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.

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.

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.

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.

Systemic allergic dermatitis caused by Apiaceae root vegetables.

BACKGROUND: Immediate hypersensitivity reactions to root vegetables of the Umbelliferae plant family (Apiaceae) is well known. Delayed-type hypersensitivity is rarely reported. OBJECTIVE: To report the first case of systemic contact dermatitis caused by root vegetables and some chemical implications. MATERIALS AND METHODS: Prick and patch testing were performed with fresh vegetables and selected allergens, and this was followed by high-performance liquid chromatography-mass spectrometry (MS)/MS analysis of the falcarinol syringe. RESULTS: The patient was contact-sensitive to celeriac, parsnip, and carrot, but tested negative to falcarinol. Subsequent analysis showed that the syringe contained falcarinol. CONCLUSION: The non-occupational sensitization resulting from both direct and systemic contact with Apiaceae root vegetables was apparently not caused by falcarinol.

Nematicidal activity of nonacosane-10-ol and 23a-homostigmast-5-en-3ß-ol isolated from the roots of Fumaria parviflora (Fumariaceae).

Two bioactive nematicidal phytochemicals, viz., nonacosane-10-ol and 23a-homostigmast-5-en-3ß-ol, were isolated from the n-hexane fraction of the roots of Fumaria parviflora through activity-guided isolation. The structures of the compounds were elucidated using ¹³C and ¹H nuclear magnetic resonance. Activity of the two compounds against eggs and juveniles (J2s) of Meloidogyne incognita was evaluated in vitro at the concentrations of 50, 100, 150, and 200 µg mL⁻¹. Over 120 h of incubation, the cumulative percent mortality and hatch inhibition of both of the compounds tested ranged from 20 to 100% and from 15 to 95.0%, respectively. In pot trials with tomato cultivar Riogrande, the two compounds, applied as soil drenches at the concentrations of 100, 200, and 300 mg/kg, significantly decreased the nematodes and plant growth parameters. Nonacosane-10-ol and 23a-homostigmast-5-en-3ß-ol reduced the numbers of galls (42.6 and 60.3), galling index (1.6 and 2.8), females per gram of root (37.3 and 57.0), eggs per gram of root (991.3 and 1273.0), reproduction factor (Rf) (0.1 and 0.2), and fresh root weight (14.33 and 17.0 g) at 300 mg/kg concentration and increased fresh shoot weight (49.0 and 48.4 g), dry shoot weight (28.0 and 25.3 g), and plant height (53.5 and 49.6 cm), respectively. These compounds could provide new insight in the search for novel nematicides against M. incognita.

An open label, pilot study of Aerosurf® combined with nCPAP to prevent RDS in preterm neonates.

BACKGROUND: Nasal continuous positive airway pressure (nCPAP) is an accepted mode of respiratory support for preterm infants with respiratory insufficiency. To avoid potential sequelae of endotracheal (ET) intubation and mechanical ventilation, prophylactic aerosolization of surfactant delivered via nCPAP has been attempted with limited success. METHODS: To determine the feasibility and safety of prophylactic aerosolization of a peptide-containing synthetic surfactant, Aerosurf® (lucinactant for inhalation) was delivered by nCPAP to preterm infants at risk for respiratory distress syndrome (RDS). Neonates were enrolled into treatment group 1 (Aerosurf retreatment separated by at least 3 h) or treatment group 2 (Aerosurf retreatment separated by at least 1 h). A vibrating membrane nebulizer Aeroneb Pro® was used to aerosolize 20 mg/mL Aerosurf. All neonates received the initial 3-h treatment, and three retreatments were permitted within 48 h based on clinical response. RESULTS: Seventeen infants were enrolled. Aerosurf was well tolerated, with transient desaturations observed during dosing without bradycardia or hypotension. Variability in output rates of the Aeroneb Pro was observed leading to different average dispensed drug volumes per treatment per patient. All infants survived; 29.4% required subsequent ET surfactant replacement therapy, 23.5% were diagnosed with RDS at 24 h, and 11.8% with bronchopulmonary dysplasia (BPD) at 28 days of life. Mean FiO2 was 0.4 at baseline, and 0.32 at 4 h posttreatment. CONCLUSIONS: Aerosurf can be safely administered via nCPAP in preterm infants at risk for RDS and may provide an alternative to surfactant administration via an ET tube. Further studies are required to evaluate this delivery approach.

Genotoxic effect of 6-gingerol on human hepatoma G2 cells.

6-gingerol, a major component of ginger, has antioxidant, anti-apoptotic, and anti-inflammatory activities. However, some dietary phytochemicals possess pro-oxidant effects as well, and the risk of adverse effects is increased by raising the use of doses. The aim of this study was to assess the genotoxic effects of 6-gingerol and to clarify the mechanisms, using human hepatoma G2 (HepG2) cells. Exposure of the cells to 6-gingerol caused significant increase of DNA migration in comet assay, increase of micronuclei frequencies at high concentrations at 20-80 and 20-40 microM, respectively. These results indicate that 6-gingerol caused DNA strand breaks and chromosome damage. To further elucidate the underlying mechanisms, we tested lysosomal membrane stability, mitochondrial membrane potential, the intracellular generation of reactive oxygen species (ROS) and reduced glutathione (GSH). In addition, the level of oxidative DNA damage was evaluated by immunocytochemical analysis on 8-hydroxydeoxyguanosine (8-OHdG). Results showed that lysosomal membrane stability was reduced after treatment by 6-gingerol (20-80 microM) for 40 min, mitochondrial membrane potential decreased after treatment for 50 min, GSH and ROS levels were significantly increased after treatment for 60 min. These suggest 6-gingerol induces genotoxicity probably by oxidative stress; lysosomal and mitochondrial damage were observed in 6-gingerol-induced toxicity.

Synthetic surfactants: where are we? Evidence from randomized, controlled clinical trials.

The benefits of exogenous synthetic or animal-derived surfactants for prevention or treatment of respiratory distress syndrome (RDS) are well established. Data from head-to-head trials comparing animal-derived surfactants primarily with the synthetic surfactant colfosceril suggest that the major clinical advantages afforded by the presence of surfactant protein (SP)-B and SP-C in animal-derived preparations relate to faster onset of action, a reduction in the incidence of RDS when used prophylactically, and a lower incidence of air leaks and RDS-related deaths. However, no benefits in terms of overall mortality or BPD have been shown in these head-to-head comparisons. Findings from trials of a new-generation synthetic surfactant containing a peptide that mimics SP-B, as well as their follow-up study suggest that its administration improves short-term clinical outcomes compared with colfosceril and results in survival through 1 year of age, which is at least comparable, if not perhaps superior, to that seen with animal-derived surfactants.

Effects of a policosanol supplement on serum lipid concentrations in hypercholesterolaemic and heterozygous familial hypercholesterolaemic subjects.

Policosanol is a mixture of higher aliphatic primary alcohols that is extracted from purified sugar cane wax or a variety of other plant sources, and has been shown to have beneficial effects on serum lipid concentrations. The objective of this study was to investigate the effects of a policosanol supplement (Octa-60) on lipid profiles of hypercholesterolaemic and heterozygous familial hypercholesterolaemic subjects. Nineteen hypercholesterolaemic and familial hypercholesterolaemic subjects completed this randomised, placebo-controlled, double-blind study. The subjects received either a daily dose of 20 mg policosanol or placebo for 12 weeks. After a wash-out period of 4 weeks, the interventions were crossed over. Lipid levels were measured at baseline and at the end of each intervention period. No significant differences in total cholesterol and LDL-cholesterol from baseline to end or between policosanol and placebo were seen in the hypercholesterolaemic or familial hypercholesterolaemic groups. There were small reductions in total cholesterol and LDL-cholesterol from baseline to end in the hypercholesterolaemic group, but these changes did not differ significantly from the changes with the placebo, indicating that the observed decrease in cholesterol in the policosanol group was not due to the specific effect of policosanol treatment. The differences in response may be ascribed to the differences in composition of the higher aliphatic primary alcohols in the previously used products, compared with the local policosanol supplement. An intake of 20 mg/d policosanol for 12 weeks had no significant effect on serum lipid levels in hypercholesterolaemic and heterozygous familial hypercholesterolaemic patients when compared with placebo intake.

A comparison of the effects of D-003 and policosanol (5 and 10 mg/day) in patients with type II hypercholesterolemia: a randomized, double-blinded study.

The main goal of hypercholesterolemia management for coronary prevention is to reduce serum low-density lipoprotein cholesterol (LDL-C) levels. D-003 is a mixture of high molecular weight aliphatic acids purified from sugarcane wax, while policosanol is a cholesterol-lowering drug purified from the same source, consisting in a mixture of higher aliphatic alcohols. No previous comparative study of both drugs in humans has been reported. This randomized, double-blind study compares the efficacy and tolerability of D-003 and policosanol (5 and 10 mg/day) in patients with type II hypercholesterolemia. After a baseline period, 100 patients were randomized to D-003 or policosanol both at 5 mg/day and 10 mg/day, for 8 weeks. D-003 and policosanol 5 mg/day reduced (p < 0.0001) LDL-C by 26.9% and 20.9%, respectively. These reductions increased with 10 mg/day (35.1% for D-003, 25.1% for policosanol. The reductions of LDL-C achieved with D-003 5 mg/day and 10 mg/day were greater (p < 0.05 and p < 0.001, respectively) than with policosanol. The frequency of patients treated with D-003 (5 mg/day) reaching LDL-C reductions > or = 15% (22/25, 88%) was greater (p < 0.01) than with policosanol (5 mg/day) (19/25, 76%), and the same was true for D-003 10 mg/day (25/25, 100%) and policosanol (22/25, 88%; p < 0.01). D-003 and policosanol (5 mg/day) also lowered (p < 0.001) total cholesterol (TC) (16.2% and 13.5%, respectively), and increased high-density lipoprotein cholesterol (HDL-C) by 15.3% (D-003) and 6.7% (policosanol). At 10 mg/day, D-003 and policosanol reduced (p < 0.001) TC (21.3% and 16.0%, respectively), while HDL-C was increased by 17.3% and 9.8%, respectively, D-003 being more effective than policosanol. Treatments did not affect triglycerides. Both drugs were well tolerated, with D-003 tolerated as well as policosanol. Three patients discontinued the study, none due to adverse events (AEs). Seven patients (three from the D-003 group and four from the policosanol group) experienced mild AEs. In conclusion, D-003 (5 and 10 mg/day) administered to patients with type II hypercholesterolemia was more effective than policosanol in lowering LDL-C and TC, and in increasing HDL-C. D-003 could be useful for treating type II hypercholesterolemia, but this subject deserves further clinical research.

A pharmacological surveillance study of the tolerability of policosanol in the elderly population.

BACKGROUND: Policosanol is a drug derived from sugar cane wax that has cholesterol-lowering and antiplatelet properties. Randomized, controlled studies are the gold standard for demonstrating drug efficacy, safety, and tolerability, but postmarketing surveillance studies are encouraged for corroborating drug effects. A valid proof of the safety of a drug is a well-documented, good tolerability profile in older individuals, since this population is more prone to drug-related adverse events (AEs). OBJECTIVE: This study investigated the tolerability of policosanol in the elderly population by monitoring the incidence and nature of AEs occurring in older Cuban patients treated with policosanol in routine clinical practice. METHODS: All patients aged > or =60 years treated with policosanol at 7 major medical centers from January 2000 to May 2003 were included. Policosanol (5, 10, or 20 mg/d) was prescribed to patients eligible to receive cholesterol-lowering and/or antiplatelet drugs, with the dosage recommended according to their individual atherosclerotic risk. Patients had follow-up visits approximately every 6 months. Data on AEs and other relevant information, including changes in policosanol treatment, concomitant medications, and discontinuations, were recorded on individual case-report forms. RESULTS: This study included 2252 patients (1306 women, 946 men): 647 (28.7%), 244 (10.8%), and 173 (7.7%) patients had coronary, cerebrovascular, and peripheral artery disease, respectively. A total of 1485 patients had hypercholesterolemia (65.9%), 1322 (58.7%) had hypertension, and 323 (14.3%) had diabetes mellitus. Of the enrolled patients, 1123 (49.9%), 644 (28.6%), and 485 (21.5%) received policosanol 5, 10, and 20 mg/d, respectively. Treatment duration varied: 2169 (96.3%), 1861 (82.6%), 1116 (49.6%), and 412 (18.3%) patients were treated for 6, 12, 24, and 36 months, respectively. Thirty-one patients (1.4%) experienced serious AEs, 18 of them fatal. Death was most often due to vascular events: myocardial infarction (4 patients), sudden cardiac arrest (1), ventricular arrhythmia (2), ischemic stroke (1), lung thromboembolism (1), cancer (5), pneumonia (1), peritonitis (1), lung edema (1), and dehydration (1). Another 13 patients (0.6%) were hospitalized, and 61 (2.7%) reported moderate or mild AEs. Overall, 21 patients (0.9%) discontinued prematurely from the study, 18 of them due to a fatal serious AE. CONCLUSIONS: Long-term tolerability of policosanol in elderly patients at high vascular risk was very good, as assessed under conditions of routine clinical practice. These results are consistent with those obtained in randomized, double-blind clinical studies of older patients treated with policosanol.

Effects of policosanol on older patients with hypertension and type II hypercholesterolaemia.

OBJECTIVE: This study was conducted to investigate the effects of policosanol administered for 12 months on the lipid profile of older patients with hypertension and type II hypercholesterolaemia and no history of coronary heart disease (CHD) or cerebrovascular disease. PATIENTS AND PARTICIPANTS: 589 older male and female patients with hypertension and type II hypercholesterolaemia and no history of CHD or cerebrovascular disease were included. METHODS: This was a prospective, randomised, double-blind, placebo-controlled study in parallel groups treated with policosanol (5 to 10 mg/day) for 1 year. After 6 weeks on a standard step I cholesterol-lowering diet, 589 patients were randomised to policosanol (5 mg) or placebo tablets, to be taken once daily for 12 months. The dosage was doubled to 10 mg/day if total cholesterol values were > 6.1 mmol/L after 6 months of therapy. RESULTS: Policosanol significantly (p < 0.00001) lowered serum low-density lipoprotein-cholesterol (LDL-C) [20.5%], total cholesterol (TC) [15.4%], triglycerides (11.9%), LDL-C/high-density lipoprotein-cholesterol (HDL-C) ratio [22.2%] and TC/HDL-C ratio (20.1%), and increased (p < 0.0001) HDL-C (12.7%). The frequency of vascular and all-cause serious adverse events (SAEs) was lower (p < 0.05) in the policosanol recipients (two vascular SAEs, 0.7%; five all-cause SAEs, 1.7%) than in the placebo recipients (six vascular SAEs, 2.0%; 12 all-cause SAEs, 4.1%). Similarly, total adverse events (AEs) were less frequent in the policosanol-treated group (29; 9.8%) compared with the placebo group (52; 17.7%) [p < 0.01]. Three placebo recipients and no policosanol recipents died during the study as a result of myocardial infarction (two patients) and sudden cardiac arrest (one). Policosanol was well tolerated, and no drug-related disturbances in safety indicators were found. Policosanol significantly decreased systolic blood pressure (BP) compared with baseline and placebo, which could be an additional advantage in this population at high coronary risk. CONCLUSIONS: Policosanol administered long term is effective in lowering LDL-C and TC as well as increasing HDL-C levels in older patients with hypertension and type II hypercholesterolaemia without a history of CHD or cerebrovascular disease. In addition, policosanol treatment also shows benefits in the occurrence of SAEs of vascular aetiology, on the general AE profile and the reduction of BP in treated patients compared with baseline.

Policosanol: a new treatment for cardiovascular disease?

Policosanol is a mixture of alcohols isolated and purified from sugar cane. Recently, Cuban researchers found 5-20 mg daily of policosanol to be effective at improving serum lipid profiles. Policosanol is believed to decrease total cholesterol (TC), low-density lipoprotein (LDL), and increase high-density lipoprotein (HDL) by inhibiting cholesterol synthesis and increasing LDL processing. Lipid profile improvements are seen in healthy volunteers, patients with type II hypercholesterolemia, type 2 diabetics with hypercholesterolemia, postmenopausal women with hypercholesterolemia, and patients with combined hypercholesterolemia and abnormal liver function tests. Additionally, policosanol has performed equal to or better than simvastatin, pravastatin, lovastatin, probucol, or acipimox with fewer side effects in patients with type II hypercholesterolemia. Policosanol also decreases several other risk factors of cardiovascular disease by decreasing LDL oxidation, platelet aggregation, endothelial damage, and smooth muscle cell proliferation. Furthermore, policosanol decreases progression and increases regression of cardiovascular disease assessed by thallium-labeled myocardial perfusion scintigraphy (TL-MPS) and Doppler-ultrasound, and decreases symptoms of cardiovascular disease assessed by the Specific Activity Scale. In post-marketing studies, only 0.31 percent of patients have had adverse events. Furthermore, in animal toxicity studies doses up to 1500 times normal human doses (on the basis of body weight) have shown no negative effects on carcinogenesis, reproduction, growth, and development. However, despite the positive research on policosanol on Cubans, policosanol produced in Cuba is not available in the United States, and only Cuban subjects have been studied. Further research is needed to determine if the same effects will be obtained in U.S. populations with non-Cuban produced policosanol.

Effects of policosanol 20 versus 40 mg/day in the treatment of patients with type II hypercholesterolemia: a 6-month double-blind study.

Policosanol is a well defined mixture of higher aliphatic primary alcohols isolated from sugar cane wax with cholesterol-lowering effects proven for a dose range from 5-20 mg/day in patients with type II hypercholesterolemia and dyslipidemia associated with noninsulin dependent diabetes mellitus. This randomized, double-blind study investigated the cholesterol-lowering efficacy and tolerability of policosanol 20 mg/day compared with 40 mg/day. Changes in low-density lipoprotein (LDL)-cholesterol levels were predefined as the primary efficacy endpoint. Patients with type II hypercholesterolemia were enrolled in the study and instructed to continue a step I cholesterol-lowering diet for 6 weeks and those eligible to be included (89) were randomly allocated to receive under double-blind conditions placebo (n = 30), policosanol 20 mg/day (n = 29) or 40 mg/day (n = 30). After 24 weeks, policosanol at 20 and 40 mg/day significantly (p < 0.00001) lowered LDL-cholesterol by 27.4% and 28.1%, total cholesterol (p < 0.00001) by 15.6% and 17.3%, and the LDL-cholesterol/high-density lipoprotein (HDL)-cholesterol ratio by 37.2% and 36.5%, respectively The ratio of total cholesterol/HDL-cholesterol was lowered by 27.1% and 27.5%, while HDL-cholesterol levels increased (p < 0.001) by 17.6% and 17.0%, respectively. Compared with baseline, policosanol 20 mg/day lowered triglycerides (p < 0.05) by 12.7%, while they were lowered (p < 0.01) by 15.6% at a dose of policosanol 40 mg/day All the above-mentioned significant differences were also different from placebo and no significant changes occurred in any lipid profile parameters in the placebo group. Based on the mean values of LDL-cholesterol levels at study completion, the mean percent reductions from baseline were 27.4% and 28.1% for the 20 and 40 mg/day groups, respectively. Thus, the effects of both policosanol doses on the main efficacy variable were practically identical. Consistent with the data obtained for LDL-cholesterol, both doses were similarly effective in changing all the other lipid profile parameters. No unexpected adverse effects were observed and there were no significant between-group differences regarding safety indicator values or reported adverse effects. In conclusion, although the tolerability profile remains excellent, according to the present results policosanol at a dose of 40 mg/day does not offer significant additional cholesterol-lowering efficacy over the 20 mg/day dose.

Final report on the safety assessment of Octyidodecyl Stearoyl Stearate.

Octyldodecyl Stearoyl Stearate functions as an occlusive skin-conditioning agent and as a nonaqueous viscosity-increasing agent in many cosmetic formulations. Current concentrations of use are between 0.7% and 23%, although historically higher concentrations were used. The chemical is formed by a high-temperature, acid-catalyzed esterification reaction of long-chain alcohols (primarily C-20) and a mixture of primarily C-18 fatty acids. Levels of stearic acid, octyldodecanol, and octylydocecyl hydroxystearate in the final product are 5% or less--no other residual compounds are reported. Only limited safety test data were available on Octyldodecyl Stearoyl Stearate, but previous safety assessments of long-chain alcohols and fatty acids found these precursors to be safe for use in cosmetic formulations. Octyldodecyl Stearoyl Stearate produced no adverse effects in acute exposures in rats. The chemical was mostly nonirritating to animal skin at concentrations ranging from 7.5% to 10%; one study did find moderate irritation in rabbit skin at a concentration of 7.5%. Clinical tests at a concentration of 10.4% confirmed the absence of significant irritation in humans. An ocular toxicity study in rabbits found no toxicity. No evidence of genotoxicity was found in either a mammalian test system or in the Ames test system, with or without metabolic activation. The available data on Octyldodecyl Stearoyl Stearate and the previously considered data on long-chain alcohols and fatty acids, however, did not provide a sufficient basis to make a determination of safety. Additional data needs include (1) chemical properties, including the octanol/water partition coefficient; and (2) if there is significant dermal absorption or if significant quantities of the ingredient may contact mucous membranes or be ingested, then reproductive and developmental toxicity data may be needed. Until such time as these data are received, the available data do not support the safety of Octyldodecyl Stearoyl Stearate as used in cosmetic formulations.

Pygeum africanum for the treatment of patients with benign prostatic hyperplasia: a systematic review and quantitative meta-analysis.

PURPOSE: To conduct a systematic review and quantitative meta-analysis of the therapeutic efficacy and tolerability of Pygeum africanum in men with symptomatic benign prostatic hyperplasia. METHODS: Studies were identified through the search of Medline (1966 to 2000), Embase, Phytodok, the Cochrane Library, bibliographies of identified trials and review articles, and contact with relevant authors and drug companies. Randomized trials were included if participants had symptomatic benign prostatic hyperplasia, the intervention was a preparation of P. africanum alone or in combination with other phytotherapeutic agents, a control group received placebo or other pharmacologic therapies for benign prostatic hyperplasia, and treatment duration was at least 30 days. Two investigators independently extracted key data on design features, subject characteristics, and therapy allocation. RESULTS: A total of 18 randomized controlled trials involving 1,562 men met the inclusion criteria and were analyzed. Many studies did not report results in a method that permitted meta-analysis. Only 1 of the studies reported a method of treatment allocation concealment, although 17 were double-blinded. The mean study duration was 64 days (range 30 to 122). Compared with placebo in 6 studies, P. africanum provided a moderately large improvement in the combined outcome of urologic symptoms and flow measures as assessed by an effect size defined by the difference of the mean change for each outcome divided by the pooled standard deviation for each outcome (-0.8 SD [95% confidence interval (CI): -1.4 to -0.3]). Summary estimates of individual outcomes were also improved by P. africanum. Men were more than twice as likely to report an improvement in overall symptoms (risk ratio = 2.1, 95% CI: 1.40 to 3.1). Nocturia was reduced by 19% and residual urine volume by 24%; peak urine flow was increased by 23%. Adverse effects due to P. africanum were mild and similar to placebo. The overall dropout rate was 12% and was similar for P. africanum (13%), placebo (11%), and other controls (8%; P = 0.4 versus placebo and P = 0.5 versus other controls). CONCLUSIONS: The literature on P. africanum for the treatment of benign prostatic hyperplasia is limited by the short duration of studies and the variability in study design, the use of phytotherapeutic preparations, and the types of reported outcomes. However, the evidence suggests that P. africanum modestly, but significantly, improves urologic symptoms and flow measures. Further research is needed using standardized preparations of P. africanum to determine its long-term effectiveness and ability to prevent complications associated with benign prostatic hyperplasia.