The effect of adding Montelukast to oxybutynin on daily urination in children with pollakiuria: a randomized clinical trial.

PURPOSE: Pollakiuria is defined as a change in the pattern of daily urination. Students have mentioned wetting their pants at school as the third tragic event after the death of a parent or going blind. In this study, the effect of adding Montelukast to oxybutynin on the improvement of urinary symptoms of patients with pollakiuria was studied. MATERIALS AND METHODS: This study was a pilot clinical trial in which children with pollakiuria aged 3-18 years old were included. These children were randomly divided into two groups of intervention (Montelukast plus oxybutynin) and the control group (only oxybutynin). At the beginning and the end of the study (after 14 days), mothers were asked about the frequency of daily urination. Finally, the gathered data were compared between two groups. RESULTS: In the present study, 64 patients were examined in two intervention and control groups (32 in each group). The results revealed that although significant changes were observed in both groups before and after intervention, the average changes in the intervention group were significantly higher (p = 0.014). CONCLUSION: The results of this study showed that adding montelukast to oxybutynin has a significant decrease in frequency of daily urination in patients with pollakiuria, although further studies are recommended in this area.

Design, Synthesis, In Vitro Antifungal Activity and Mechanism Study of the Novel 4-Substituted Mandelic Acid Derivatives.

Plant diseases caused by phytopathogenic fungi are a serious threat in the process of crop production and cause large economic losses to global agriculture. To obtain high-antifungal-activity compounds with novel action mechanisms, a series of 4-substituted mandelic acid derivatives containing a 1,3,4-oxadiazole moiety were designed and synthesized. In vitro bioassay results revealed that some compounds exhibited excellent activity against the tested fungi. Among them, the EC50 values of E13 against Gibberella saubinetii (G. saubinetii), E6 against Verticillium dahlia (V. dahlia), and E18 against Sclerotinia sclerotiorum (S. sclerotiorum) were 20.4, 12.7, and 8.0 mg/L, respectively, which were highly superior to that of the commercialized fungicide mandipropamid. The morphological studies of G. saubinetii with a fluorescence microscope (FM) and scanning electron microscope (SEM) indicated that E13 broke the surface of the hyphae and destroyed cell membrane integrity with increased concentration, thereby inhibiting fungal reproduction. Further cytoplasmic content leakage determination results showed a dramatic increase of the nucleic acid and protein concentrations in mycelia with E13 treatment, which also indicated that the title compound E13 could destroy cell membrane integrity and affect the growth of fungi. These results provide important information for further study of the mechanism of action of mandelic acid derivatives and their structural derivatization.

Fesoterodine treatment of pediatric patients with neurogenic detrusor overactivity: A 24-week, randomized, open-label, phase 3 study.

BACKGROUND: Neurogenic detrusor overactivity (NDO) can damage the upper urinary tract leading to chronic renal impairment. Antimuscarinic therapy is used to improve urinary incontinence and protect the upper urinary tract in patients with NDO. OBJECTIVE: This study investigated safety and efficacy of fesoterodine, a muscarinic receptor antagonist, in 6‒<18-year-old patients with NDO (NCT01557244). STUDY DESIGN: This open-label phase 3 study included 2 pediatric cohorts. Patients in Cohort 1 (bodyweight >25 kg) were randomized to fesoterodine 4 or 8 mg extended-release tablets or oxybutynin XL tablets administered over the 12-week active comparator-controlled phase. The safety extension phase evaluated fesoterodine 4 and 8 mg for a further 12 weeks, with patients in the oxybutynin arm allocated to fesoterodine 4 or 8 mg. Patients in Cohort 2 (bodyweight ≤25 kg) were randomized to fesoterodine 2 or 4 mg extended-release beads-in-capsule (BIC) administered over a 12-week efficacy phase and 12-week safety extension phase. Patients with stable neurologic disease and clinically or urodynamically proven NDO were included. The primary endpoint was change from baseline to Week 12 in maximum cystometric bladder capacity (MCC). Secondary efficacy endpoints included detrusor pressure at maximum bladder capacity, bladder volume at first involuntary detrusor contraction, bladder compliance, and incontinence episodes. Safety endpoints included adverse event incidence, and specific assessments of cognition, behavior and vision. The pharmacokinetics of 5-hydroxymethyl tolterodine (5-HMT; fesoterodine's active metabolite) was determined using population-pharmacokinetic analysis. RESULTS: In Cohort 1 (n = 124), fesoterodine 4 and 8 mg treatment resulted in significant increases from baseline in the primary endpoint of MCC at Week 12. In Cohort 2 (n = 57), fesoterodine 2 and 4 mg BIC treatment resulted in improvements in MCC from baseline. Fesoterodine 4 and 8 mg and fesoterodine 4 mg BIC led to improvements in some secondary efficacy endpoints. The most common treatment-related adverse reactions were gastrointestinal effects, such as dry mouth, which occurred more frequently with oxybutynin than fesoterodine. No detrimental effects on visual accommodation or acuity, or on cognitive function or behavior were observed. DISCUSSION: These safety and efficacy results are consistent with limited published data on fesoterodine treatment in pediatric populations with overactive bladder or NDO. Study limitations include the lack of placebo control and the small sample size, which limits the ability to make formal efficacy comparisons and detect rare adverse reactions. CONCLUSION: Fesoterodine has a favorable benefit-risk profile in 6‒<18-year-old patients with NDO and may represent an additional option for pediatric NDO treatment.

Phytochemicals from the flowers of Prunus persica (L.) Batsch: Anti-adipogenic effect of mandelamide on 3T3-L1 preadipocytes.

Flowers of Prunus persica (L.) Batsch (Rosaceae), known as peach blossoms, have been reported to exert anti-obesity effects by improving hepatic lipid metabolism in obese mice. However, little is known regarding the anti-adipogenic effects of the phenolic compounds isolated from P. persica flowers. This study investigated the inhibitory effects of compounds extracted from P. persica flowers (PPF) on adipogenesis in 3T3-L1 murine preadipocytes using adipogenic differentiation assays. Additionally, we compared the anti-adipogenic effects of the phenolic compounds isolated from PPF, such as prunasin amide (1), amygdalin amide (2), prunasin acid (3), mandelamide (4), methyl caffeate (5), ferulic acid (6), chlorogenic acid (7), benzyl α-l-xylpyranosyl-(1 â†’ 6)-ß-d-glucopyranoside (8), prunin (9), naringenin (10), nicotiflorin (11), astragalin (12), afzelin (13), and uridine (14), on adipogenesis in 3T3-L1 murine preadipocytes. PPF and compounds 4-7 and 10 significantly inhibited adipogenesis. Among them, mandelamide (4) exhibited the maximum inhibitory activity with an IC50 of 36.04 ± 1.82 µM. Additionally, mandelamide downregulated the expression of key adipogenic markers, such as extracellular signal-regulated kinase, c-Jun-N-terminal kinase, P38, CCAAT/enhancer-binding protein α, CCAAT/enhancer-binding protein ß, peroxisome proliferator activated receptor γ, and glucocorticoid receptor. These results indicate that mandelamide is an active ingredient of PPF possessing anti-obesity properties.

Design, synthesis and antifungal evaluation of novel mandelic acid derivatives containing a 1,3,4-oxadiazothioether moiety.

A series of novel mandelic acid derivatives containing a 1,3,4-oxadiazothioether moiety were designed and synthesized. Bioassay results showed that some target compounds exhibited certain antifungal activity against six kinds of pathogenic fungi in vitro. Among the compounds, the EC50 values of T41 against Gibberella saubinetii, Verticillium dahlia and Sclerotinia sclerotiorum were 31.0, 27.0 and 32.1 µg/ml, respectively, and the EC50 value of T14 against S. sclerotiorum was 14.7 µg/ml. The antifungal activity against the resistant fungus S. sclerotiorum indicated that this series of target compounds may have the similar action modes or sites as the commercialized succinate dehydrogenase inhibitor carboxin. A morphological study with fluorescence microscope demonstrated that T41 can significantly destroy the membrane integrity of G. saubinetii.

Antimicrobial Properties of Mandelic Acid, Gallic Acid and their Derivatives.

PURPOSE: Alpha-hydroxy acids (AHAs) are one of the classes of hydroxy acids being beneficial for human health. The manuscript summarizes the biological properties of two popular members of AHAs, i.e., Mandelic Acid (MA) and Gallic Acid (GA), with particular emphasis on antimicrobial properties. Moreover, attempts to design new derivatives improving the natural properties of AHAs by using the chemical and physical approach are discussed. METHODS: Antimicrobial properties of MA, an arylalkyl AHA containing phenyl group attached to α- carbon, and GA, an aromatic trihydroxybenzoic acid containing the phenolic ring and carboxylic acid functional group, and their derivatives against common human and plant pathogenic fungi have been reviewed. RESULTS: The antimicrobial activity of MA and GA is a complex phenomenon strictly correlated with other properties exhibited by these acids, e.g., pro-oxidative activity and hydrophobicity. In most cases, the acids derivatives exhibited higher antimicrobial activity than the acids themselves. This is probably because of the higher lipophilicity of moiety that allows better penetration through the cell membrane. CONCLUSION: MA and GA present an excellent health-promoting tool and are valuable starting materials for the design of new compounds such as metal complexes with alkali, or alkali earth metals. The lipophilic, antimicrobial, and pro-oxidative properties act synergistically, supporting the pharmacological and therapeutic effect of acids and their derivatives.

Toxicity studies and anti-arthritic effect of mandelic acid (2-hydroxy -2-phenyl acetic acid) using in vitro and in vivo techniques.

The major concern to search for new anti-arthritic drugs is primarily to prevent systemic complications and to maintain quality of life. As these drugs are prescribed for long duration so the objective is to ensure their safety in terms of toxicity. By keeping in view this concept, the present study was investigated to determine new anti-arthritic potential using in-vitro and in-vivo methods. The in-vitro tests comprised of protein denaturation (BSA and egg albumin) and Human Red Blood cell (HRBC) membrane stabilization assays at 50-6400µg/mL, for in-vivo testing, formaldehyde-induced arthritic rats were treated with 40, 80 and 160mg/kg mandelic acid. Mandelic acid (MA) inhibited the protein denaturation and stabilized the membrane of HRBC in a concentration dependent manner. Likewise, mandelic acid exhibited dose dependent reduction in paw volume induced by formaldehyde. For acute and sub-acute treatment, MA did not show any sign of toxicity and mortality in each rat and LD50 might be greater than 2000mg/kg. In addition, histopathological assessment presented slight increased interstitial spaces in the kidney, disorganization of glomerulus, dilated sinusoids at highest dose 800mg/kg which were not observed in sub-chronic therapy. Hence, these results conclude that mandelic acid has the potential to treat rheumatoid arthritis with observed no significant signs of toxicity and should be tested further to determine anti-arthritic mechanism of drug action at cellular level.

Posicionamiento de la AEU en la administración transdérmica de fármacos: una evolución determinante en la terapia urológica funcional / AEU positioning statement on transdermal drug administration: determinant evolution of functional urologic therapy

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Effect of Antimuscarinic Drugs on Cognitive Functions in the Management of Overactive Bladder in Elderly.

BACKGROUND: overactive bladder (OAB) affects 17-41% older adults in community dwelled setting. For several years, antimuscarinics have been validated as the first-line medical treatment for OAB. Despite abundant data obtained from clinical trials provisions the use of antimuscarinics, investigation about the effect of this drug on cognitive function in elderly remains scarce. The objective of this study is to investigate the effect of antimuscarinics therapy on cognitive functions in OAB geriatric patients. METHODS: this study design is a systematic review and meta-analysis. Studies were collected using several search engines; those were PubMed, Science Direct, Cochrane, and EBSCOhost using predetermined MeSH keywords with Boolean operators. Selection of studies was done by three reviewers. Studies which fulfilled the inclusion and exclusion criteria underwent full-text review. For every selected full text, we extracted the following data if available: patients demographics, types of antimuscarinics used, placebo, dose, follow-up period, and Mini-Mental State Examination (MMSE) total score. RESULTS: a total of 8 studies from an initial 146 publications were selected. There were 8 antimuscarinic agents evaluated in the studies, including Oxybutynin, Darifenacin, Tolterodine, Trospium, Imidafenacin, Propiverine hydrochloride, Fesoterodine, and Solifenacin. Oxybutynin was shown to have largest effect towards the decline of MMSE score [Mean difference: -2.90; 95% CI: -4.07, -1.73]. Darifenacin and Tolterodine were also shown to be significant in the decline of total MMSE score, although still inferior to Oxybutynin. CONCLUSION: the use of most antimuscarinics medication has little to no effect towards the cognitive function in the management of overactive bladder in elderly patients. However, Oxybutynin, Darifenacin, and Tolterodine was shown to have significant decrease in cognitive functions, as shown in the decline of total MMSE score.

dl-Mandelic acid exhibits high sperm-immobilizing activity and low vaginal irritation: A potential non-surfactant spermicide for contraception.

dl-Mandelic acid (MA), an alpha-hydroxycarboxylic acid, has been widely used as an intermediate of pharmaceutical and fine chemicals. Here, we evaluated the sperm-immobilizing activity of MA and its safety profiles. Spermatozoon motility was assessed by computer-aided sperm analysis, the integrity of the plasma membrane and. mitochondrial potential was assessed using fluorescein isothiocyanate-pisum sativum agglutinin and JC-1, respectively. The local tolerance of the MA-containing gel formulation was evaluated using a rabbit vaginal irritation test. We found that MA inhibited sperm motility and movement patterns in a concentration-dependent manner. Within 20 s, MA-induced spermatozoa immobilization occurred with a minimum effective concentration and a median effective concentration of 0.86 and 0.54 mg/mL, respectively. Plasma membrane disruptions of MA-treated spermatozoa were relatively mild, but mitochondrial depolarization occurred. Histopathological examination showed that MA exposure did not exert obvious effects on the integrity of spermatozoa membrane structures and only caused slight irritation to the rabbit vaginal epithelium. The vaginal irritation scores of the vehicle control and the nonoxynol -9 gel control groups were 1.38 ± 0.65 and 7.88 ± 1.67, respectively (p < 0.01), whereas those of the MA gel groups at 10, 20, and 40 mg/mL were 1.69 ± 1.04, 2.98 ± 0.77, and 4.35 ± 1.04 with p values of >0.05, >0.05, and <0.05 (vs. vehicle control), respectively, which were within the clinically acceptable range (<8). Therefore, our results confirmed that MA exhibited significant sperm-immobilizing effects and caused mild plasma membrane injury, suggesting that it has potential for development as a future non-surfactant spermicide.

Medications used to treat bladder disorders may alter effects of neuromodulation.

AIMS: Neuromodulation (nerve stimulation) can produce analgesia. One form, bilateral pudendal nerve stimulation (bPNS), suppresses responses to urinary bladder distension (UBD) in hypersensitive rats. Drugs can modify this effect (eg, benzodiazepines, but not opioids, suppress bPNS effects). Prior to a clinical trial of bPNS effects on bladder pain, we felt it was prudent to survey the effects of medications commonly used in patients with bladder disorders. METHODS: Bladder hypersensitivity was produced by neonatal bladder inflammation in rat pups coupled with a second inflammatory insult as an adult. Antimuscarinic (oxybutynin), ß3 -adrenoceptor agonist (mirabegron, CL316243), α1 -adrenoceptor antagonist (tamsulosin), antidepressant (amitriptyline), muscle relaxing (baclofen), and sedative (propofol) agents were administered and effects of bPNS on responses to UBD assessed. bPNS consisted of bilateral biphasic electrical stimulation of the mixed motor/sensory component of the pudendal nerves. Visceromotor responses (VMRs; abdominal muscle contractile responses) were used as nociceptive endpoints. RESULTS: Many of these drugs directly inhibited the VMRs to UBD, but only mirabegron, at the doses employed, significantly reduced inhibitory effects of bPNS. In the presence of the other drugs, bPNS continued to produce statistically significant inhibition of VMRs to UBD. CONCLUSIONS: This study suggests that concurrent therapy with drugs used to treat bladder disorders could affect assessment of the effects of bPNS on bladder hypersensitivity. This study gives guidance to clinical trials using bPNS for the treatment of painful bladder syndromes and suggests potential clinical use of some of these medications in the treatment of these same disorders.

Diversity of complexes based on p-nitrobenzoylhydrazide, benzoylformic acid and diorganotin halides or oxides self-assemble: Cytotoxicity, the induction of apoptosis in cancer cells and DNA-binding properties.

Eight organotin(IV) complexes (C1-C8) have been synthesized and characterized by elemental analysis, fourier transform infrared spectroscopy (FT-IR), multinuclear nuclear magnetic resonance (1H, 13C and 119Sn NMR), high resolution mass spectroscopy (HRMS) and single crystal X-ray structural analysis. Crystallographic data show that C1 was a tetranuclear 16-membered macrocycle complex, C2-C4 and C7 were centrosymmetric dimer distannoxane and there was a Sn2O2 four-membered ring in the middle of the molecule, respectively, C5 and C6 are monoorganotin complexes due to the dehydroalkylation effect during the reaction, while C8 forms a one-dimensional chain structure. The cytotoxicity of all complexes were tested by 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assays against three human tumor cell lines NCI-H460, MCF-7 and HepG2. The dibutyltin complex C2 has been shown to be more potent antitumor agents than other complexes and carboplatin. Cell apoptosis study of C2 with the high activity on HepG2 and MCF-7 cancer cell lines was investigated by flow cytometry, it was shown that the antitumor activity of C2 was related to apoptosis, but it has different cell cycle arrest characteristics from platinum compounds, and the proliferation was inhibited by blocking cells in S phase. The DNA binding activity of the C2 was studied by UV-visible absorption spectrometry, fluorescence competitive, viscosity measurements and gel electrophoresis, results shown C2 can be well embedded in the double helix of DNA and cleave DNA.

The anticholinergic drug oxybutynin inhibits voltage-dependent K+ channels in coronary arterial smooth muscle cells.

This study demonstrates the inhibitory effect of anticholinergic drug oxybutynin on voltage-dependent K+ (Kv) channels in rabbit coronary arterial smooth muscle cells. Oxybutynin inhibited vascular Kv channels in a concentration-dependent manner, with an IC50 value of 11.51 ± 0.38 µmol/L and a Hill coefficient (n) of 2.25 ± 0.12. Application of oxybutynin shifted the activation curve to the right and the inactivation curve to the left. Pretreatment with the Kv1.5 subtype inhibitor DPO-1 and the Kv2.1 subtype inhibitor guangxitoxin suppressed the oxybutynin-induced inhibition of the Kv current. However, application of the Kv7 subtype inhibitor linopirdine did not affect the inhibition by oxybutynin of the Kv current. The anticholinergic drug atropine did not inhibit the Kv current nor influence oxybutynin-induced inhibition of the Kv current. From these results, we concluded that oxybutynin inhibited the vascular Kv current in a concentration-dependent manner by influencing the steady-state activation and inactivation curves independent of its anticholinergic effect.

Which antimuscarinic agents used in the treatment of overactive bladder increase heart rate? a prospective randomized clinical trial.

PURPOSE: To compare the heart rate increase side effect of different antimuscarinic drugs used in overactive bladder (OAB). METHODS: Overall 341 patients were consecutively randomized to take seven different antimuscarinic drugs between January 2014 and June 2016 at three institutions, and 250 patients who completed the follow-up visits were accepted into this study. Ninety-one patients who never came to visits were excluded. Drugs were classified into two groups as selective (darifenacin hydrobromide, solifenacin succinate and oxybutynin hydrochloride) and non-selective (fesoterodine fumarate, tolterodine tartrate, trospium chloride and propiverine hydrochloride) antimuscarinic drugs. The cardiac pulse rates and the blood pressures were recorded during the baseline, first visit (1 week) and second visit (1 month). Data were compared for drugs and two groups (selective versus non-selective) by using ANOVA test. RESULTS: Baseline characteristics were similar among the patients using different antimuscarinic drugs. Statistically significant increase in heart rate occurred in patients treated with non-selective antimuscarinic drugs compared to those treated with selective drugs (p < 0.001), and this increase was especially evident in patients treated with trospium chloride, tolterodine tartrate, fesoterodine fumarate and propiverine hydrochloride (p < 0.001, 0.003, 0.011 and 0.37, respectively). There was no statistical difference for the other side effects. CONCLUSIONS: Our results showed that heart rate significantly increased in OAB patients treated with non-selective antimuscarinic drugs. Trospium chloride, tolterodine tartrate, fesoterodine fumarate and propiverine hydrochloride seem to have the most unfavorable properties with regard to increased heart rate side effect when compared to the other antimuscarinic drugs (darifenacin hydrobromide, solifenacin succinate and oxybutynin hydrochloride).

HPLC-ESI-MSn Identification and NMR Characterization of Glucosyloxybenzyl 2R-Benzylmalate Deriva-Tives from Arundina Graminifolia and Their Anti-Liver Fibrotic Effects In Vitro.

Four new glucosyloxybenzyl 2R-benzylmalate derivatives, named Arundinoside H (2), I (5), J (6), K (8) as well as four known compounds Arundinoside D (1), G (3), F (4), E (7) were isolated and characterized by a combination of chemical and spectroscopic methods, including HR-ESI-MS, 1D and 2D NMR experiments. Besides, 24 unreported compounds were inferred from ESI-MSn data. The anti-liver fibrotic activities of the isolates were determined as proliferation inhibition of lipopolysaccharide (LPS)-induced activation of rat hepatic stellate cells (HSC-T6). The result suggested Arundinosides D, H, F, I and K showed moderate inhibitory effects in vitro.

Effects of Topical Mandelic Acid Treatment on Facial Skin Viscoelasticity.

Mandelic acid is an α-hydroxy acid with reported benefit in treating acne and hyperpigmentation. The authors have developed a topical mandelic acid formulation that subjectively improves the quality of aged skin. Although the gold standard for assessing outcomes, photographic documentation is limited by subjective interpretation. Tools for measuring physical skin properties allow for an objective assessment of changes in skin quality. The authors sought to objectively study the viscoelastic changes to the skin following treatment with topical mandelic acid, using the Cutometer MPA 580. Twenty-four patients, twenty females and four males, aged 42 to 68 years, were studied over a four-week period. Mandelic acid was applied topically to the face twice a day for four weeks. The lower eyelid skin viscoelastic properties were assessed weekly using the Cutometer. After four weeks of topical mandelic acid treatment, the elasticity of lower eyelid skin increased 25.4% (P = .003). Skin firmness increased 23.8% (P = .029). Improvement in photographic appearance correlated with these findings. Mandelic acid is another topical treatment option for improving skin quality, and is well tolerated by patients. The authors feel that the Cutometer or similar device should be used routinely in facial plastic surgery to objectively assess outcomes of various treatment modalities.

Short-term benefit of smoking cessation along with glycopirronium on lung function and respiratory symptoms in mild COPD patients: a retrospective study.

INTRODUCTION: Tobacco smoke is the leading cause of chronic obstructive pulmonary disease (COPD). Smoking cessation can change the natural history of COPD, as we know from the GOLD guidelines. Little is known about the short-term clinical and functional effects of smoking cessation treatment combined with anti-muscarinic bronchodilators. OBJECTIVE: To determine whether quitting smoking, obtained by smoking cessation treatment combined with the use of a new long-acting muscarinic antagonist bronchodilator (LAMA), can improve lung function tests and respiratory symptoms more than the use of LAMA alone. METHODS: We evaluated, in a retrospective analysis, the functional and clinical data, collected in one year, of 120 patients who were current smokers affected by mild COPD and who quit smoking using smoking cessation treatment combined with glycopirronium. We compared them with a group of 80 patients with mild COPD undergoing the same treatment but who did not quit smoking. All patients underwent functional and clinical tests at baseline and at a third-month check. MEASUREMENTS AND MAIN RESULTS: The two groups were homogeneous in terms of demographic data without significant differences. All patients used varenicline for smoking cessation. They all performed the following tests: a spirometry with detection of resistances, the 6 min walking test, haemogasanalysis, the exhaled CO test, the COPD assessment test (CAT) and finally the modified Medical Research Council test (mMRC). A significant improvement in the functional tests at the third-month check was found in both groups-quitters and non-quitters. However, a notable increase in the examined parameters was registered in the group of patients who quit smoking, in particular, we observed a significant increase at the third-month check of the parameter forced expiratory volume in 1 s (FEV1) of more than 200 ml with p < 0.001. A comparison between quitters and non-quitters revealed a major benefit derived from smoking cessation in terms of functional changes and symptom relief. In particular, not only FEV1 but also forced expiratory flow at 25%-75% of vital capacity (FEF 25-75) (p < 0.01) and CAT (p < 0.001) were found to be significantly improved in patients who quit than in patients who did not at the check time point. CONCLUSIONS: Smoking cessation treatment obtained by varenicline was confirmed as a crucial therapeutic option, especially when combined with bronchodilator in mild COPD. Patients who quit smoking could already benefit from both treatments in the short term, improving lung function and respiratory symptoms and therefore improving their quality of life.

Isolation of quercetin and mandelic acid from Aesculus indica fruit and their biological activities.

BACKGROUND: In this study Aesculus indica fruit was subjected to isolation of phytochemicals. Two antioxidants quercetin and Mandelic acid were isolated in pure state. The free radical scavenging and acetyl choline esterase inhibitory potential of the crude extract and sub fractions were also determined. RESULTS: The antioxidant capacity of crude extract, fractions and isolated compounds were determined by DPPH and ABTS methods. Folin-Ciocalteu reagent method was used to estimate the total phenolic contents and were found to be 78.34 ± 0.96, 44.16 ± 1.05, 65.45 ± 1.29, 37.85 ± 1.44 and 50.23 ± 2.431 (mg/g of gallic acid) in crude extract, ethyl acetate, chloroform, n-hexane and aqueous fractions respectively. The flavonoid concentration in crude extract, ethyl acetate, chloroform, n-hexane and aqueous fraction were; 85.30 ± 1.20, 53.80 ± 1.07, 77.50 ± 1.12, 26.30 ± 1.35 and 37.78 ± 1.25 (mg/g of quercetin) respectively. The chloroform fraction was more potent against enzymes, acetyl choline esterase and butyryl choline esterase (IC50 = 85 and 160 µg/ml respectively). The phenolic compounds in the crude extract and fractions were determined using HPLC standard method. Chlorogenic acid, quercetin, phloroglucinol, rutin, mandelic acid and hydroxy benzoic acid were detected at retention times 6.005, 10.062, 22.623, 30.597, 35.490 and 36.211 in crude extract and different fractions. The ethyl acetate fraction was rich in the targeted compounds and was therefore subjected to column isolation. The HPLC chromatogram of isolated compounds showed single peak at specified retention times which confirms their isolation in pure state. The isolated compounds were then characterized by FTIR and NMR spectrophotometric techniques. CONCLUSION: The Aesculus indica fruit extracts showed antioxidant and anticholine esterase inhibitory potentials. Two bioactive compounds were isolated in the pure form ethyl acetate fraction. From results it was concluded that the fruit of this plant could be used to minimize oxidative stress caused by reactive oxygen species.

Structure-function insights into chikungunya virus capsid protein: Small molecules targeting capsid hydrophobic pocket.

The crystal structure of chikungunya (CHIKV) virus capsid protease domain has been determined at 2.2Å. Structure reveals a chymotrypsin-like protease fold with a conserved hydrophobic pocket in CHIKV capsid protein (CP) for interaction with the cytoplasmic tail of E2 (cdE2) similar to the capsid protein of other alphaviruses. Molecular contacts between CP-cdE2 were determined by fitting structures of CHIKV CP and cdE2 into the cryo-EM map of Venezuelan equine encephalitis virus (VEEV). Binding of (S)-(+)-Mandelic acid (MDA) and Ethyl 3-aminobenzoate (EAB) to the hydrophobic pocket of CP was evaluated by molecular docking. Surface plasmon resonance (SPR) and fluorescence spectroscopy experiments confirmed MDA and EAB binding to the CP. The binding constants (KD) obtained from SPR for MDA and EAB were 1.2 × 10-3 M and 0.2 × 10-9 M, respectively. This study adds to the understanding of chikungunya virus structural proteins and may serve as the basis for antiviral development against chikungunya disease.

Potentiating Effect of Mandelate and Lactate on Chemically Induced Germination in Members of Bacillus cereus Sensu Lato.

Endospores of the genus Bacillus can be triggered to germinate by a limited number of chemicals. Mandelate had powerful additive effects on the levels and rates of germination produced in non-heat-shocked spores of Bacillus anthracis strain Sterne, Bacillus cereus, and Bacillus thuringiensis when combined with l-alanine and inosine. Mandelate had no germinant effect on its own but was active with these germinants in a dose-dependent manner at concentrations higher than 0.5 mM. The maximum rate and extent of germination were produced in B. anthracis by 100 mM l-alanine with 10 mM inosine; this was equaled by just 25% of these germinants when supplemented with 10 mM mandelate. Half the maximal germination rate was produced by 40% of the optimum germinant concentrations or 15% of them when supplemented with 0.8 mM mandelate. Germination rates in B. thuringiensis were highest around neutrality, but the potentiating effect of mandelate was maintained over a wider pH range than was germination with l-alanine and inosine alone. For all species, lactate also promoted germination in the presence of l-alanine and inosine; this was further increased by mandelate. Ammonium ions also enhanced l-alanine- and inosine-induced germination but only when mandelate was present. In spite of the structural similarities, mandelate did not compete with phenylalanine as a germinant. Mandelate appeared to bind to spores while enhancing germination. There was no effect when mandelate was used in conjunction with nonnutrient germinants. No effect was produced with spores of Bacillus subtilis, Clostridium sporogenes, or C. difficileIMPORTANCE The number of chemicals that can induce germination in the species related to Bacillus cereus has been defined for many years, and they conform to specific chemical types. Although not a germinant itself, mandelate has a structure that is different from these germination-active compounds, and its addition to this list represents a significant discovery in the fundamental biology of spore germination. This novel activity may also have important applied relevance given the impact of spores of B. cereus in foodborne disease and B. anthracis as a threat agent. The destruction of spores of B. anthracis, for example, particularly over large outdoor areas, poses significant scientific and logistical problems. The addition of mandelate and lactate to the established mixtures of l-alanine and inosine would decrease the amount of the established germinants required and increase the speed and level of germination achieved. The large-scale application of "germinate to decontaminate" strategy may thus become more practicable.