic group in comparison with the control group. On the contrary, in the dermis, caspase-3 was significantly higher in skin adnexa while completely absent in the psoriatic group. Strong caspase-3 expression was significantly in favour of high PASI score, early onset lesions and lesions in the extremities. Significant positive correlation was found between caspase-3 percent and PASI score (r= +0.53, p-value=0.03). CONCLUSION: Caspase-3 over expression in the psoriatic lesion proposes a potential role in the pathogenesis of psoriasis. Positive correlation between the caspase-3 expression and the early onset psoriatic lesion located in the extremities implies a possible poor prognostic impact of caspase-3 over expression.

Evaluation of the effect and mechanism of action of local phenytoin in treatment of vitiligo.

There are many theories explaining vitiligo such as genetic, autoimmune, neural, free radicals, biochemical, intrinsic defect, melanocytorrhagy, and convergent theories. Phenytoin is a widely used anticonvulsant, which is used in cutaneous medicine for treatment of ulcers and epidermolysis bullosa. The aim of this study is to assess the effectiveness of topical phenytoin gel in the treatment of vitiligo patients and explaining the underlying mechanism using immunohistochemistry for evaluation of HMB45, CD4, and CD8. Only 9 patients out of 28 experienced response to phenytoin in the form of dull, white color change and light brown color. Post-phenytoin treatment biopsies showed decreased density of inflammation, increased melanin and increased HMB45 positive cells together with an increased number of CD4 positive lymphocytes and decreased number of CD8 positive lymphocytes. These observations did not reach significant level (P > 0.05). A high percentage of CD4 positive lymphocytes was significantly associated with a long duration of vitiligo (p = 0.03) and segmental vitiligo type (p = 0.02). The current study applied phenytoin as 2% concentrated gel for 3 months, which is a relatively short duration without observed side effects throughout the period. These results indicate that topical phenytoin of low concentrations may have beneficial effects through immunomodulatory activity by affecting CD4 and CD8 counts and subsequently the ratio between them. Further studies are recommended to combine phenytoin with other antivitiligo agents as local corticosteroids or phototherapy to clarify if it could potentiate their effects.

Enantioselective Total Synthesis of (+)-Sieboldine A.

The first total synthesis of (+)-sieboldine A was completed starting from 5-(p-methoxybenzyloxy)pentyne in 19 steps. The enantioselective Keck allylation provided the dienyne derivative, which was exposed to the Pauson-Khand conditions to afford the bicyclo[4.3.0]nonenone derivative with high stereoselectivity with an ee value of 93%. The following Ueno-Stork reaction formed the cis-hydrindane core with a quaternary carbon center. The late-stage Schmidt glycosylation led to the formation of the N-hydroxyazacyclononane ring.

Efficacy and safety of tamsulosin as a medical expulsive therapy for stones in children.

OBJECTIVES: To evaluate the efficacy of tamsulosin for promoting ureteric stone expulsion in children, based on the confirmed efficacy of tamsulosin as a medical expulsive therapy in adults. PATIENTS AND METHODS: From February 2010 to July 2013, 67 children presenting with a distal ureteric stone of <1 cm as assessed on unenhanced computed tomography were included in the study. The patients were randomised into two groups, with group 1 (33 patients) receiving tamsulosin 0.4 mg and ibuprofen, and group 2 (34) receiving ibuprofen only. They were followed up for 4 weeks. Endoscopic intervention was indicated for patients with uncontrolled pain, recurrent urinary tract infection, hypersensitivity to tamsulosin and failure of stone passage after 4 weeks of conservative treatment. RESULTS: Sixty-three patients completed the study. There were no statistically significant differences between the groups in patient age, body weight and stone size, the mean (SD) of which was 6.52 (1.8) mm in group 1 vs. 6.47 (1.79) mm in group 2 (P = 0.9). The mean (SD) time to stone expulsion in group 1 was 7.7 (1.9) days, vs. 18 (1.73) days in group 2 (P < 0.001). The analgesic requirement (mean number of ketorolac injections) in group 1 was significantly less than in group 2, at 0.55 (0.8) vs. 1.8 (1.6) (P < 0.001). The stone-free rate was 87% in group 1 and 63% in group 2 (P = 0.025). CONCLUSIONS: Tamsulosin used as a medical expulsive therapy for children with ureteric stones is safe and effective, as it facilitates spontaneous expulsion of the stone.

An unusual cause of fetomaternal distress at term: uterine vessel rupture in pregnancy.

This report describes a case of spontaneous bleeding from uterine vessels presenting as hyperstimulation and fetomaternal distress at term. A 40-week primigravid woman underwent an emergency caesarean section for fetal distress, which unexpectedly revealed a spontaneous haemoperitoneum. Clinical assessment and investigations postoperatively gave a diagnosis of a right-sided uterine artery aneurysm that, it was believed, had ruptured, causing the haemoperitoneum. This was successfully treated postnatally using interventional radiological techniques leading to expeditious maternal recovery and discharge home.

Synthesis, biological investigation and molecular docking study of N-malonyl-1,2-dihydroisoquinoline derivatives as brain specific and shelf-stable MAO inhibitors.

A group of N-malonyl-1,2-dihydroisoquinoline derivatives were synthesized and investigated as brain specific and shelf-stable MAO inhibitors. N-malonyl-1,2-dihydroisoquinoline redox carrier system was linked through amidic bond to 4-chloro and 4-nitrobenzylidenehydrazines (9a-b), as monoamine oxidase inhibitors (MAOIs), and ß-phenethylamine (14), as a model drug, to afford a novel group of N-malonyl-1,2-dihydroisoquinoline chemical delivery systems (DHIQCDSs) (13a-b and 18). These systems are expected to be stable against air oxidation due to the presence of the carbonyl group close to nitrogen of the dihydroisoquinoline. The synthesized DHIQCDS (18) was subjected to various chemical and biological investigations to evaluate its stability and prove its ability to cross the blood brain barrier and "lock-in" the brain. The in vitro chemical and enzymatic oxidation studies showed reasonable stability and adequate rate of conversion of DHIQCDS (18) to its corresponding quaternary metabolites. In vivo distribution study in rats revealed preferential concentration of the active moiety in the brain. Moreover, compounds (9a-b, 12a-b and 17) were screened for their in vitro MAO inhibitory activity compared to clorgyline as a reference compound. The inhibition profile was found to be competitive for both MAO-A and MAO-B isozymes with more selectivity toward MAO-A. Molecular docking study of compounds (9a-b, 12a-b and 17) and the suggested metabolites was carried out on both MAO-A and MAO-B isozymes. Observation of the docked poses revealed many interactions with many residues previously reported to have an effect on the inhibition of MAO enzyme.

TMEM158 and FBLP1 as novel marker genes of cisplatin sensitivity in non-small cell lung cancer cells.

Even after development of molecular targeting therapies, platinum-based chemotherapy is still a standard care for treatment of locally advanced non-small cell lung cancer (NSCLC). So far, critical molecular markers capable to predict the therapeutic response in NSCLC patients remain undetermined. We here attempted to identify novel biomarker genes for cisplatin (CDDP) for a tailored therapy. Initial screening to explorer association of IC(50) values of CDDP obtained by MTT assay and gene expression levels measured with oligonucleotide microarray and real-time RT-PCR provided 6 candidate genes, namely, NUBPL, C9orf30, ZNF12, TMEM158, GSK3B, and FBLP1 using 9 lung cancer cells consisting of 3 small and 6 NSCLC cells. These 6 genes together with 5 reported biomarkers, i.e., GSTP1, ERCC1, BRCA1, FRAP1, and RRM1, were subjected to a linear regression analysis using 12 NSCLC cell lines including 6 additional NSCLC cells: only FBLP1 and TMEM158 genes showed positive associations with statistical significances (P = .016 and .026, respectively). The biological significance of these genes was explored by in vitro experiments: Knockdown experiments in PC-9/CDDP cells revealed that the reduced expression of TMEM158 significantly decreased the chemo-resistance against CDDP (P <.0001), while 2 transformants of PC-6 cells stably over-expressing FBLP1 resulted in an enhanced resistance to CDDP (P = .004 and P = .001). Furthermore, a stepwise multiple regression analysis demonstrated the best prediction formula could be fixed when we used expression data of TMEM158 and FBLP1 (R(2) = 0.755, P = .0018). TMEM158 and FBLP1 may be powerful predictive biomarkers for CDDP therapy in NSCLC.