Combined Treatment of 6-Gingerol Analog and Tobramycin for Inhibiting Pseudomonas aeruginosa Infections.

Pseudomonas aeruginosa is a ubiquitous human pathogen that causes severe infections. Although antibiotics, such as tobramycin, are currently used for infection therapy, their antibacterial activity has resulted in the emergence of multiple antibiotic-resistant bacteria. The 6-gingerol analog, a structural derivative of the main component of ginger, is a quorum sensing (QS) inhibitor. However, it has a lower biofilm inhibitory activity than antibiotics and the possibility to cause toxicity in humans. Therefore, novel and more effective approaches for decreasing dosing concentration and increasing biofilm inhibitory activity are required to alleviate P. aeruginosa infections. In this study, a 6-gingerol analog was combined with tobramycin to treat P. aeruginosa infections. The combined treatment of 6-gingerol analog and tobramycin showed strong inhibitory activities on biofilm formation and the production of QS-related virulence factors of P. aeruginosa compared to single treatments. Furthermore, the combined treatment alleviated the infectivity of P. aeruginosa in an insect model using Tenebrio molitor larvae without inducing any cytotoxic effects in human lung epithelial cells. The 6-gingerol analog showed these inhibitory activities at much lower concentrations when used in combination with tobramycin. Adjuvant effects were observed through increased QS-disrupting processes rather than through antibacterial action. In particular, improved RhlR inactivation by this combination is a possible target for therapeutic development in LasR-independent chronic infections. Therefore, the combined treatment of 6-gingerol analog and tobramycin may be considered an effective method for treating P. aeruginosa infections. IMPORTANCE Pseudomonas aeruginosa is a pathogen that causes various infectious diseases through quorum-sensing regulation. Although antibiotics are mainly used to treat P. aeruginosa infections, they cause the emergence of resistant bacteria in humans. To compensate for the disadvantages of antibiotics and increase their effectiveness, natural products were used in combination with antibiotics in this study. We discovered that combined treatment with 6-gingerol analog from naturally-derived ginger substances and tobramycin resulted in more effective reductions of biofilm formation and virulence factor production in P. aeruginosa than single treatments. Our findings support the notion that when 6-gingerol analog is combined with tobramycin, the effects of the analog can be exerted at much lower concentrations. Furthermore, its improved LasR-independent RhlR inactivation may serve as a key target for therapeutic development in chronic infections. Therefore, the combined treatment of 6-gingerol analog and tobramycin is suggested as a novel alternative for treating P. aeruginosa infections.

Safety, Tolerability, Pharmacokinetics, and Food Effects on TAC-302 in Healthy Participants: Randomized, Double-Blind, Placebo-Controlled, Single-Dose and Multiple-Dose Studies.

TAC-302 stimulates neurite outgrowth activity and is expected to restore urinary function in patients with lower urinary tract dysfunction. We conducted 2 phase 1, randomized, placebo-controlled studies to confirm the safety and pharmacokinetics (PK) of TAC-302 in healthy adult Japanese male volunteers. In the first-in-human single-dose study (n = 60), TAC-302 was administered at doses from 100 to 1200 mg after an overnight fast. The effects of a meal on the PK of TAC-302 400 mg were also examined. A multiple-dose study (n = 36) evaluated the effects of meal fat content on the PK of single doses of TAC-302 (100, 200, or 400 mg) and multiple doses of TAC-302 administered for 5 days (100, 200, and 400 mg twice daily). TAC-302 showed linear PK up to doses of 1200 mg in the fasting state, and across the dose range of 100-400 mg in the fed state. No accumulation of TAC-302 was observed. Food, particularly with high fat content, increased TAC-302 plasma concentrations. No differences were observed in the adverse event incidence between the TAC-302 and placebo groups in either study. TAC-302 showed a wide safety margin.

Acne treatment efficacy of intense pulsed light photodynamic therapy with topical licochalcone A, l-carnitine, and decanediol: A spilt-face, double-blind, randomized controlled trial.

BACKGROUND: Depending on disease severity, standard acne treatments can vary from topical to systemic therapy. However, poor compliance caused by adverse events and antibiotic resistance is a major cause of treatment failure. AIMS: To determine the effectiveness of photodynamic therapy (PDT) with intense pulsed light (IPL) in the treatment of acne when combined with a cream containing licochalcone A, L-carnitine and decanediol (so-called, 'active formulation') versus PDT alone. PATIENTS/METHODS: Twenty-nine volunteers, aged 21-39 years (26 women and 3 men, mean age 29.41 ± 5.24 years), with mild to severe facial acne, were enrolled. Each subject's face sides were randomized in a split-face manner to either receive PDT (IPL with a 400-720 nm cut-off filter, at 4 sessions with two-week intervals) combined with the active formulation cream twice daily for 10 weeks on one face side; or PDT and the vehicle cream on the other side, with the same treatment protocol. Reduction in acne quantity, melanin index and erythema index were assessed 2 weeks after the second treatment (day 28), 1 week after the fourth treatment (day 49), and 1 month after the fourth treatment (day 70). RESULTS: Compared to baseline, patients in the active formulation group demonstrated a faster onset of reduction in the number of lesions at 2 weeks after the second treatment (p=0.010 for inflammatory acne and p=0.001 for non-inflammatory acne). A significantly greater reduction in lesion count was observed in the active formulation group compared with the vehicle group at all timepoints of evaluation for noninflammatory acne (day 28, day 49, and day 70; p=0.003, 0.005 and 0.002 respectively), and at 1 month after the fourth treatment for inflammatory acne (p=0.036). Compared to the vehicle group, the melanin index of the active formulation group decreased significantly at 1 month after the fourth treatment (p=0.015). CONCLUSION: PDT is more effective in treating acne when combined with a topical cream containing licochalcone A, L-carnitine and decanediol, than PDT alone. Significant acne reduction and improvements in post-inflammatory hyperpigmentation were observed, which offers acne patients a better therapeutic option. It is a safe and effective combination treatment for patients with moderate and severe acne.

A Novel Phytantriol-Based In Situ Liquid Crystal Gel for Vaginal Delivery.

The purpose of this paper was to evaluate the potential of in situ liquid crystal (LC) gels based on phytantriol (PYT) for vaginal delivery. The PYT-based in situ liquid crystal gels (PILGs) were prepared by a vortex method using PYT, ethanol (ET), and water (in the ratio of 64:16:20, w/w). The internal structures of PILGs and cubic LC gels (formed by PILG phase conversion) were confirmed by crossed polarized light microscopy (PLM) and small-angle X-ray scattering (SAXS). And the rheological tests showed that PILGs had small viscosity and excellent fluidity. The viscosities of cubic LC gels were 4~5 orders of magnitude higher than PILGs. In vitro phase conversion experiment showed that PILGs required little vaginal fluid (64.56 µL/100 mg) and time (3.92 s) to transform to LC gels. Furthermore, cubic LC gels could reside in the vaginas for more than 12 h in vivo. The in vitro release revealed that sinomenine hydrochloride (SMH) could be sustained released from the cubic gels over a period of 144 h, which was prior to SMH solution and carbomer gels. An in vivo vaginal mucosa irritation study indicated that PILGs were nonirritant and might be suitable for various vaginal applications. In conclusion, PILGs might represent a potential vaginal delivery strategy to overcome the limitations of traditional treatments.

Efficacy and Safety of Policosanol Plus Fenofibrate Combination Therapy in Elderly Patients with Mixed Dyslipidemia: A Randomized, Controlled Clinical Study.

BACKGROUND: Policosanol is a mixture of long-chain alcohols isolated from sugar cane. This controlled, randomized clinical trial was designed to compare the efficacy and safety of fenofibrate, policosanol and a combination of these 2 in lowering low-density-lipoprotein cholesterol (LDL-C) in elderly patients with mixed dyslipidemia. METHODS: A total of 102 patients aged ≥60years were randomly assigned into 3 groups: patients receiving a 24-week therapy of fenofibrate (200 mg/day), policosanol (20 mg/day) or fenofibrate + policosanol combination. Lipids were evaluated at baseline, after 16 and after 24 weeks of therapy. Brachial-ankle pulse wave velocity (ba-PWV) was performed, and SF-36 questionnaires were used to evaluate the patients' quality of life. The primary endpoint was the percentage reduction in LDL-C. The secondary end points included percentage change in nonhigh density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), triglyceride, high-density-lipoprotein cholesterol (HDL-C), ba-PWV and SF-36 scores. Safety was assessed by adverse events and laboratory parameters. RESULTS: LDL-C, non-HDL-C and TC were decreased, respectively after treatment with policosanol for 24 weeks (P < 0.01). Treatment with policosanol + fenofibrate resulted in significantly greater reductions in TC, non-HDL-C and LDL-C compared to fenofibrate alone (P < 0.01, respectively). There were significant increases in SF-36 scores in the policosanol and policosanol + fenofibrate groups (P < 0.05), and significant improvements of ba-PWV in the 2 groups (P < 0.01). There were no serious adverse events or significant changes in laboratory variables after any of the treatment regimens. CONCLUSIONS: Policosanol + fenofibrate combination therapy significantly improved lipid parameters, arterial stiffness, and quality of life, with good tolerability.

Antibiofilm and Antivirulence Activities of 6-Gingerol and 6-Shogaol Against Candida albicans Due to Hyphal Inhibition.

Candida albicans is an opportunistic pathogen and responsible for candidiasis. C. albicans readily forms biofilms on various biotic and abiotic surfaces, and these biofilms can cause local and systemic infections. C. albicans biofilms are more resistant than its free yeast to antifungal agents and less affected by host immune responses. Transition of yeast cells to hyphal cells is required for biofilm formation and is believed to be a crucial virulence factor. In this study, six components of ginger were investigated for antibiofilm and antivirulence activities against a fluconazole-resistant C. albicans strain. It was found 6-gingerol, 8-gingerol, and 6-shogaol effectively inhibited biofilm formation. In particular, 6-shogaol at 10 µg/ml significantly reduced C. albicans biofilm formation but had no effect on planktonic cell growth. Also, 6-gingerol and 6-shogaol inhibited hyphal growth in embedded colonies and free-living planktonic cells, and prevented cell aggregation. Furthermore, 6-gingerol and 6-shogaol reduced C. albicans virulence in a nematode infection model without causing toxicity at the tested concentrations. Transcriptomic analysis using RNA-seq and qRT-PCR showed 6-gingerol and 6-shogaol induced several transporters (CDR1, CDR2, and RTA3), but repressed the expressions of several hypha/biofilm related genes (ECE1 and HWP1), which supported observed phenotypic changes. These results highlight the antibiofilm and antivirulence activities of the ginger components, 6-gingerol and 6-shogaol, against a drug resistant C. albicans strain.

Liposomal borrelidin for treatment of metastatic breast cancer.

Borrelidin is an inhibitor of threonyl-tRNA synthetase with both anticancer and antiangiogenic activities. Although borrelidin could be a potent drug that can treat metastatic cancer through synergistic therapeutic effects, its severe liver toxicity has limited the use for cancer therapeutics. In this study, we developed a liposomal formulation of borrelidin to treat metastatic breast cancer effectively through its combined anticancer and antiangiogenic effects while reducing the potential liver toxicity. The liposomal formulation was optimized to maximize loading stability and efficiency of lipophilic borrelidin in the liposomal membrane and its delivery efficiency to primary tumor in a mouse model of metastatic breast cancer. Liposomal borrelidin showed significant in vitro therapeutic effects on proliferation and migration of tumor cells and angiogenesis of endothelial cells. Furthermore, liposomal borrelidin exhibited superior inhibitory effects on primary tumor growth and lung metastasis in vivo compared to free borrelidin. More importantly, liposomal borrelidin did not induce any significant systemic toxicity in the mouse model after multiple injections.

Efficacy and safety of sugarcane policosanol on dyslipidemia: A meta-analysis of randomized controlled trials.

SCOPE: This study aimed to systematically investigate whether sugarcane policosanol was effective and safe on dyslipidemia. METHODS AND RESULTS: A total of 11 databases including the PubMed, Web of science, Embase, Scopus, the Cochrane library and SinoMed databases were searched for available studies investigating the effects of policosanol on dyslipidemia. A total of 22 studies including 1886 subjects were included in the analysis. The pooled results showed that compared with placebo, sugarcane policosanol could significantly reduce total cholesterol (TC, 95% CI: -0.87 to -0.30 mmol/L) and low density lipoprotein cholesterol (LDL-c, 95% CI: -1.02 to -0.40 mmol/L) and increase high density lipoprotein cholesterol; however, no significant effects were observed on triglyceride (TG) and body weight. Subgroup analysis suggested the studies from Cuba obtained more effective data than those outside this country, and the effects were not proportional to the dose. The adverse effects analysis demonstrated that sugarcane policosanol was safer than the control agents. CONCLUSION: The pooled results supported the lipid-lowering effects and safety of policosanol. Because of the high heterogeneity, the better treatment effects observed in the Cuban studies and the inconsistent dose-response relationship, more clinical trials are needed to further confirm the efficacy of policosanol on dyslipidemia.

Comparison of the efficacy and tolerability of chondroitin plus glucosamine and D-002 (beeswax alcohols) in subjects with osteoarthritis symptoms.

BACKGROUND/AIMS: Osteoarthritis (OA), the commonest joint disorder, is a leading cause of disability. Symptomatic slow-acting drugs for OA (SYSADOA), particularly glucosamine plus chondroitin sulphate (GS/CS), are effective for symptom relief, protect joint cartilage and delay OA progression, with a good safety profile. D-002, a mixture of beeswax alcohols that inhibits both cyclooxygenase and 5-lipoxygenase activities, has been effective in experimental and clinical OA studies, showing also a chondroprotective effect. OBJECTIVES: To compare the effects of D-002 and GS/SC administered for 12 weeks on OA symptoms. METHODS: Participants were randomized to GS/CS (375/300 mg) or 50 mg D-002 once daily for 12 weeks. Symptoms were assessed by the Western Ontario and McMaster Individual Osteoarthritis Index (WOMAC) and the Visual Analogy Scale (VAS) scores. The primary outcome was the reduction of the total WOMAC score. Secondary outcomes included WOMAC pain, stiffness and function scores, VAS score and rescue medication consumption. RESULTS: Of 60 randomized patients, 59 completed the study. D-002 and GS/SC reduced significantly total WOMAC score (72.1% and 78.5%, respectively), and pain, joint stiffness and physical function scores versus baseline. VAS scores decreased significantly with D-002 (76.6%) and GS/SC (76.8%). The reductions, significant from the second week, were enhanced over the trial. Rescue medications were consumed by 3/30 D-002 and 4/30 GS/SC patients. No differences between groups were found. Treatments were well tolerated. CONCLUSIONS: D-002 (50 mg/day) administered for 12 weeks was safe and comparable to GS/SC for alleviating OA symptoms (pain, stiffness, and functional limitation) (RPCEC00000180).

Consumption of policosanol enhances HDL functionality via CETP inhibition and reduces blood pressure and visceral fat in young and middle-aged subjects.

It is well-known that policosanol can improve serum lipid profiles, although the physiological mechanism is still unknown. Here, we investigated functional and structural changes in lipoproteins after consumption of policosanol. To investigate the physiological effect of policosanol, we analyzed serum parameters in young non-smoker (YN; n=7, 24.0±2.4 years), young smoker (YS; n=7, 26.3±1.5 years), and middle-aged subjects (MN; n=11, 52.5±9.8 years) who consumed policosanol daily (10 mg/day) for 8 weeks. After 8 weeks, systolic blood pressure was significantly lowered to 4% (7 mmHg, p=0.022) from initial levels in the YS and MN groups. Moisture content of facial skin increased up to 38 and 18% from initial levels in the YS and MN groups, respectively. Serum triglyceride (TG) levels decreased to 28 and 26% from initial levels in the YN and MN groups, respectively. The percentage of high-density lipoprotein-cholesterol (HDL-C) in total cholesterol was elevated in all subjects (YN, 36%; YS, 35%; MN, 8%) after 8 weeks of policosanol consumption. All groups showed a reduction in serum glucose and uric acid levels. Serum cholesteryl ester transfer protein (CETP) activity was significantly diminished up to 21 and 32% from initial levels in the YN and MN groups, respectively. After 8 weeks, oxidation of the low-density lipoprotein fraction was markedly reduced accompanied by decreased apolipoprotein B (apoB) fragmentation. In the HDL fraction, paraoxonase activity was elevated by 17% along with elevation of apoA-I and cholesterol contents. Electron microscopy revealed that the size and number of HDL particles increased after 8 weeks, and the YS group showed a 2-fold increase in particle size. Daily consumption of policosanol for 8 weeks resulted in lowered blood pressure, reduced serum TG level and CETP activity, and elevated HDL-C contents. These functional enhancements of HDL can prevent and/or attenuate aging-related diseases, hypertension, diabetes and coronary heart disease.

[Long-term effect of policosanol on the functional recovery of non-cardioembolic ischemic stroke patients: a one year study]. / Efecto a largo plazo del policosanol en la recuperacion funcional de pacientes con ictus isquemico no cardioembolico: estudio de un año.

INTRODUCTION: Stroke is a leading cause of mortality and disability. Policosanol has been effective in brain ischemia models. The aim of this study is to investigate whether policosanol, added to aspirin therapy within 30 days of stroke onset, is better than placebo + aspirine for the long-term recovery of non-cardioembolic ischemic stroke subjects. PATIENTS AND METHODS: Randomized, double-blind, placebo-controlled study. Eighty patients (mean age: 69 years) within 30 days of onset, with a modified Rankin Scale score (mRS) 2 to 4, were included. They were randomized in two groups (policosanol + aspirine or placebo + aspirine) for 12 months. RESULTS: Policosanol + aspirine decreased significantly mean mRS from the first interim check-up (1.5 months). The treatment even improved after long-term therapy. More policosanol + aspirin (87.5%) than placebo + aspirine (0%) patients achieved mRSs <= 1. Policosanol + aspirine increased significantly Barthel Index, lowered LDL-cholesterol and increased HDL-cholesterol versus placebo + aspirin. CONCLUSIONS: Long-term (12 months) administration of policosanol + aspirin given after suffering non-cardioembolic ischemic stroke was shown to be better than placebo + aspirin in improving functional outcomes when used among patients with non-cardioembolic ischemic stroke of moderate severity.

TITLE: Efecto a largo plazo del policosanol en la recuperacion funcional de pacientes con ictus isquemico no cardioembolico: estudio de un año.Introduccion. El ictus es una causa principal de mortalidad y discapacidad. El policosanol ha sido eficaz en modelos de isquemia cerebral. Este estudio investiga si el tratamiento a largo plazo con policosanol, añadido a la terapia con acido acetilsalicilico (AAS), dentro de los 30 dias posteriores a un ictus, es mejor que el placebo + AAS en la recuperacion de los pacientes. Pacientes y metodos. Estudio aleatorizado, doble ciego, controlado con placebo. Se incluyeron 80 pacientes (edad media: 69 años) que sufrieron un ictus en los 30 dias previos y con una puntuacion de 2-4 en la escala de Rankin modificada (mRS). Se distribuyeron aleatoriamente en dos grupos y recibieron policosanol + AAS o placebo + AAS durante 12 meses. Resultados. El tratamiento con policosanol + AAS disminuyo significativamente la puntuacion en la mRS desde el primer control intermedio (1,5 meses). El efecto del tratamiento incluso mejoro con la terapia a largo plazo. El numero de pacientes que alcanzaron valores de mRS menores o iguales a 1 fue superior en el grupo de policosanol + AAS (87,5%) que en el de placebo + AAS (0%). El tratamiento con policosanol + AAS aumento significativamente el indice de Barthel, disminuyo el colesterol LDL y aumento el colesterol HDL frente a placebo + AAS. Conclusiones. El tratamiento a largo plazo (12 meses) con policosanol + AAS fue mas efectivo que el tratamiento con placebo + AAS en la recuperacion funcional de los pacientes despues de sufrir un ictus isquemico no cardioembolico de moderada gravedad.

Zero-inflated Poisson model based likelihood ratio test for drug safety signal detection.

In recent decades, numerous methods have been developed for data mining of large drug safety databases, such as Food and Drug Administration's (FDA's) Adverse Event Reporting System, where data matrices are formed by drugs such as columns and adverse events as rows. Often, a large number of cells in these data matrices have zero cell counts and some of them are "true zeros" indicating that the drug-adverse event pairs cannot occur, and these zero counts are distinguished from the other zero counts that are modeled zero counts and simply indicate that the drug-adverse event pairs have not occurred yet or have not been reported yet. In this paper, a zero-inflated Poisson model based likelihood ratio test method is proposed to identify drug-adverse event pairs that have disproportionately high reporting rates, which are also called signals. The maximum likelihood estimates of the model parameters of zero-inflated Poisson model based likelihood ratio test are obtained using the expectation and maximization algorithm. The zero-inflated Poisson model based likelihood ratio test is also modified to handle the stratified analyses for binary and categorical covariates (e.g. gender and age) in the data. The proposed zero-inflated Poisson model based likelihood ratio test method is shown to asymptotically control the type I error and false discovery rate, and its finite sample performance for signal detection is evaluated through a simulation study. The simulation results show that the zero-inflated Poisson model based likelihood ratio test method performs similar to Poisson model based likelihood ratio test method when the estimated percentage of true zeros in the database is small. Both the zero-inflated Poisson model based likelihood ratio test and likelihood ratio test methods are applied to six selected drugs, from the 2006 to 2011 Adverse Event Reporting System database, with varying percentages of observed zero-count cells.

Marine compound rhizochalinin shows high in vitro and in vivo efficacy in castration resistant prostate cancer.

Development of drug resistance is an inevitable phenomenon in castration-resistant prostate cancer (CRPC) cells requiring novel therapeutic approaches. In this study, efficacy and toxicity of Rhizochalinin (Rhiz) - a novel sphingolipid-like marine compound - was evaluated in prostate cancer models, resistant to currently approved standard therapies. In vitro activity and mechanism of action of Rhiz were examined in the human prostate cancer cell lines PC-3, DU145, LNCaP, 22Rv1, and VCaP. Rhiz significantly reduced cell viability at low micromolar concentrations showing most pronounced effects in enzalutamide and abiraterone resistant AR-V7 positive cells. Caspase-dependent apoptosis, inhibition of pro-survival autophagy, downregulation of AR-V7, PSA and IGF-1 expression as well as inhibition of voltage-gated potassium channels were identified as mechanisms of action. Remarkably, Rhiz re-sensitized AR-V7 positive cells to enzalutamide and increased efficacy of taxanes.In vivo activity and toxicity were evaluated in PC-3 and 22Rv1 NOD SCID mouse xenograft models using i.p. administration. Rhiz significantly reduced growth of PC-3 and 22Rv1 tumor xenografts by 27.0% (p = 0.0156) and 46.8% (p = 0.047) compared with controls with an increased fraction of tumor cells showing apoptosis secondary to Rhiz exposure. In line with the in vitro data, Rhiz was most active in AR-V7 positive xenografts in vivo. In animals, no severe side effects were observed.In conclusion, Rhiz is a promising novel marine-derived compound characterized by a unique combination of anticancer properties. Its further clinical development is of high impact for patients suffering from drug resistant prostate cancer especially those harboring AR-V7 mediated resistance to enzalutamide and abiraterone.

Allergic contact dermatitis from cetearyl alcohol in Thrombocid® ointment.

Thrombocid® ointment (Lacer, Barcelona, Spain) is widely used in Spain and other countries for varicose veins and 22 hematomas. To our knowledge, there are no reported cases of allergic contact dermatitis following its use. Herein we present 23 two cases of allergic contact dermatitis to Thrombocid® ointment, owing to cetearyl alcohol.

Safety and efficacy of policosanol in patients with high on-treatment platelet reactivity after drug-eluting stent implantation: two-year follow-up results.

OBJECTIVES: To investigate safety and efficacy of policosanol in patients with high on-treatment platelet reactivity after drug-eluting stent implantation. BACKGROUND: Certain number of patients has high residual platelet reactivity on clopidogrel after coronary intervention, and their risk of thrombotic events is high. METHOD: In this prospective, randomized trial conducted in four Chinese sites, 350 patients with high on-treatment platelet reactivity (HPR, defined as platelet aggregation >65%) were randomized by the ratio of 1:3:3 to: group A, clopidogrel 75 mg/d for 1 year (n=50); group B, clopidogrel 150 mg/d for 30 days followed by 75 mg/d until 1 year (n=150); or group C, policosanol 40 mg/d for 6 month and clopidogrel 75 mg/d for 1 year (n=150). All of them were treated with aspirin. The primary endpoint was the reversion rate of HPR at 1 month (reversion was defined as platelet aggregation <65%). The secondary endpoints were 6-month major adverse cardiac events (MACE), which included cardiac death, nonfatal myocardial infarction, or ischemic symptoms driven target vessel revascularization. RESULTS: At 30 days, the reversion rate of HPR was 34.0%, 55.2%, and 48.7% in group A, group B, and group C, respectively (P=.029). Major adverse cardiac events occurred in 4 (8.0%), 6(4.0%), and 5(3.3%) patients (P=.342). There was 1 (0.7%) major bleeding and 1 (0.7%) minor bleeding event in high maintenance dose clopidogrel group, no major or moderate bleeding in the other two groups. The minimal bleeding in group B was significantly higher than group C (10.7% vs 2.7%, P=.022). At 2-year follow-up, the benefits of policosanol on bleedings persisted compared with group B. CONCLUSIONS: Policosanol reduced platelet reactivity to a similar extent as high maintenance dose of clopidogrel without increasing bleeding rate.

Genetic Variants of LDLR and PCSK9 Associated with Variations in Response to Antihypercholesterolemic Effects of Armolipid Plus with Berberine.

BACKGROUND: Armolipid Plus (AP) is a nutraceutical that contains policosanol, fermented rice with red yeast, berberine, coenzyme Q10, folic acid, and astaxanthin. It has been shown to be effective in reducing plasma LDL cholesterol (LDLc) levels. In the multicenter randomized trial NCT01562080, there was large interindividual variability in the plasma LDLc response to AP supplementation. We hypothesized that the variability in LDLc response to AP supplementation may be linked to LDLR and PCSK9 polymorphisms. MATERIAL AND METHODS: We sequenced the LDLR 3' and 5' untranslated regions (UTR) and the PCSK9 5' UTR of 102 participants with moderate hypercholesterolemia in trial NCT01562080. In this trial, 50 individuals were treated with AP supplementation and the rest with placebo. RESULTS: Multiple linear regression analysis, using the response of LDLc levels to AP as the dependent variable, revealed that polymorphisms rs2149041 (c.-3383C>G) in the PCSK9 5' UTR and rs14158 (c.*52G>A) in the LDLR 3' UTR explained 14.1% and 6.4%, respectively, of the variability after adjusting for gender, age, and BMI of individuals. Combining polymorphisms rs2149041 and rs14158 explained 20.5% of this variability (p < 0.004). CONCLUSIONS: Three polymorphisms in the 3' UTR region of LDLR, c.*52G>A, c.*504G>A, and c.*773A>G, and two at the 5' UTR region of PCSK9, c.-3383C>G and c.-2063A>G, were associated with response to AP. These results could explain the variability observed in the response to berberine among people with moderate hypercholesterolemia, and they may be useful in identifying patients who could potentially benefit from supplementation with AP.

1-Triacontanol cerotate; isolated from Marsilea quadrifolia Linn. ameliorates reactive oxidative damage in the frontal cortex and hippocampus of chronic epileptic rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Marsilea quadrifolia Linn. (MQ) has been used for insomnia and epileptic disorders in traditional Indian medicine. The present study is to isolate the active component responsible for antiepileptic property of MQ by evaluating its ability to minimize the reactive oxidative damage in brain due to chronic epilepsy in rat. MATERIALS AND METHODS: 1-Triacontanol cerotate (1TAC) was isolated after chromatography on a silica gel from dried petroleum ether fraction of methanolic extract of MQ. Acute oral toxicity studies of 1TAC were carried out and efficacy of 1TAC on malondialdehyde (MDA) and reduced glutathione (GSH) production in different brain areas of chronic pentylenetetrazole (PTZ) induced epileptic rats were evaluated. RESULTS: Our results showed that PTZ-kindled chronic epileptic rats had an increase MDA and decreased GSH concentration in the frontal cortex as well as hippocampus, compared to the normal control. MDA and GSH concentrations in those brain areas were normalized after treatment with sodium valproate (SV) in 200 mg kg(-1)bw; as well as 1TAC in 40 and 80 mg kg(-1)bw doses. CONCLUSION: Production of reactive oxygen species (ROS) is known to worsen epileptogenesis. The isolated component 1TAC which reduced the reactive oxidative damage in hippocampus and frontal cortex of PTZ kindled rats could be responsible for antiepileptic property of MQ. Its action is found to be dose dependent, with 80 mg kg(-1)bw showing even better efficacy than 200 mg kg(-1)bw of SV.