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  1. Discovery of azetidine based ene-amides as potent bacterial enoyl ACP reductase (FabI) inhibitors
    Takhi M, Sreenivas K, Reddy CK, Munikumar M, Praveena K, Sudheer P, et al.
    Eur J Med Chem, 2014 Sep 12;84:382-94.
    PMID: 25036796 DOI: 10.1016/j.ejmech.2014.07.036
    A novel and potent series of ene-amides featuring azetidines has been developed as FabI inhibitors active against drug resistant Gram-positive pathogens particularly staphylococcal organisms. Most of the compounds from the series possessed excellent biochemical inhibition of Staphylococcus aureus FabI enzyme and whole cell activity against clinically relevant MRSA, MSSA and MRSE organisms which are responsible for significant morbidity and mortality in community as well as hospital settings. The binding mode of one of the leads, AEA16, in Escherichia coli FabI enzyme was determined unambiguously using X-ray crystallography. The lead compounds displayed good metabolic stability in mice liver microsomes and pharmacokinetic profile in mice. The in vivo efficacy of lead AEA16 has been demonstrated in a lethal murine systemic infection model.
    Matched MeSH terms: Dose-Response Relationship, Drug
  2. Effects of ascorbic acid on PVS2 cryopreservation of Dendrobium Bobby Messina's PLBs supported with SEM analysis
    Antony JJ, Keng CL, Mahmood M, Subramaniam S
    Appl Biochem Biotechnol, 2013 Sep;171(2):315-29.
    PMID: 23832189 DOI: 10.1007/s12010-013-0369-x
    Regrowth of the cryopreserved protocorm-like bodies (PLBs) of Dendrobium Bobby Messina was assessed based on the plant vitrification solution 2 (PVS2) optimisation conditions. The optimized protocol obtained based on TTC spectrophotometrical analysis and growth recovery were 3-4 mm of PLBs size precultured in 0.2 M sucrose for 1 day, treated with a mixture of 2 M glycerol and 0.4 M sucrose supplemented with half-strength liquid MS media at 25 °C for 20 min and subsequently dehydrated with PVS2 at 0 °C for 20 min prior to storage in liquid nitrogen. Following rapid warming in a water bath at 40 °C for 90 s, PLBs were treated with unloading solution containing half-strength liquid MS media supplemented with 1.2 M sucrose. Subsequently, the PLBs were cultured on half-strength semi-solid MS media supplemented with 2 % (w/v) sucrose without any growth regulators and resulted in 40 % growth recovery. In addition, ascorbic acid treatment was used to evaluate the regeneration process of cryopreserved PLBs. However, growth recovery rates of non-cryopreserved and cryopreserved PLBs were 30 and 10 % when 0.6 mM ascorbic acid was added. Scanning electron microscopy analysis indicates that there are not much damages observed on both cryopreserved and non-cryopreserved PLBs in comparison to PLBs stock culture.
    Matched MeSH terms: Dose-Response Relationship, Drug
  3. Report: Wound healing activity of Hymenocallis littoralis - Moving beyond ornamental plant
    Sundarasekar J, Sahgal G, Murugaiyah V, Lay LK, Thong OM, Subramaniam S
    Pak J Pharm Sci, 2018 Nov;31(6):2537-2543.
    PMID: 30473529
    Spider lily (Hymenocallis littoralis) belongs to Amaryllidaceae family is a well-known plant species for its medicinal properties. The inhibitory effects of H. littoralis methanol sonication extracts were evaluated for wound healing activity. This is the first report on the wound healing activity of Malaysian origin H. littoralis. The bulb, flower, root, anther, stem and leaves of H. littoralis methanol sonication extracts were used for scratch-wound assay. The cell line was treated with two different concentrations; 1 and 10μg/ml of extracts. The extracts were prepared freshly by dissolving in sterile phosphate saline buffer (PBS) and the healing activity was observed from 2, 4, 8, 12, 24, 36 and 48 h. The bulb, root, stem and anther methanol extracts demonstrated active wound healing activities at 1 μg mL-1at 36 h of treatment. At the low concentration the bulb, root, stem and anther methanol extracts heals the wound compared to leaf and flower extracts. It's demonstrated that these extracts contain effective phytochemical substances which are responsible for wound healing process. This finding suggests the potential application of H. littoralis methanol extract in wound healing activity.
    Matched MeSH terms: Dose-Response Relationship, Drug
  4. Failure of clonidine in tardive dystonia: implications for nosology
    Adityanjee, Singh S, Subramaniam M
    Biol Psychiatry, 1989 Jun;26(2):199-202.
    PMID: 2567611
    Matched MeSH terms: Dose-Response Relationship, Drug
  5. Andrographolide inhibits growth of acute promyelocytic leukaemia cells by inducing retinoic acid receptor-independent cell differentiation and apoptosis
    Manikam SD, Manikam ST, Stanslas J
    J Pharm Pharmacol, 2009 Jan;61(1):69-78.
    PMID: 19126299 DOI: 10.1211/jpp/61.01.0010
    The growth inhibiting potential of andrographolide was evaluated in three acute promyelocytic leukaemia cell line models (HL-60, NB4 and all-trans retinoic acid (ATRA)-resistant NB4-R2).
    Matched MeSH terms: Dose-Response Relationship, Drug
  6. Fulltext Benzylidene derivatives of andrographolide inhibit growth of breast and colon cancer cells in vitro by inducing G(1) arrest and apoptosis
    Jada SR, Matthews C, Saad MS, Hamzah AS, Lajis NH, Stevens MF, et al.
    Br J Pharmacol, 2008 Nov;155(5):641-54.
    PMID: 18806812 DOI: 10.1038/bjp.2008.368
    BACKGROUND AND PURPOSE: Andrographolide, the major phytoconstituent of Andrographis paniculata, was previously shown by us to have activity against breast cancer. This led to synthesis of new andrographolide analogues to find compounds with better activity than the parent compound. Selected benzylidene derivatives were investigated for their mechanisms of action by studying their effects on the cell cycle progression and cell death.
    EXPERIMENTAL APPROACH: Microculture tetrazolium, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and sulphorhodamine B (SRB) assays were utilized in assessing the in vitro growth inhibition and cytotoxicity of compounds. Flow cytometry was used to analyse the cell cycle distribution of control and treated cells. CDK1 and CDK4 levels were determined by western blotting. Apoptotic cell death was assessed by fluorescence microscopy and flow cytometry.
    KEY RESULTS: Compounds, in nanomolar to micromolar concentrations, exhibited growth inhibition and cytotoxicity in MCF-7 (breast) and HCT-116 (colon) cancer cells. In the NCI screen, 3,19-(2-bromobenzylidene) andrographolide (SRJ09) and 3,19-(3-chloro-4-fluorobenzylidene) andrographolide (SRJ23) showed greater cytotoxic potency and selectivity than andrographolide. SRJ09 and SRJ23 induced G(1) arrest and apoptosis in MCF-7 and HCT-116 cells, respectively. SRJ09 downregulated CDK4 but not CDK1 level in MCF-7 cells. Apoptosis induced by SRJ09 and SRJ23 in HCT-116 cells was confirmed by annexin V-FITC/PI flow cytometry analysis.
    CONCLUSION AND IMPLICATIONS: The new benzylidene derivatives of andrographolide are potential anticancer agents. SRJ09 emerged as the lead compound in this study, exhibiting anticancer activity by downregulating CDK4 to promote a G(1) phase cell cycle arrest, coupled with induction of apoptosis.
    Matched MeSH terms: Dose-Response Relationship, Drug
  7. Fulltext Exposure-effect relationship of mycophenolic acid and prednisolone in adult patients with lupus nephritis
    Abd Rahman AN, Tett SE, Abdul Gafor HA, McWhinney BC, Staatz CE
    Br J Clin Pharmacol, 2015 Nov;80(5):1064-75.
    PMID: 25959850 DOI: 10.1111/bcp.12678
    AIMS: The aim was to examine relationships between total and unbound mycophenolic acid (MPA) and prednisolone exposure and clinical outcomes in patients with lupus nephritis.
    METHODS: Six blood samples were drawn pre- and at 1, 2, 4, 6 and 8 h post-dose and total and unbound MPA and prednisolone pre-dose (C0 ), maximum concentration (Cmax ) and area under the concentration-time curve (AUC) were determined using non-compartmental analysis in 25 patients. The analyses evaluated drug exposures in relation to treatment response since starting MPA and drug-related adverse events.
    RESULTS: Dose-normalized AUC varied 10-, 8-, 7- and 19-fold for total MPA, unbound MPA, total prednisolone and unbound prednisolone, respectively. Median values (95% CI) of total MPA AUC(0,8 h) (21.5 [15.0, 42.0] vs. 11.2 [4.8, 30.0] mg l(-1) h, P= 0.048) and Cmax (11.9 [6.7, 26.3] vs. 6.1 [1.6, 9.2] mg l(-1) , P = 0.016) were significantly higher in responders than non-responders. Anaemia was significantly associated with higher total (37.8 [14.1, 77.5] vs. 18.5 [11.7, 32.7] mg l(-1) h, P = 0.038) and unbound MPA AUC(0,12 h) (751 [214, 830] vs. 227 [151, 389] mg l(-1) h, P = 0.004). Unbound prednisolone AUC(0,24 h) was significantly higher in patients with Cushingoid appearance (unbound: 1372 [1242, 1774] vs. 846 [528, 1049] nmol l(-1) h, P = 0.019) than in those without. Poorer treatment response was observed in patients with lowest tertile exposure to both total MPA and prednisolone as compared with patients with middle and higher tertile exposure (17% vs. 74%, P = 0.023).
    CONCLUSIONS: This study suggests a potential role for therapeutic drug monitoring in individualizing immunosuppressant therapy in patients with lupus nephritis.
    KEYWORDS: lupus nephritis; mycophenolic acid; pharmacodynamics; pharmacokinetics; prednisolone; treatment outcome
    Study site: Nephrology and SLE Clinics, Pusat Perubatan Universiti Kebangsaan Malaysia (PPUKM), Kuala Lumpur, Malaysia
    Matched MeSH terms: Dose-Response Relationship, Drug
  8. Fulltext Outcomes in Antiplatelet-Associated Intracerebral Hemorrhage in the TICH-2 Randomized Controlled Trial
    Law ZK, Desborough M, Roberts I, Al-Shahi Salman R, England TJ, Werring DJ, et al.
    J Am Heart Assoc, 2021 02;10(5):e019130.
    PMID: 33586453 DOI: 10.1161/JAHA.120.019130
    Background Antiplatelet therapy increases the risk of hematoma expansion in intracerebral hemorrhage (ICH) while the effect on functional outcome is uncertain. Methods and Results This is an exploratory analysis of the TICH-2 (Tranexamic Acid in Intracerebral Hemorrhage-2) double-blind, randomized, placebo-controlled trial, which studied the efficacy of tranexamic acid in patients with spontaneous ICH within 8 hours of onset. Multivariable logistic regression and ordinal regression were performed to explore the relationship between pre-ICH antiplatelet therapy, and 24-hour hematoma expansion and day 90 modified Rankin Scale score, as well as the effect of tranexamic acid. Of 2325 patients, 611 (26.3%) had pre-ICH antiplatelet therapy. They were older (mean age, 75.7 versus 66.5 years), more likely to have ischemic heart disease (25.4% versus 2.7%), ischemic stroke (36.2% versus 6.3%), intraventricular hemorrhage (40.2% versus 27.5%), and larger baseline hematoma volume (mean, 28.1 versus 22.6 mL) than the no-antiplatelet group. Pre-ICH antiplatelet therapy was associated with a significantly increased risk of hematoma expansion (adjusted odds ratio [OR], 1.28; 95% CI, 1.01-1.63), a shift toward unfavorable outcome in modified Rankin Scale (adjusted common OR, 1.58; 95% CI, 1.32-1.91) and a higher risk of death at day 90 (adjusted OR, 1.63; 95% CI, 1.25-2.11). Tranexamic acid reduced the risk of hematoma expansion in the overall patients with ICH (adjusted OR, 0.76; 95% CI, 0.62-0.93) and antiplatelet subgroup (adjusted OR, 0.61; 95% CI, 0.41-0.91) with no significant interaction between pre-ICH antiplatelet therapy and tranexamic acid (P interaction=0.248). Conclusions Antiplatelet therapy is independently associated with hematoma expansion and unfavorable functional outcome. Tranexamic acid reduced hematoma expansion regardless of prior antiplatelet therapy use. Registration URL: https://www.isrctn.com; Unique identifier: ISRCTN93732214.
    Matched MeSH terms: Dose-Response Relationship, Drug
  9. Differential permethrin susceptibility of head lice sampled in the United States and Borneo
    Pollack RJ, Kiszewski A, Armstrong P, Hahn C, Wolfe N, Rahman HA, et al.
    Arch Pediatr Adolesc Med, 1999 Sep;153(9):969-73.
    PMID: 10482215 DOI: 10.1001/archpedi.153.9.969
    BACKGROUND: Pediculiasis is treated aggressively in the United States, mainly with permethrin- and pyrethrin-containing pediculicides. Increasingly frequent anecdotal reports of treatment failure suggest the emergence of insecticidal resistance by these lice.

    OBJECTIVE: To confirm or refute the susceptibility of head lice sampled in the United States to permethrin.

    DESIGN: Survey. Head lice were removed from children residing where pediculicides are readily available and where such products are essentially unknown. Their survival was compared following exposure to residues of graded doses of permethrin in an in vitro bioassay.

    SETTING: School children from Massachusetts, Idaho, and Sabah (Malaysian Borneo).

    SUBJECTS: In the United States, 75 children aged 5 to 8 years. In Sabah, 59 boys aged 6 to 13 years. Virtually all sampled US children had previously been treated with pediculicides containing pyrethrins or permethrin; none of the Sabahan children were so exposed.

    MAIN OUTCOME MEASURE: Survival of head lice exposed to permethrin.

    RESULTS: Permethrin did not affect head lice sampled from chronically infested US children who had previously been treated for pediculiasis. The slope of the dose-response regression line for these lice did not differ significantly from zero (P = .66). This pediculicide immobilized lice sampled in Sabah. Mortality correlated closely with permethrin concentration (P = .008).

    CONCLUSIONS: Head lice in the United States are less susceptible to permethrin than are those in Sabah. The pyrethroid susceptibility of the general population of head lice in the United States, however, remains poorly defined. Accordingly, these relatively safe over-the-counter preparations may remain the pediculicides of choice for newly recognized louse infestations.
    Matched MeSH terms: Dose-Response Relationship, Drug
  10. Role of protein kinase C in hydroxyapatite- induced phagocytosis by a murine macrophage cell line (RAW264.7)
    Gopinath VK, Musa M, Samsudin AR, Sosroseno W
    Immunopharmacol Immunotoxicol, 2006;28(3):485-9.
    PMID: 16997796
    The role of protein kinase C (PKC) in hydroxyapatite (HA)-induced phagocytosis by RAW 264.7 cells was investigated. The cells were incubated with HA particles at various incubation time and the levels of PKC activity were determined from the cell lysate. To determine the role of PKC, particles were incubated with the cells pretreated with the various concentrations of bisindolylmaleimide, a PKC inhibitor, and phagocytosis was then assessed at 60 min. Latex beads were used as a control. Our results showed that following incubation with HA particles, the levels of PKC activity in RAW264.7 cells was highest at 7 min and then decreased to reach the baseline levels of the controls at 30 min. Pretreatment of the cells with bisindolylmaleimide significantly reduced phagocytosis of HA particles in a dose-dependent pattern. The results of our present study suggest therefore that ingestion of HA by RAW264.7 cells may depend on PKC activity that may act in the early stages of phagocytosis.
    Matched MeSH terms: Dose-Response Relationship, Drug
  11. Effect of sodium fluoride on the murine splenic immune response to Porphyromonas gingivalis in vitro
    Sosroseno W
    Immunopharmacol Immunotoxicol, 2003 Feb;25(1):123-7.
    PMID: 12675204
    Spleen cells from saline- and Porphyromonas gingivalis-primed mice were cultured and stimulated with or without P. gingivalis and added with or without various concentration of sodium fluoride (NaF). Cell proliferation, antigen-specific IgG antibodies and both IFN-gamma and IL-10 levels were determined by a colorimetric assay, ELISA and commercial ELISA kits respectively. The results showed that NaF at concentration of 1 x 10(-6) M enhanced but at concentration of 1 x 10(-1) M abolished the immune response to P. gingivalis, suggesting that NaF at low concentration may act as an adjuvant but at high concentration may be toxic to the P. gingivalis-induced murine splenic immune response in vitro.
    Matched MeSH terms: Dose-Response Relationship, Drug
  12. Influence of antenatal glucocorticoid on preterm lamb diaphragm
    Mahzabin T, Pillow JJ, Pinniger GJ, Bakker AJ, Noble PB, White RB, et al.
    Pediatr Res, 2017 Sep;82(3):509-517.
    PMID: 28388600 DOI: 10.1038/pr.2017.99
    BackgroundPregnant women at a high risk of preterm delivery receive glucocorticoids to accelerate fetal lung maturation and surfactant synthesis. However, the effect of antenatal steroids on the developing diaphragm remains unclear. We hypothesized that maternal betamethasone impairs the fetal diaphragm, and the magnitude of the detrimental effect increases with longer duration of exposure. We aimed to determine how different durations of fetal exposure to maternal betamethasone treatment influence the fetal diaphragm at the functional and molecular levels.MethodsDate-mated merino ewes received intramuscular injections of saline (control) or two doses of betamethasone (5.7 mg) at an interval of 24 h commencing either 2 or 14 days before delivery. Preterm lambs were killed after cesarean delivery at 121-day gestational age. In vitro contractile measurements were performed on the right hemidiaphragm, whereas molecular/cellular analyses used the left costal diaphragm.ResultsDifferent durations of fetal exposure to maternal betamethasone had no consistent effect on the protein metabolic pathway, expression of glucocorticoid receptor and its target genes, cellular oxidative status, or contractile properties of the fetal lamb diaphragm.ConclusionThese data suggest that the potential benefits of betamethasone exposure on preterm respiratory function are not compromised by impaired diaphragm function after low-dose maternal intramuscular glucocorticoid exposure.
    Matched MeSH terms: Dose-Response Relationship, Drug
  13. Cardamonin, inhibits pro-inflammatory mediators in activated RAW 264.7 cells and whole blood
    Ahmad S, Israf DA, Lajis NH, Shaari K, Mohamed H, Wahab AA, et al.
    Eur J Pharmacol, 2006 May 24;538(1-3):188-94.
    PMID: 16650843
    Some chalcones, such as hydroxychalcones have been reported previously to inhibit major pro-inflammatory mediators such as nitric oxide (NO), prostaglandin E(2) (PGE(2)), tumor necrosis factor-alpha (TNF-alpha) and reactive oxygen species production by suppressing inducible enzyme expression via inhibition of the mitogen-activated protein kinase (MAPK) pathway and nuclear translocation of critical transcription factors. In this report, the effects of cardamonin (2',4'-dihydroxy-6'-methoxychalcone), a chalcone that we have previously isolated from Alpinia rafflesiana, was evaluated upon two cellular systems that are repeatedly used in the analysis of anti-inflammatory bioactive compounds namely RAW 264.7 cells and whole blood. Cardamonin inhibited NO and PGE(2) production from lipopolysaccharide- and interferon-gamma-induced RAW cells and whole blood with IC(50) values of 11.4 microM and 26.8 microM, respectively. Analysis of thromboxane B(2) (TxB(2)) secretion from whole blood either stimulated via the COX-1 or COX-2 pathway revealed that cardamonin inhibits the generation of TxB(2) via both pathways with IC(50) values of 2.9 and 1.1 microM, respectively. Analysis of IC(50) ratios determined that cardamonin was more COX-2 selective in its inhibition of TxB(2) with a ratio of 0.39. Cardamonin also inhibited the generation of intracellular reactive oxygen species and secretion of TNF-alpha from RAW 264.7 cells in a dose responsive manner with IC(50) values of 12.8 microM and 4.6 microM, respectively. However, cardamonin was a moderate inhibitor of lipoxygenase activity when tested in an enzymatic assay system, in which not a single concentration tested was able to cause an inhibition of more than 50%. Our results suggest that cardamonin acts upon major pro-inflammatory mediators in a similar fashion as described by previous work on other closely related synthetic hydroxychalcones and strengthens the conclusion of the importance of the methoxyl moiety substitution on the 4' or 6' locations of the A benzene ring.
    Matched MeSH terms: Dose-Response Relationship, Drug
  14. Effect of various antagonists on the Channa striatus fillet extract antinociception in mice
    Zakaria ZA, Sulaiman MR, Mat Jais AM, Somchit MN
    Can J Physiol Pharmacol, 2005 Jul;83(7):635-42.
    PMID: 16091789
    The effects of an aqueous supernatant of haruan (ASH) (Channa striatus) fillet extract on various antinociception receptor system activities were examined using a mouse abdominal-constriction model. Mice that were pretreated with distilled water, s.c., followed 10 min later by administration of 25%, 50%, and 100% concentration ASH, s.c., produced a significant concentration-dependent antinociceptive activity (p < 0.001). Pretreatment with naloxone (0.3, 1.0, and 3.0 mg/kg body mass), 10 min before ASH administration, failed to block the extract antinociception. Pretreatment of the 100% concentration ASH with mecamylamine (5 mg/kg), pindolol (10 mg/kg), and haloperidol (1 mg/kg) also did not cause any significant change in its antinociception. However, pretreatment with atropine (5 mg/kg), bicuculline (10 mg/kg), phenoxybenzamine (10 mg/kg), and methysergide (5 mg/kg) were found to reverse ASH antinociception. Based on the above findings, the ASH is suggested to contain different types of bioactive compounds that act synergistically on muscarinic, GABAA, alpha-adrenergic, and serotonergic receptor systems to produce the observed antinociception.
    Matched MeSH terms: Dose-Response Relationship, Drug
  15. Bioefficacy of Insect Growth Regulators Against Aedes albopictus (Diptera: Culicidea) From Sarawak, Malaysia: A Statewide Survey
    Lau KW, Chen CD, Lee HL, Low VL, Sofian-Azirun M
    J Econ Entomol, 2018 05 28;111(3):1388-1394.
    PMID: 29617840 DOI: 10.1093/jee/toy071
    The susceptibility status of Aedes albopictus (Skuse; Diptera: Culicidea) larvae collected from 13 districts in Sarawak state, Malaysia was evaluated against five insect growth regulators (IGRs) namely, methoprene, pyriproxyfen, diflubenzuron, cyromazine, and novaluron. Field populations of Ae. albopictus were susceptible to methoprene, pyriproxyfen, cyromazine and novaluron with resistance ratios (RRs) ranging from 0.19-0.38, 0.05-0.14, 0.50-0.95, and 0.75-1.00, respectively. Nevertheless, tolerance towards diflubenzuron (0.33-1.33) was observed in this study. In general, these IGRs exhibited promising results and can be used as alternative control agents against field populations of Ae. albopictus in Sarawak, Malaysia.
    Matched MeSH terms: Dose-Response Relationship, Drug
  16. A review on the use of statins and tocotrienols, individually or in combination for the treatment of osteoporosis
    Abdul-Majeed S, Mohamed N, Soelaiman IN
    Curr Drug Targets, 2013 Dec;14(13):1579-90.
    PMID: 23848479
    Skeletal tissue undergoes continuous remodeling which makes it unique among other body tissues. Osteoporosis is a common bone metabolic disorder affecting both men and women. Osteoporosis and its complications mainly osteoporotic fractures, have a high impact on health and economy. Current approved medications are associated with numerous side effects, which limit their use. Identification of a new and safe therapy is mandatory. Statins, also known as HMGCoA reductase inhibitors, are frequently used for the treatment of hypercholesterolemia and for the prevention of morbidity and mortality associated with cardiovascular disease. Statins improved bone health status in intact and ovariectomised rodents following high clinically intolerable oral doses. However, this beneficial effect of statins could not be significantly demonstrated in humans. The reason behind this discrepancy might be due to the safety and bioavailability of the currently used oral statins. Vitamin E, especially the tocotrienols at the dose 60 mg/kg/day provided significant antiosteoporotic effects in different animal models of osteoporosis. The use of the aforementioned dose of tocotrienols was shown to be safe in both humans and animals. Enhancement of bone formation and reduction of bone resorption were achieved more effectively by a combination of tocotrienols and statins than by either treatment when supplemented separately at clinically tolerable doses. Therefore, the adverse effects associated with high statin doses might be avoided with the coadministration of tocotrienols. Moreover, the combination therapy strategy might be useful for patients who are at high risk of osteoporosis, cardiovascular events and hypercholesterolaemia.
    Matched MeSH terms: Dose-Response Relationship, Drug
  17. Fulltext Safety and efficacy of tocotrienol supplementation for bone health in postmenopausal women: protocol for a dose-response double-blinded placebo-controlled randomised trial
    Shen CL, Mo H, Yang S, Wang S, Felton CK, Tomison MD, et al.
    BMJ Open, 2016 12 23;6(12):e012572.
    PMID: 28011809 DOI: 10.1136/bmjopen-2016-012572
    INTRODUCTION: Osteoporosis is a major health concern in postmenopausal women, and oxidative stress contributes to the development of bone loss. Cellular studies and ovariectomised rat model mimicking bone loss in postmenopausal women show the bone-protective effect of tocotrienols (TTs) with antioxidant capability. We aim to access the safety and efficacy of TT consumption for bone health in postmenopausal women.

    METHODS AND ANALYSIS: In this 12-week randomised double-blinded placebo-controlled trial for the effects of dietary TT supplementation in postmenopausal women, postmenopausal women aged 45 years and older with at least 1 year after menopause and bone mineral density T-score at the spine and/or hip 2.5 or more below the reference values will be randomly assigned to 3 daily supplements: (1) placebo group receiving 860 mg olive oil, (2) low TT group receiving 430 mg of 70% pure TTs (containing 300 mg TT) and (3) high TT group receiving 860 mg of 70% pure TTs (600 mg TT). The primary outcome measure will be urinary N-terminal telopeptide. The secondary outcome measures will be serum bone-specific alkaline phosphatase, receptor activator of nuclear factor-κB ligand, osteoprotegerin, urinary 8-hydroxy-2'-deoxyguanosine and quality of life. At 0, 6 and 12 weeks, the following will be assessed: (1) primary and secondary outcome measures; (2) serum TT and tocopherol concentrations; (3) physical activity and food frequency questionnaires. Liver function will be monitored every 6 weeks for safety. 'Intent-to-treat' principle will be employed for data analysis. A model of repeated measurements with random effect error terms will be applied. Analysis of covariance, χ2 analysis and regression will be used for comparisons.

    ETHICS AND DISSEMINATION: This study was approved by the Bioethics Committee of the Texas Tech University Health Sciences Center. The findings of this trial will be submitted to a peer-reviewed journal in the areas of bone or nutrition and international conferences.

    TRIAL REGISTRATION NUMBER: NCT02058420; results.

    Matched MeSH terms: Dose-Response Relationship, Drug
  18. Fulltext Annatto-Derived Tocotrienol Promotes Mineralization of MC3T3-E1 Cells by Enhancing BMP-2 Protein Expression via Inhibiting RhoA Activation and HMG-CoA Reductase Gene Expression
    Wan Hasan WN, Chin KY, Abd Ghafar N, Soelaiman IN
    Drug Des Devel Ther, 2020;14:969-976.
    PMID: 32184566 DOI: 10.2147/DDDT.S224941
    PURPOSE: Annatto-derived tocotrienol (AnTT) has been shown to improve bone formation in animal models of osteoporosis and promote differentiation of pre-osteoblastic cells. However, the mechanism of action of AnTT in achieving these effects is unclear. This study aims to investigate the mechanism of action of AnTT on MC3T3-E1 pre-osteoblasts via the mevalonate pathway.

    METHODS: Murine pre-osteoblastic cells, MC3T3-E1, were cultured with the density of 1 × 104 cells/mL and treated with 4 concentrations of AnTT (0.001-1 µg/mL). Expression of HMG-CoA reductase (HMGR) gene was carried out using qPCR after treatment with AnTT for 21 days. RhoA activation and bone morphogenetic protein-2 (BMP-2) were measured using immunoassay after 9 and 15 days of AnTT treatment. Lovastatin was used as the positive control. Mineralized nodules were detected using Von Kossa staining after 21 days of AnTT treatment.

    RESULTS: The results showed that HMGR was up-regulated in the lovastatin group on day 9 and 21 compared to the control. Lovastatin also inhibited RhoA activation (day 9 and 15) and increased BMP-2 protein (day 15). On the other hand, AnTT at 0.001 μg/mL (day 3) and 0.1 μg/mL (day 21) significantly down-regulated HMGR gene expression compared to the control. On day 21, HMGR gene expression was significantly reduced in all groups compared to day 15. AnTT at 0.1 μg/mL significantly decreased RhoA activation on day 9 compared to the control. AnTT at 1 μg/mL significantly increased BMP-2 protein on day 15 compared to the control (P<0.05). Mineralized calcium nodules were more abundant in AnTT treated groups compared to the control on day 21.

    CONCLUSION: AnTT suppresses the mevalonate pathway by downregulating HMGR gene expression and inhibiting RhoA activation, leading to increased BMP-2 protein in MC3T3-E1 cells. This explains the stimulating effects of AnTT on osteoblast mineralization.

    Matched MeSH terms: Dose-Response Relationship, Drug
  19. Chronic intestinal pseudo-obstruction: a rare first manifestation of systemic lupus erythematosus
    Khairullah S, Jasmin R, Yahya F, Cheah TE, Ng CT, Sockalingam S
    Lupus, 2013 Aug;22(9):957-60.
    PMID: 23761180 DOI: 10.1177/0961203313492873
    Chronic intestinal pseudo-obstruction (CIPO) is a rare clinical syndrome of ineffective intestinal motility characterised by clinical and radiological evidence of intestinal obstruction with no identifiable mechanical lesion. CIPO can either be idiopathic or secondary to a systemic disease, like systemic lupus erythematosus (SLE). Fewer than 30 cases of CIPO secondary to SLE have been reported so far. Here we describe a case of SLE with the initial presentation of CIPO. In SLE-related CIPO, treatment includes a combination of high-dose intravenous corticosteroids, immunosuppressants and supportive care. With awareness of this condition, unnecessary surgical intervention and repeated invasive procedures could be avoided. Early initiation of treatment would avoid complications and bring about resolution of symptoms.
    Matched MeSH terms: Dose-Response Relationship, Drug
  20. Fulltext Determination of insecticide susceptibility in Culex quinquefasciatus Say adults by rapid enzyme microassays
    Lee HL, Abimbola O, Singh KI
    Southeast Asian J. Trop. Med. Public Health, 1992 Sep;23(3):458-63.
    PMID: 1488701
    Rapid enzyme microassays for the detection of resistance due to organophosphate and carbamate in individual field-collected strains of Culex quinquefasciatus adults were conducted. These tests allowed accurate differentiation by eye, on the basis of color changes of susceptible and resistant individuals. Two separate tests were conducted for the biochemical assays. In the insensitive acetylcholinesterase (AChE) test, acetylthiocholine iodide (ACTH) and 5,5-dithiobis-(2-nitrobenzoic acid) (DTNB) were used as substrate and coupling agent respectively. The resulting yellow chromophore indicated AChE activity. Test results showed that the color intensity decreased as increasing concentrations of propoxur were added, thereby confirming the susceptibility of the enzyme to inhibitor. Assay of non-specific esterase however, indicated elevated levels which were correlated with degree of malathion resistance. Electrophoretic data revealed the presence of 2 esterase bands in all strains. It was concluded that such a pattern was not contributory to malathion resistance in adults.
    Matched MeSH terms: Dose-Response Relationship, Drug
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