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Background: End-point based studies have demonstrated a direct relationship between coronary disease and elevated serum levels of low density lipoprotein cholesterol (LDL-C) and total cholesterol, as well as the benefits of lowering LDL-C with statins on clinical end-points. Policosanol is a mixture of very long chain fatty alcohols purified from sugar cane wax, with dislipidemia controlling effects, proved in numerous clinical assays in which patients with different conditions were included. The efficacy and tolerability of policosanol in the elderly have been also investigated in several clinical trials, being effective, safe and well tolerated. Objectives: To investigate the effects of policosanol treatment during three years on lipid profile with a proportional intensity to the initial dislipidemia severity in older hypercholesterolemic patients. Methods: The present analysis was obtained from the data of all patients treated with policosanol included in a previous prevention study. One thousand, ford hundred seventy old patients of both sexes, between 60 to 85 years old, with type II hypercholesterolemia, and ³ 1 non-lipid coronary risk factors, were randomized in two groups and treated with policosanol or placebo, during three years. Significant changes on lipid profile with a proportional intensity to the initial dislipidemia severity were considered primary efficacy variables. The analysis was done by Intention-to-treat method. Results: An analysis of the response intensity show that after treatment, reductions of LDL-C, total cholesterol and triglycerides were greater, and according to the initial hypercholesterolemia severity, so that, patients with severe hypercholesterolemia showed the better responses, followed by moderate and mild hypercholesterolemia. An opposite pattern, however, was observed for HDL-C serum concentration. Triglycerides did not respond in the same way. The frequency of vascular serious adverse events was lower in the policosanol group (15 events) compared with those on placebo group (49 events). There were 109 patients who experienced serious adverse events: 83 (11.3 %) in placebo and 26 (3.5 %) in policosanol group (p

Background Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of diseases ranging from steatosis to steatohepatitis and cirrhosis. Given the increasing incidence of NAFLD and the long-term consequences of this disease, it is important to identify the risk factors and therapeutic measures. Abexol is a mixture of beeswax alcohols with antioxidant, gastro-protective and anti-inflammatory effects. The aim was to conduct a pooled analysis of clinical trials data of the effects of Abexol treatment in patients with NAFLD. Methods The present analysis includes the data of all patients with NAFLD obtained from medium-term randomized, double-blinded, placebo controlled clinical studies with Abexol. One hundred patients with NAFLD received Abexol (100 mg/day) or placebo for 6 months. Significant changes in the ultrasound analysis of the liver were considered a primary efficacy variable. Secondary endpoints were decreased homeostasis model assessment (HOMA) index and insulin levels, and improved clinical symptoms. Statistical analysis of all data was according to the intention-to-treat method. Results Both groups were statistically homogeneous at baseline conditions. At 6 months of treatment, the number of Abexol-treated patients exhibiting a normal liver echo pattern on ultrasonography was greater than that of the placebo patients (P < 0.05). Abexol significantly reduced (P < 0.05) insulin levels and HOMA index. The proportion of Abexol patients showing symptom improvement was higher (P < 0.01) than that of the placebo group. Treatments were safe and well tolerated. Conclusions Treatment of Abexol during 6 months significantly ameliorates liver fat accumulation and insulin resistances, meanwhile improving clinical evolution in patients with NAFLD. The treatment was safe and well tolerated in these patients.

Reflux esophagitis, a common gastrointestinal disease, may be induced by duodeno gastroesophageal-reflux, and by duodeno-esophageal reflux (DER), the reflux of the biliary content only. D-002, a mixture of six higher primary alcohols purified from the beeswax, has exhibited gastric and esophageal protection experimentally. The aim of this work was to investigate the effects of D-002 on the esophageal histological changes in rats with DER-induced esophagitis. Rats were randomized into six groups: a negative control and five with DER: a positive control, three D-002- (50, 200 and 400mg/kg, respectively) and one omeprazole (20 mg/kg) group, treated for 14 days. Microscopic studies of esophagus were performed looking for reflux esophagitis indicators, such as basal cell hyperproliferation, papillae elongation, inflammatory cell infiltrates, epithelial erosions and ulcerations. The thickness of esophageal epithelium was measured and leukocytes were counted. Histological characteristics of esophagitis were evaluated. Negative controls had normal esophagus, while positive controls exhibited marked esophagitis. The values of the histological score, thickness of the esophageal epithelium and leukocyte infiltration in the positive control group were higher (p

Introduction: Stroke is one of the leading causes of mortality and disability. Clinical studies conducted in patients with a recent ischemic stroke and treated with policosanol (20 mg/day) + standard aspirin (AS) (125 mg/day) therapy have shown benefits versus placebo + AS to patients with recent ischemic stroke. The objective of the present paper is to a preliminary retrospective analysis of the policosanol treatment effects in the patients included in ischemic stroke recovery trials. Methods: This report analysed the records of all patients included in four ischemic stroke recovery studies. Patients with a modified Rankin Scale score (mRSs) 2 to 4 were randomized, within 30 days of onset, to policosanol+AS or placebo+AS, for 6 and 12 months. The primary outcome was mRSs reduction. Decreases on low-density lipoprotein-cholesterol (LDL-C), total cholesterol and increases on high-density lipoprotein-cholesterol (HDL-C) were secondary outcomes. Results: Two hundred and seventy one patients (mean age: 67 years) were included in the analysis. At the six months more policosanol+AS (117/136, 86 %) than placebo+AS patients (10/135, 7.3 %) achieved mRSs goals. In correspondence, at the 12 months of the study more policosanol+AS (50/59, 84.7 %) than placebo+AS patients (5/59, 8.5 %) achieved mRSs goals. Treatment with policosanol+AS significantly decreased mean mRSs from the first interim check-up. The treatment effect did not wear off, even improved, after 6 and 12 months therapy when the net decrease versus placebo+AS was 56 % and 70.8 %, respectively. In addition, policosanol+AS reduced significantly LDL-C (21.6 %) and total cholesterol (12.5 %), and increased HDL-C (6.3 %). Treatments were safe and well tolerated. Eight patients reported serious adverse events (6 placebo+AS, 2 policosanol+AS) and other 13 patients (8 placebo+AS, 5 policosanol+AS) reported moderate or mild adverse events. Conclusions: The preliminary retrospective analysis of the effects of policosanol+AS on ischemic stroke patients indicate that this treatment for 6 and 12 months proved to be more effective than the placebo+AS treatment in the functional recovery of these patients.&nbsp

Background: Benign prostatic hyperplasia (BPH), a common urological disease in aging men, frequently produces lower urinary tract symptoms (LUTS). Clinical studies have shown that terazosin relaxes the smooth muscle of the prostate and bladder, facilitates bladder emptying, improves LUTS, increases maximum urinary flow, and reduces the residual volume of urine. D-004, a lipid extract of the fruit of the Cuban royal palm ( Roystonea regia), presents a similar efficacy to Saw palmetto. Clinical studies have demonstrated its efficacy and safety in short- and medium-term trials in patients with BPH. The objective of this study was to compare the efficacy and tolerability of D-004 with terazosin for 6 months on LUTS in patients with BPH. Methods: The present phase III study had an open, randomized, comparative design, with two parallel groups who received D-004 (320 mg/day) or terazosin (5 mg/day) for 6 months. The study included men at least 50 years of age, with evidence of the LUTS of moderate intensity according to the International Symptoms of the Prostate (IPSS). The effects on the IPSS Scale was the primary efficacy variable. The effects on the size of the prostate and the residual volume were secondary variables. The subjective self-perception of symptom relief at trial completion was a collateral outcome. Analysis was done by intention-to-treat. Results: The study included 100 men with a diagnosis of BPH, confirmed by digital rectal examination and ultrasonography, and moderate LUTS (IPSS score >7, Conclusions: D-004 administered at a dose of 320 mg/day for 6 months showed comparable efficacy with terazosin (5 mg/day) in reducing the LUTS (IPSS score), producing a significant decrease in prostate volume and postvoid residual volume. Both treatments were safe, with better tolerability for D-004 as compared with terazosin.

Context • Nonsteroidal, anti-inflammatory drugs effectively relieve osteoarthritis (OA) symptoms but also induce adverse effects (AEs) that limit their long-term use, which drives a search for safer treatments. D-002, a mixture of beeswax alcohols, and D-003, a mixture of sugarcane wax acids, have been effective in experimental and clinical studies for patients with OA. Objective • The study intended to investigate the effects on OA symptoms of a combined therapy using D-002 and D-003 (D-002/D-003), which were administered for 6 wk. Design • The study was a randomized, double-blind, placebo-controlled trial. Setting • The study was conducted at the Surgical Medical Research Center in Havana, Cuba. Participants • Participants were patients with mild-to-moderate OA. Intervention • Participants were randomly assigned to 1 of 4 groups-(1) a control group, which received a placebo; (2) the D-002 group (intervention group), which received 50 mg/d of D-002; (3) the D-003 group (intervention group), which received 10 mg/d of D-003; or (4) the D-002/D-003 group (intervention group), which received a combined therapy of 50 mg/d of D-002 plus 10 mg/d of D-003. The control group received tablets that were indistinguishable in appearance from the D-002 and D-003 tablets and had a similar composition, except that the active ingredients were replaced by lactose. The groups took the medications once per day for 6 wk. Outcome Measures • Symptoms were assessed using the Western Ontario and McMaster Individual Osteoarthritis Index (WOMAC) and a visual analogue scale (VAS). The primary outcome was the reduction in the total WOMAC score. The subscale scores on the WOMAC for pain, stiffness, and physical function, the VAS scores, and the use of rescue medications were secondary outcomes. Results • Of the 120 enrolled participants, 116 completed the study. The treatments with D-002, D-003, and D-002/D-003 reduced the mean total WOMAC scores significantly from baseline to postintervention, by 75.1%, 72.8%, and 91.2%, respectively. Compared with the placebo, the treatments decreased the mean WOMAC scores for pain, joint stiffness, and physical function significantly. The VAS scores significantly decreased, showing a 71.4%, a 66.9%, and an 84.7% reduction for the D-002, D-003, and D-002/D-003 groups, respectively. All the reductions were significant from the first week and were enhanced during the trial. The D-002/D-003 treatment was more effective in improving all of the scores than either monotherapy. With respect to rescue medications, 3/30, 2/30, and 2/30 used the medications in the D-002, D-003, and D-002/D-003 groups, respectively, vs 17/30 in the control group. The treatments were well tolerated. Conclusions • Administered for 6 wk, 50 mg/d of D-002 and 10 mg/d of D-003 ameliorated OA symptoms, but the combined therapy, D-002/D-003, was more effective than either monotherapy. All treatments were well tolerated.

Introduction: the gastric mucosa is susceptible to the effects of aggressive factors, which are counterbalanced by mucosal defensive factors. Acid peptic diseases result from the imbalance between these aggressive and defensive factors. Aspirin-induced ulcer is a model of NSAIDs-induced damage in which neutrophil infiltration plays a key role. Objective: this paper investigates the protective effect of D-002 against aspirin-induced ulcers and associated neutrophil infiltration in the gastric mucosa. Methods: rats were randomized into six groups of 8 rats each. A negative vehicle control, and five aspirin (300 mg/kg)-treated groups: a positive control, orally treated with the vehicle, three with D-002 (25, 50 and 100 mg/kg, respectively) and other with 10 mg/kg Omeprazole. Five hours after induced damage the rats were sacrificed. The stomachs were removed and opened, and lesions examined macroscopically and microscopically. Ulcer indexes and neutrophil infiltration per ulcer areas were measured. Results: all positive, none negative, controls exhibited aspirin-induced ulcers. Oral treatment with D-002 (25-100 mg/kg) dose-dependently and significantly reduced aspirin-induced gastric lesions (37 to 75 %), the mean number of microscopic ulcers (40 to 72 %) and neutrophil infiltration (41.7 to 83.1 %) in the rat gastric mucosa. Conclusion: Oral treatment with D-002 (25-100 mg/kg) effectively protects against aspirin-induced ulcers and decreases the neutrophil infiltration in the gastric mucosa induced by aspirin ulceration.Introducción: la integridad de la mucosa gástrica depende del balance entre los factores agresivos y defensivos. La úlcera inducida por aspirina es un modelo de daño por antiinflamatorios no esteroidales en el cual el infiltrado de neutrófilos desempeña una función fundamental. Objetivo: evaluar el efecto protector del D-002 sobre la úlcera inducida por aspirina asociada al infiltrado de neutrófilos en la mucosa gástrica. Métodos: las ratas fueron aleatorizadas en seis grupos de ocho animales cada uno. Un control negativo con vehículo y cinco grupos tratados con aspirina (300 mg/kg): un control positivo, tratado por vía oral con vehículo, tres grupos con D-002 (25, 50 and 100 mg/kg respectivamente) y otro con omeprazol 10 mg/kg. Cinco horas después de inducido el daño las ratas fueron sacrificadas y se extrajeron sus estómagos para su análisis morfológico. Se determinó el índice de úlcera, el número de úlceras microscópicas y el número de neutrófilos por área ulcerada. Resultados: todos los controles positivos y ninguno negativo mostraron lesiones en la mucosa. El tratamiento por vía oral con D-002 (25-100 mg/kg) redujo de modo significativo y dependiente de la dosis el índice de úlceras gástricas (37-75 %), el promedio de úlceras microscópicas (40- 72 %) y la infiltración de neutrófilos (41,7-83,1 %) en la mucosa de las ratas. Conclusiones: el tratamiento por vía oral con D-002 (25-100 mg/kg) protege la mucosa gástrica de las ratas del daño inducido por aspirina, lo que disminuye el índice de úlcera y el infiltrado de neutrófilos.

Estudios experimentales y clínicos han demostrado que el tratamiento oral con Abexol® (previamente D-002), mezcla de seis alcoholes alifáticos superiores purificada de la cera de abejas, produce efectos gastroprotectores y antioxidantes. Bajos niveles plasmáticos de vitamina C han sido reportados en sujetos que sufren de gastritis crónica con respecto a voluntarios sanos. El presente estudio aleatorizado, a doble ciegas, controlado con placebo tuvo como objetivo investigar los efectos del Abexol® en sujetos con síntomas habituales de gastritis, así como investigar también sus efectos sobre los niveles plasmáticos de vitamina C. En la consulta 2 (inclusión) 45 hombres y mujeres (edad media: 67 años) elegibles recibieron aleatoriamente Abexol® (50 mg) o placebo, dos tabletas/d durante seis semanas. Después de tres semanas de tratamiento la dosis fue titulada a tres tabletas diarias en los casos que no mejoraron los síntomas. Los síntomas fueron evaluados a través de la Escala de Gradación de Síntomas Gastrointestinales [Gastrointestinal Symptom Rating Scale (GSRS)] y la percepción de salud a través de un sistema de tres puntajes. La variable primaria de eficacia fue obtener una reducción significativa del puntaje GSRS total comparado con el placebo, mientras que la reducción de los distintos dominios de la encuesta y la mejoría de la percepción de salud fueron variables secundarias y el aumento de los niveles plasmáticos de vitamina C fue una variable colateral. En el grupo placebo no se produjeron cambios significativos. Tras seis semanas de tratamiento, el Abexol® redujo significativamente el puntaje total GSRS con respecto al nivel basal y al grupo placebo (80,2 % diferencia vs. placebo), reducción que fue significativa desde el control intermedio (tres semanas de tratamiento). Al final del estudio, la frecuencia de sujetos tratados con Abexol® que reportaron una mejoría en su percepción de salud (21/21, 100 %) fue significativamente mayor que en el grupo placebo (0/24, 0 %). Ningún sujeto tratado con Abexol® (0/21, 0 %), en comparación con 24/24 (100 %) y 23/24 (95,8 %) del grupo placebo, requirió titulación de la dosis ni consumo de antiácidos, respectivamente (p < 0.0001 para ambas comparaciones). El Abexol® no afectó los indicadores físicos o de laboratorio, con excepción de un aumento significativo de los niveles de vitamina C, con relación al grupo placebo. El Abexol® fue bien tolerado, ningún sujeto abandonó el ensayo y solo tres del grupo placebo reportaron EA durante el estudio. En conclusión, este estudio demostró que el Abexol® (100 mg/d) administrado durante seis semanas mejoró los síntomas en sujetos con padecimientos gastrointestinales habituales, ya que redujo el puntaje total de la escala GSRS, mejoró la percepción de salud y redujo el consumo de antiácidos con respecto al placebo. Además, el Abexol® también produjo un aumento significativo de los niveles plasmáticos de vitamina C.

Increased platelet aggregation contributes to vascular risk. D-003, a mixture of high molecular weight sugarcane wax acids, has shown antiplatelet effects in experimental models and healthy volunteers. This randomised, double-blinded, placebo-controlled study investigated the effects of titrated doses of D-003 (5-20 mg/d) on platelet aggregation in hypercholesterolemic patients. After a 4-week baseline phase, 56 patients were randomised to D-003 5 mg/d or placebo. The doses were doubled every 15 days if arachidonic acid (AA)-induced platelet aggregation was not inhibited at least by 15%. AA (0.75 and 1.5 mmol/L) and collagen (1 microg/mL)-induced platelet aggregation, laboratory and physical safety indicators were assessed at baseline and every 15 days thereafter, when adverse events (AE) were also reported. No significant change of platelet aggregation was found in the placebo group. After 15, 30 and 45 on therapy, D-003 reduced platelet aggregation induced with both AA 0.75 mmol/L (18.1%, 19.0% and 30.3%, respectively) and AA 1.5 mmol/L (17.0%, 16.3% and 22.5%, respectively), and also collagen-induced platelet aggregation (26.6%, 20.8% and 29.4%) (p < 0.01 at days 15 and 30 versus placebo, p < 0.0001 at study completion). The mean inhibition of platelet aggregation with D-003 at day 15, at which all patients had received the lowest dose, was over 15%. Nineteen out of 28 D-003 randomised patients (67.9%) required dose titration to achieve such goal. At trial completion, the mean estimated dose was 11.6 mg/d. D-003 lowered low-density lipoprotein (22.0 %), total cholesterol (14.7%) and raised high-density lipoprotein-cholesterol (10.9%) (p < 0.0001 versus placebo). Six patients (2 placebo, 4 D-003) withdrew from the trial, none due to AE. D-003 did not modify the safety indicators with respect to placebo. Four patients (2 placebo, 2 D-003-treated) reported AE: pruritus and increased blood pressure (2 placebo) and rash and polyphagla (2 D-003). In conclusion, D-003 (5-20 mg/d) given as doses titrated every 15 days (5-20 mg/d) inhibited AA- and collagen-induced platelet aggregation in hypercholesterolemic patients and was well tolerated.

La artritis reumatoide, poliartritis inflamatoria más común del adulto, que afecta cerca del 1 % de la población mundial, predomina más en mujeres que en hombres, se presenta con mayor frecuencia entre los 30 y 50 años de edad, y conlleva a una gran discapacidad del paciente. Se caracteriza por una sinovitis erosiva simétrica, en la cual el tejido conjuntivo prolifera (pannus), invade y erosiona el cartílago y el hueso de las articulaciones y, a veces, por una afectación multisistémica. En la mayoría de los pacientes la enfermedad sigue una evolución crónica fluctuante que, si no se trata, ocasiona una progresiva destrucción, deformidad e incapacidad de las articulaciones afectadas. La enfermedad evoluciona con cifras elevadas de factor reumatoideo y /o anticuerpos anti-citrulinas. Constituyen aspectos esenciales del tratamiento óptimo de la enfermedad: el diagnóstico diferencial precoz; el tratamiento inicial con antiinflamatorios no esteroideos; el uso de fármacos modificadores del curso de la enfermedad; el uso posible de glucocorticoides, a dosis bajas por vía oral, o en inyección intraarticular; la evaluación periódica de la adecuación del tratamiento (monitorización radiológica, sérica y funcional de la progresión de la enfermedad y de la toxicidad asociada al tratamiento), y las intervenciones de educación y rehabilitación del paciente. Para evaluar nuevas terapias para el tratamiento de la artritis reumatoide, los modelos más usados son: el de la artritis inducida por adyuvante en ratas y artritis inducida por colágeno en ratas y ratones. Otros modelos recientes muestran datos limitados. La eficacia de varios compuestos revela que su efecto terapéutico es más predictivo de eficacia clínica en humano cuando se estudian los modelos de artritis por adyuvante y por colágeno, que los datos de un solo modelo.The rheumatoid arthritis, is the inflammatory polyarthritis commonest in adults affecting about the 1 % of world population, more predominant in women than men and more frequent in those aged 30 and 50 and entails a high level of inability of patient. It is characterized by a symmetrical erosive synovitis with proliferation of conjunctival tissue (pannus), invading and eroding the cartilage and joint bones, and sometimes, by a multisystem affection. In most patients the disease follows a fluctuating chronic course, which it is not treated, provoke a progressive destruction, deformity and inability of involved joints. The disease evolves with high figures of rheumatoid factor and/or anti- citrulline antibodies. These are essential features of an optimal treatment of this entity include: early differential diagnosis, initial treatment with non-steroidal anti-inflammatory drugs (NSAIDs), the use of disease course modifying drugs, the potential use of oral low-dose glucocorticoid agents or intra-articular injections, and a periodical assessment of treatment fitting (radiological serum and functional monitoring of disease progression and of treatment-associated toxicity) and the educational and rehabilitations interventions of patient. To assess the new therapies for treatment of rheumatoid arthritis, the more uses models are: that of the arthritis induced by adjuvant drugs in rats and the arthritis induced by collagen in rats and mice. Other new models show limited data. Effectiveness of several compounds reveals that its therapeutic effect is more predictive of the clinical effect in the human being when models of arthritis due to adjuvant drugs and collagen than data from an only one model.

La osteoartritis (OA) es un síndrome anatomoclínico caracterizado por dolor mecánico y rigidez asociada que conduce a una pérdida o disminución progresiva de la función articular provocando discapacidad física y afectación de la calidad de vida. Su frecuencia aumenta con la edad y al aumentar la expectativa de vida de la población se prevé un aumento de su incidencia y del consumo de anti-inflamatorios no esteroidales (AINEs) para su tratamiento. Muchos factores contribuyen directa o indirectamente a la degeneración de la articulación provocando un aumento del catabolismo de la matriz extracelular, alteración del hueso subcondral y posterior reacción inflamatoria, responsable de la destrucción ósea y del cartílago. Este no se regenera y puede desaparecer, si no en su totalidad, sí en forma importante y extensa. El hueso subcondral responde dando lugar a la producción de osteofitos que se evidencian al exterior, capaces de irritar estructuras vecinas. La OA se considera un estado final de degeneración cuyo inicio puede estar condicionado por numerosos factores. La primera terapia para manejar la OA son los cambios en el estilo de vida. Las medidas ortopédicas son medidas adicionales. En otros casos, el tratamiento anti-inflamatorio y analgésico sintomático es esencial y muchas veces, es la única terapia farmacológica que se prescribe. En casos refractarios o severos, se incluye el tratamiento quirúrgico. Los AINEs, medicamentos inhibidores de la enzima ciclo-oxigenasa, son los más utilizados para el alivio del dolor y la inflamación, si bien no evitan el daño del cartílago. El paracetamol es el tratamiento de elección para el alivio del dolor. Por otro lado, se plantea que el consumo de grandes cantidades de condroitina y glucosamina puede ayudar en el reemplazo del material que se pierde en el proceso catabólico, si bien, los resultados de estos estudios son variables y contradictorios, lo cual sugiere que el beneficio de esta terapia puede tener sus limitaciones. Algunos fitofármacos antioxidantes limitan la degradación de cartílago humano in vitro y mantienen la arquitectura de la articulación en animales de experimentación, pero estas evidencias son aún más limitadas.

La osteonecrosis (ON), enfermedad que afecta fundamentalmente a hombres jóvenes, se produce por una reducción del flujo sanguíneo del hueso, en que la oclusión vascular y la isquemia del tejido óseo conduce a la necrosis de las células de la médula ósea y de los osteocitos. La ON es un proceso progresivo que puede conducir a la fragmentación y hundimiento de la estructura ósea. La ON es más frecuente en los extremos de los huesos largos (zona epifisaria), principalmente en la cabeza femoral y su etiología puede ser traumática y no traumática. Entre las causas traumáticas se destacan las fracturas y luxaciones de cadera, y entre las no traumáticas, el consumo de corticoides, alcohol y diversas hemoglobinopatías. Para diagnosticar la ON son importantes el criterio clínico y el imagenológico. Su presencia puede variar desde una forma asintomática hasta otra de gran limitación y dolor. Actualmente no existe ninguna droga aprobada para el tratamiento de la ON y su tratamiento farmacológico se encamina al control de la causa subyacente. El tratamiento farmacológico de la ON de cadera incluye agentes hipolipemiantes, anticoagulantes, análogos de la prostaciclina y los bisfosfonatos. Esta reseña incluye la fisiopatología de la enfermedad, su diagnóstico, principales estrategias de tratamiento y varios modelos experimentales que sustentan el estudio de nuevas alternativas para conjunta o indistintamente prevenir o tratar la ON.

Aunque el colesterol de las lipoproteinas de baja densidad (LDL-C) continua siendo el principal objetivo en el manejo de la dislipidemia, la prevencion de la enfermedad coronaria incluye ademas, la modificacion de otros indicadores tales como la disminucion del colesterol no unido a las lipoproteinas de alta densidad y los trigliceridos sericos (TG), asi como el incremento de las HDL-C. Se reconoce que los aceites de pescado ricos en acidos grasos omega 3 (AG-OMEGA3), los cuales reducen los TG sericos y el colesterol no unido a HDL, pueden disminuir el riesgo de los eventos cardiovasculares a traves de estos efectos y a traves de otros efectos no relacionados con los lipidos (reduccion de la frecuencia cardiaca, efectos antiarritmicos, discreta reduccion de la hipertension arterial y de la agregacion plaquetaria). El efecto de AG-OMEGA3 sobre las HDL y el colesterol total (CT) puede ser variable y en ocasiones tiende a incrementar las concentraciones de las LDL-C en el suero. El policosanol ha demostrado que reduce las LDL-C y CT mientras que incrementa las HDL-C en individuos normocolesterolemicos e hiperlipidemicos, con un efecto marginal e inconsistente sobre los trigliceridos. El policosanol administrado concomitantemente con OMEGA-3-FA durante un corto periodo demostro que reduce la LDL-C y el CT mientras que aumenta las HDL-C mas que el placebo AG-OMEGA3 + placebo, sin afectar el efecto reductor de los TG de los AG-OMEGA3. No se ha reportado, sin embargo, la persistencia de tales efectos. Este estudio investiga si los beneficios de la administracion de AG-OMEGA3 + policosanol (AG-OMEGA3-poli) persisten despues de una terapia mas prolongada (24 semanas). Despues de un periodo de dieta solamente, 60 pacientes se distribuyeron, aleatoriamente y a doble ciegas, en dos grupos. Uno de los grupos fue tratado con AG-OMEGA3 (1 g/d) + placebo (AG-OMEGA3-pla) mientras que el otro recibio AG-OMEGA3 (1 g/d) + policosanol 10 mg/d . Las variables de laboratorio fueron evaluadas al inicio y cada 12 semanas mientas que los indicadores del examen fisico, la tolerabilidad y las experiencias adversas fueron controlados cada seis semanas. Despues de 12 semanas de tratamiento con AG-OMEGA3-pla, los TG se redujeron significativamente (p > 0,000 1) con respecto a los valores iniciales (15,8 %) mientras que a las 24 semanas disminuyeron (p < 0,000 1), (22,8 %) y se observo un incremento de HDL-C (p < 0,05), (1,4 %), sin cambios en otras variables lipidicas. A las semanas 12 y 24, AG-OMEGA3-poli redujo (p < 0,000 1) LDL-C (23,4 y 26,0 %, respectivamente), TC (15,4 y 16,6 %) y aumento HDL-C (9,0 y 14,5 %) comparado con el valor inicial y con AG-OMEGA3 + placebo, mientras que disminuyo (p < 0,000 1) los TG (16,7 y 23,3 %, respectivamente) contra los valores iniciales, pero no contra AG-OMEGA3 + placebo. No se produjo ninguna salida del estudio. Siete pacientes reportaron EA ligeras, sin diferencias entre los grupos. En conclusion, la terapia combinada AG-OMEGA3-poli durante 24 semanas demostro beneficios complementarios persistentes sobre el perfil de los lipidos sericos comparado con AG-OMEGA3 + placebo y fue bien tolerado por los pacientes hipercolesterolemicos.

El D-003 es una mezcla de ácidos grasos alifáticos superiores purificada de la cera de caña de azúcar (Saccharum officinarum L.) con efecto hipolipemiante y antiagregante plaquetario, que disminuye las concentraciones plasmáticas de tromboxano B2 y aumenta las de prostaciclina, lo que indirectamente sugiere que el D-003 ejerce un efecto beneficioso sobre el endotelio vascular. Teniendo en cuenta que el número de células endoteliales circulantes en plasma (endotelemia) refleja indirectamente el daño endotelial, el objetivo de este estudio fue investigar el efecto del D-003 (5 a 200 mg/kg) sobre la endotelemia en ratas a las que se les indujo daño endotelial con citrato de sodio. Los animales se distribuyeron aleatoriamente en seis grupos, un control negativo, tratado solo con el vehículo y cinco grupos inyectados con citrato de sodio, uno tratado con el vehículo (control positivo) y cuatro con D-003 (5, 25, 100 y 200 mg/kg, respectivamente). Los tratamientos (vehículo o D-003) se les administraran dosis únicas orales mediante entubación gástrica. La inyección de citrato de sodio incrementó significativamente el conteo de células endoteliales circulantes en plasma respecto al control negativo, mientras que el tratamiento con D-003 (5, 25, 100 y 200 mg/kg) disminuyó significativamente (p < 0,05) y de manera dosis dependiente estos valores en un 23,6; 35,4, 53,3 y 57,1 %, respectivamente. Estos resultados aportan nuevas evidencias de la acción protectora del D-003 sobre el endotelio vascular.

El ictus es una de las tres principales causas de discapacidad y mortalidad a nivel mundial. Tras la aparición de un ataque transitorio de isquemia (ATI) o ictus se incrementa notablemente el riesgo de un ictus recurrente. La terapia antiplaquetaria, fundamentalmente la aspirina, representa la terapia de primera línea en la prevención de los ATI recurrentes y/o ictus y los agentes antihipertensivos e hipolipemiantes desempeñan también un importante papel en esta estrategia. El policosanol, droga con acción hipolipemiante y efectos antiplaquetarios concomitantes, ha demostrado efectos neuroprotectores en modelos experimentales. Un estudio previo reveló que la adición del policosanol (20 mg/d) a la aspirina durante la fase aguda del ictus y posterior a ella mejoró la recuperación neurológica y los eventos recurrentes. Este estudio mostró los beneficios del policosanol (20 mg/d) administrados desde el alta hospitalaria hasta los 60 meses después en 55 pacientes de ambos sexos con ictus quienes habían sufrido un ATI previo. En cada consulta, se les realizó examen físico y neurológico aplicándose la Escala Canadiense modificada, se registraron las experiencias adversas y se realizaron los exámenes de laboratorio correspondientes. Todos los nuevos eventos fueron registrados. En adición al ATI previo, los factores de riesgo más frecuentes presentes en esta población fueron: hipertensión (98,2 %), hipercolesterolemia (81,8 %), tabaquismo (32,7 %) y enfermedad coronaria (29,1 %). Todos los pacientes completaron el estudio. El puntaje de la Escala se incrementó significativamente y progresivamente durante el primer año y esta mejoría persistió durante todo el estudio. Sólo cinco pacientes (9,1 %) sufrieron un nuevo evento: un nuevo ictus y cuatro nuevos ATI. Después de tres meses, las concentraciones de colesterol se redujeron significativamente (21,3 %) comparado con el nivel basal, efecto que se incrementó durante la terapia a largo plazo. La mejoría del puntaje de la Escala se correlacionó con la reducción del colesterol total (r = 0,987). El tratamiento no produjo cambios en los indicadores de seguridad investigados. Se concluye que el tratamiento con policosanol (20 mg/d) + aspirina (125 mg/d) después del alta hospitalaria produce resultados favorables en la recuperación neurológica, la recurrencia de eventos y el control del colesterol en pacientes con ictus y ATI previo, pero estos beneficios deben ser confirmados en estudios aleatorizados, a doble ciegas y controlados.

La reducción de las concentraciones séricas del colesterol transportado por las lipoproteínas de baja densidad (LDL-C) y del colesterol total (CT) ha demostrado reducir la morbilidad y mortalidad coronaria, incluso en sujetos con concentraciones normales o limítrofes de colesterol. Los alcoholes de alto peso molecular de la cera de caña de azúcar (ACCA) han demostrado reducir las concentraciones séricas de LDL-C y CT y aumentar las del colesterol transportado por las lipoproteínas de alta densidad (HDL-C), sin cambios importantes de los triglicéridos (TG), en sujetos normocolesterolémicos e hipercolesterolémicos. Sin embargo, los datos que sustentan los efectos de la dosis de 10 mg/d en individuos con concentraciones séricas de CT limítrofes o normales son relativamente escasos. El objetivo de este estudio aleatorizado, a doble ciegas y controlado con placebo consistió en confirmar la eficacia y seguridad de los ACCA (10 mg/d) en sujetos con concentraciones séricas de CT ¿ 5,9 mmol/L. Cincuenta y cinco hombres y mujeres (edad promedio: 63 años) fueron aleatorizados para recibir tabletas de placebo ó ACCA durante 12 semanas. El tratamiento redujo significativamente las concentraciones de LDL-C (22,1 %, p < 0 000 01), CT (11,7 %, p < 0,000 01) y aumentó las de HDL-C (9,6 %, p < 0,05) con respecto a las iniciales y al grupo placebo. Los indicadores de seguridad no se afectaron. Sólo un sujeto (placebo) abandonó prematuramente el ensayo, pero no a causa de EA, y dos sujetos (un tratado, un placebo) refirieron alguna EA (artralgia) durante el estudio. Este estudio confirma que los ACCA (10 mg/d) administrados durante 12 semanas fueron efectivos en reducir las LDL-C, el CT, el cociente LDL-C /HDL-C y en aumentar las HDL-C, siendo seguros y bien tolerados en sujetos con concentraciones séricas de CT normales o limítrofes.

Los alcoholes de la cera de abejas (ACA) (Abexol®) (anteriormente D-002, mezcla de seisalcoholes alifáticos purificada de la cera de abejas), han demostrado efectos gastroprotectores en estudios experimentales y clínicos. Estudios experimentales demostraron que los ACA reducen el daño gástrico mediante un mecanismo citoprotector multifactorial que involucra, entre otros, efectos antioxidantes sobre la mucosa gástrica y el aumento de la cantidad de mucus gástrico y de su contenido de proteínas totales, glicoproteínas neutrales y macromoleculas sulfatadas, relevantes factores defensivos de la mucosa gástrica. Estudios clínicos previos han demostrado que el Abexol® (ACA) es efectivo en reducir síntomas gastrointestinales comúnmente presente en la población general, en individuos tratados con antiinflamatorios no esteroidales (AINEs) y en pacientes con úlceras duodenales, pero ninguno de ellos había utilizado una escala de síntomas validada internacionalmente. Este estudio aleatorizado, a doble ciegas y controlado con placebo investigó los efectos del Abexol® sobre los síntomas gastrointestinales de sujetos de edad media y avanzada de ambos sexos, sanos por demás, utilizando la Escala Graduada de Síntomas Gastrointestinales (EGSG). Sesenta individuos fueron aleatoriamente distribuidos para recibir tabletas de Abexol® (ACA - 50 mg) o placebo dos veces al día durante 8 semanas. Al culminar la semana 4 de tratamiento, la dosis se aumentó a tres tabletas/d en aquellos sujetos que no percibieron mejoría de los síntomas. Las características basales estuvieron bien balanceadas en ambos grupos. Tras 8 semanas de tratamiento, el Abexol® redujo significativamente (p < 0,000 1) el puntaje total de la escala EGSG respecto a los valores basales y al placebo (40,8 % versus placebo), reducción que resultó significativa desde la segunda semana de tratamiento. La frecuencia de casos que consumieron tres tabletas por día fue menor en el grupo Abexol® (4/30, 13,3 %) (p < 0,01) que en el placebo (16/30, 53,3 %). Comparado con el placebo, el Abexol® redujo significativamente los síntomas siguientes: acidez/pirosis, regurgitación, distensión abdominal, sensación de vaciado estomacal y flatulencia. El Abexol® no afectó ningún indicador físico o sanguíneo. Hubo siete bajas (cinco placebo, dos Abexol®), pero solo una (placebo) se debió a una experiencia adversa (aumento transitorio de presión arterial). En conclusión, el Abexol® (100 a 150 mg/d) administrado durante 8 semanas mejoró el puntaje total de la escala EGSC (la cual refleja el total de síntomas gastrointestinales) y específicamente, algunos síntomas característicos de trastornos ácido pépticos en sujetos de edad media y avanzada. El Abexol® resultó seguro y bien tolerado. Estos resultados son consistentes con los preliminares de otros estudios clínicos y sustentan la utilidad del Abexol® en sujetos de edad media y avanzada que experimentan síntomas gastrointestinales.

La hiperplasia prostática benigna (HPB), muy frecuente en hombres de > 50 años, es el alargamiento benigno de la próstata que desencadena síntomas del tracto bajo urinario. El D-004, extracto lipídico del fruto de la palma real (Roystonea regia), ha mostrado inhibir la 5 a-reductasa prostática, prevenir la hiperplasia prostática inducida con testosterona en roedores y bloquear las respuestas mediadas por los receptores a1-adrenérgicos. El D-004, sin embargo, no muestra toxicidad asociada, por lo que presenta un perfil promisorio para el manejo de la HPB. El presente estudio Fase I, aleatorizado, a doble ciegas y controlado con placebo investigó la tolerabilidad de dosis únicas y repetidas de D-004, administrado por vía oral (320 a 960 mg/d) y la reversibilidad de sus posible efectos. El estudio comprendió dos etapas. La I investigó los efectos de dosis únicas orales (320 a 960 mg) y su reversibilidad, evaluada a través de 14 d, y la II, que investigó los efectos de dosis repetidas (320 a 960 mg/d) durante 21 d, con controles intermedios cada siete días, seguidos de un período de suspensión de tratamiento (lavado) de 14 d. Cuarenta hombres sanos, elegibles según criterios de selección, se distribuyeron aleatoriamente en cuatro grupos: un placebo, tres tratados con D-004 (320, 640 y 960 mg). Las características basales de todos los grupos fueron similares. Durante el estudio no hubo bajas y el tratamiento no produjo, en ninguna etapa, cambios diferentes a los del grupo placebo, incluida su actividad sexual. Además, todas las variables estuvieron dentro de rangos normales. Las experiencias adversas (EA) referidas, todas gastrointestinales, fueron leves. En conclusión, el D-004, como dosis únicas (320 a 960 mg) o repetidas por 21 d, fue bien tolerado por los sujetos del estudio, sin producir EA características de esta clase terapéutica, como hipotensión postural o cambios en las concentraciones séricas de antígeno prostático, testosterona o estradiol.

El D-003 es una mezcla de ácidos alifáticos superiores purificada de la cera de caña, cuyo componente mayoritario es el ácido octacosanoico, metabolito activo del policosanol. Por su analogía estructural y metabólica ambas sustancias presentan efectos farmacológicos similares, como inhibir la síntesis de colesterol regulando la actividad de la hidroximetilglutaril-CoA reductasa, enzima clave de esta ruta, causando efectos hipocolesterolemizantes y antiosteoporóticos, e inhibiendo la peroxidación lipídica, lo que contribuye a sus efectos antiosteoporóticos. Sin embargo, el D-003 ha sido más efectivo que el policosanol como hipolipemiante y antioxidante, lo que sugiere un mayor potencial antiosteoporótico, si bien ningún estudio previo ha comparado sus efectos en modelos de osteoporosis (OP). Este estudio tuvo como objetivo comparar los efectos del D-003 y el policosanol en ratas ovariectomizadas, el modelo que mejor reproduce la OP característica de mujeres post-menopáusicas. Ratas SD hembras se ovariectomizaron y se distribuyeron en cuatro grupos: un control falso-operado, un control positivo y dos tratados con D-003 o policosanol, ambos a 50 mg/kg, respectivamente. Tras tres meses de tratamiento las ratas se sacrificaron y se extrajo su fémur derecho y su quinta vértebra lumbar. Las secciones de hueso se descalcificaron y procesaron para evaluar los efectos sobre variables morfométricas e indicadores de resorción-formación. Ambos tratamientos previnieron la pérdida ósea y el aumento de la resorción ósea inducidas por la ovariectomía, ya que previnieron la disminución en el número y espesor de las trabéculas, y el aumento del espacio inter-trabecular y el número y perímetro de los osteoclastos respecto al control positivo, sin modificar la superficie de osteoblastos, indicador de formación ósea. Los efectos del D-003 sobre todas las variables fueron superiores a los del policosanol, confirmando la hipótesis del estudio.

Las mujeres postmenopáusicas presentan concentraciones mayores de colesterol total (CT) y del transportado por lipoproteínas de baja densidad (LDL-C) y menores del transportado por lipoproteínas de alta densidad (HDL-C) que las premenopáusicas y controlar su dislipidemia implica reducir las concentraciones de las LDL-C. El policosanol (5 a 20 mg/d) es un hipocolesterolemizante efectivo y la atorvastatina (10 a 80 mg/d) una de las estatinas más efectivas. Este estudio, aleatorizado y a simple-ciegas, comparó la eficacia y tolerabilidad del policosanol y la atorvastatina en mujeres postmenopáusicas con hipercolesterolemia. Tras un período basal de dieta, 60 mujeres recibieron policosanol o atorvastatina 10-mg/d, durante 8 semanas. El policosanol y la atorvastatina redujeron significativamente (p < 0 000 01) las concentraciones de LDL-C (32,8 y 39,7 %, respectivamente), CT (23,6 y 29,1 %) y (p < 0,001) TG (11,3 y 17,6 %), y aumentaron (p < 0,000 1 y p < 0,001) las de HDL-C (11,3 % y 9,9 %, respectivamente). La atorvastatina fue más efectiva en reducir (p < 0,001) LDL-C, CT y ( p < 0,05) TG. Ambos tratamientos fueron bien tolerados. La atorvastatina aumentó significativamente (p < 0,01) y el policosanol redujo (p < 0,05) las transaminasas y la creatinfosfoquinasa. Tres pacientes tratados con atorvastatina, causaron baja por experiencias adversas. Con atorvastatina (cinco pacientes) estas fueron más frecuentes que con policosanol (un paciente). El tratado con policosanol refirió dolor de cabeza, los de atorvastatina refirieron erupción (3), taquicardia (1), náuseas (1), vómitos (1), dolor abdominal (1), calambres (1), disnea (1) y sudoración (1). En conclusión, ambos tratamientos, administrados a 10 mg/d por 8 semanas a mujeres postmenopáusicas hipercolesterolémicas, modificaron favorablemente el perfil lipídico, la atorvastatina fue más efectiva en reducir LDL-C, CT y TG, y el policosanol mejor tolerado.

El policosanol es un medicamento hipocolesterolemizante bien tolerado en diferentes poblaciones, incluyendo aquellas con elevado consumo de medicamentos concomitantes, y la frecuencia de eventos adversos (EA) ha sido muy baja, sugiriendo un bajo riesgo de interaciones adversas de medicamentos. Las benzodiazepinas (BZPs) se consumen ampliamente para el manejo de la ansiedad y los trastornos del sueño en la vejez. Las interaciones medicamentosas (IM) con BZP son frecuentes debido a que esta se metaboliza principalmente a través del sitema hepático citocromo P450 (CYP 450), subsistema CYP 3A4, el cual oxida muchas drogas, representando un riesgo potencial para serios EA. A pesar de que el policosanol no se elimina a través del sistema CYP 450, existen reportes de IM con BZP. Por esta razón se ha investigado si la BZP administrada conjuntamente con el policosanol induce EA distinto que cuando se administra con placebo sobre la base de los registros de todos los pacientes que tomaron BDP (118 que recibieron placebo + BZPs y 121 policosanol + BZPs) incluidos en un estudio de prevención a largo plazo. El análisis fue realizado según el criterio de intención de tratar. Ambos grupos fueron homogéneos al inicio del tratamiento. Después de un año de tratamiento el policosanol redujo (p < 000 1) el colesterol de lipoproteína de baja densidad (LDL-C) (21,3 %), el colesterol total TC (15,8 %), y los triglicéridos TG (p < 0,01) mientras que por otra parte incremento el colesterol de lipoproteína de alta densidad (HDL-C) (10,2 %), manteniéndose estos efectos durante el ensayo. Al finalizar el estudio, el policosanol redujo (p < 0,0001 LDL-C (31,0 %), TG (23,0 %) e incrementó HDL-C (17,8 %). Hubo 43 (18,0 %) bajas (27 placebo y 16 policosanol), 17 (10 placebo y 7 policosanol) debido a EA. El tratamiento no afectó los indicadores de seguridad, el policosanol redujo la presión sanguínea diastólica y sistólica, siendo sus valores normales. La proporción de EA fue similar en ambos grupos. El policosanol mostró una eficacia persistente y fue bien tolerado en pacientes ancianos bajo tratamiento con BZP, ya que no se incrementaron los EA ni se afectaron los indicadores de seguridad. El policosanol puede por tanto ser indicado conjuntamente con BZP en pacientes ancianos.

El D-004 es un extracto lipídico obtenido de los frutos de la palma real (Roystonea regia) (Arecaceae) que consiste en una mezcla reproducible de ácidos grasos. Para evaluar si el D-004 presenta actividad estrogénica, se empleó el modelo de ratas ovarectomizadas. Se utilizaron ratas Sprague Dawley hembras, distribuidas aleatoriamente en cuatro grupos experimentales. A tres grupos de animales se les practicó la ovarectomía bilateral. Uno fue tratado oralmente con el vehículo; al segundo, se le administró por vía subcutánea estradiol 30 ¿g/kg; y el otro recibió tratamiento con 400 mg/kg de D-004 por vía oral. El cuarto grupo fue el control del procedimiento quirúrgico (CPQ). Al inicio del tratamiento, el peso corporal de todos los grupos de ratas ovarectomizadas fue significativamente mayor que el del grupo CPQ. Después de los 14 días, la diferencia del peso corporal de los grupos control negativo y D-004 respecto al CPQ se mantuvo ( p < 0,001), si bien desapareció la diferencia de peso entre el control positivo y el CPQ. El peso del útero del grupo control positivo mostró un marcado incremento (más de 10 veces) que el control negativo. Por otra parte, los valores del grupo D-004 fueron estadísticamente similares a los del control negativo. El D-004 carece de efectos estrogénicos en el modelo utilizado y a las dosis de tratamiento empleadas.

Las enfermedades cardiovasculares (ECV) y la osteoporosis son causas frecuentes de morbilidad en la población adulta, cuya frecuencia aumenta con la edad, por lo que al aumentar la expectativa de vida, constituyen importantes problemas de salud. El riesgo a padecer ambas patologías depende de factores de riesgo, y la prevención consiste en controlar los modificables. Las ECV y la osteoporosis presentan factores etiológicos comunes que involucran la biosíntesis del colesterol y la oxidación lipídica, cuya dilucidación representa una línea priorizada de investigación. El crecimiento y mantenimiento del esqueleto depende del equilibrio entre la formación y la resorción ósea a través de los procesos de modelado y remodelado óseo, controlados por células óseas (osteoblastos -OB-, osteoclastos -OC- y osteocitos), los OB son responsables de la formación ósea, los OC de la resorción ósea y los osteocitos de la red mecano sensorial. Entre los nexos de las ECV y la osteoporosis se encuentra el papel de la vía del mevalonato en la síntesis de colesterol y en la activación de OC, y el papel de los lípidos oxidados en el desarrollo de la aterosclerosis y en la transformación de las células precursoras de OB en adipocitos, disminuyendo la formación de OB activos y favoreciendo la osteoporosis. Ello justifica que sustancias hipolipemiantes y antioxidantes puedan ejercer efectos protectores sobre el hueso, y que la búsqueda de sustancias que actúen sobre ambos blancos sea un aspecto de interés en la prevención o el manejo de estas enfermedades.

Stroke is a major health problem worldwide. Its pharmacological management includes thrombolytic therapy for the acute phase and antiplatelet drugs for stroke recovery and prevention. Statins can help in the acute phase and in preventing stroke in secondary prevention patients. Policosanol is a cholesterol-lowering drug with concomitant antiplatelet effects, with protective effects in stroke models. This observational study investigated the effects of policosanol (20 mg/day) administered during the acute phase and for 5 years later on the neurological recovery of patients with ischemic stroke treated with antiplatelets and vitamins. After hospital discharge, patients were followed up every 3 (first year) and 6 (thereafter) months. Neurological improvement was assessed with the modified Canadian Neurological Scale. Adverse events were recorded. Fifty patients were included; all completed the study. Neurological score improved throughout the study. No patient died, and most [40 (80.0%)] did not experience new vascular events; only one (2.0%) suffered a new stroke, and two (4.0%) suffered more than one transient ischemic attack. The time to the first recurrent event was 46.2 months. Policosanol persistently lowered serum total cholesterol, with such reduction correlating with the neurological improvement (R = 0.995253301). Triglycerides were unchanged. Treatment was well tolerated. Policosanol administered to patients suffering ischemic stroke treated with aspirin and vitamins showed good results on neurological outcomes and recurrent events. This study, however, has limitations, since it was open and uncontrolled, and patients also consumed aspirin and vitamins. New randomized, controlled studies are needed to assess the usefulness of policosanol in stroke management.

Background:Policosanol is a mixture of long-chain primary aliphatic alcoholspurified from sugar cane wax that has cholesterol lowering and antiplatelet effects. Omega-3 fatty acids (FA) have triglyceride lowering and antiplatelet effects. Combination treatment with policosanol and omega-3 FA (Ω23FA) has been associated with significant inhibition of platelet aggregation in rabbits compared with either drug alone.Objective:The aim of this study was to investigate the effects of combination treatment with Ω3FA (1 g/d) and policosanol (Ω3FA+Poli) compared with Ω3FA (1 g/d) plus placebo (Ω3FA+Pla) on platelet aggregation in human patients with hypercholesterolemia.Methods:This randomized, double-blind, clinical study at the Surgical Medical Research Center (Havana City, Cuba) recruited outpatients from lipid clinics, with some atherosclerotic risk factors. Outpatients of both sexes aged 20 to 75 years with serum total cholesterol (TC) levels ≥5 and

El D-003 es una mezcla de ácidos alifáticos de muy alto peso molecular purificada de la cera de la caña de azúcar con efectos hipocolesterolemizante y antiagregante plaquetario demostrados experimentalmente y en estudios clínicos Fase I y II. Los estudios experimentales y clínicos culminados han mostrado que el D-003 es seguro y bien tolerado. Sin embargo, la farmacología de la seguridad de nuevos medicamentos investiga sus efectos sobre diversos sistemas que pudieran ser blancos potenciales de toxicidad. Teniendo en cuenta que los efectos adversos relacionados con el Sistema Nervioso (SN) están entre los más frecuentes para diversas áreas terapéuticas, estos estudios suelen investigar los efectos de las sustancias sobre la función y estructura del SN. La investigación de los efectos sobre patrones conductuales de roedores comúnmente representa la primera etapa de estos estudios. De acuerdo con ello, el presente estudio tuvo como objetivo investigar los efectos del tratamiento oral con D-003 (dosis únicas y repetidas) sobre la actividad exploratoria, la respuesta al plato caliente, la sujeción y ejecución en varilla rotatoria y la evitación pasiva de una sola prueba de aprendizaje en ratones. Los animales se distribuyeron aleatoriamente en cinco grupos experimentales (10 animales/grupo): uno control que recibió el vehículo goma acacia-H20 y cuatro tratados con D-003 (5, 25, 100 y 400 mg/kg, respectivamente). El tratamiento oral con dosis únicas y repetidas de D-003 (400 mg/kg) aumentó de forma modesta, pero significativa, la actividad exploratoria con respecto al grupo control. Sin embargo, el D-003 no modificó la respuesta en el ensayo de plato caliente, la capacidad de sujeción y ejecución motora en varilla rotatoria ni la retención del aprendizaje en el ensayo de evitación pasiva. Se necesitan estudios ulteriores que diluciden las causas por las cuales el D-003 aumenta la actividad exploratoria en ratones y que investiguen otros posibles efectos del D-003 sobre el SN para determinar los riesgos o beneficios potenciales asociados.

La hipercolesterolemia es uno de los más importantes factores de riesgo coronario. El principal objetivo en el control de la dislipidemia es la disminución de las concentraciones elevadas de LDL- C. El policosanol es un medicamento hipocolesterolemizante purificado de la cera de la caña de azúcar con un intervalo terapéutico entre 5 y 20 mg ¤ d, que reduce significativamente la concentración de LDL - C en el suero sanguíneo. La atorvastatina es un inhibidor de la HMGCoA reductasa, el cual a través de su intervalo terapéutico (10 a 80 mg/d) muestra un marcado efecto hipolipemiante, superior a otras estatinas hasta ahora disponibles. Este estudio se lleva a cabo para comparar la eficacia, seguridad y tolerabilidad del policosanol y la atorvastatina en pacientes con hipercolesterolemia tipo II. Este estudio se realizó en pacientes de ambos sexos de forma aleatorizada y a simple ciegas con grupos paralelos. Después de 5 semanas de dieta baja en colesterol, 175 pacientes con valores de colesterol ³ 3,4 mmol ¤ L se trataron aleatoriamente con policosanol o atorvastatina ( 10 mg ) una vez al día en horario de la cena y durante 8 semanas. Serealizó la evaluación del perfil de los lípidos el suero y de los indicadores de seguridad, así como de los eventos adversos (EA). Después de 8 semanas el policosanol (10 mg¤d) disminuyó significativamente (p < 0,000 001 vs línea de base) la LDL - C (27,0 %), TC (19,6 %), LDL-C/colesterol de lipoproteina de alta densidad (HDL-C) (30,1 %) y TC/HDL-C (23,9 %), así como TG (12,4 %). (p < 0,000 1 vs valores basales). Por otra parte, la atorvastatina (10 mg /d) redujo significativamente (p < 0,000 001 vs valores basales) la LDL - C (35,2 % ), TC (26,2 %), LDL-C/HDL-C (34,5 %), TC/HDL-C (25,9 %) y (p < 0,000 1) TG (10,2 %). La atorvastatina fue más efectiva que el policosanol (p < 0,001) para reducir la LDL-C y TC (p< 0,000 1). El policosanol, pero no la atorvastatina incrementó las HDL - C de manera significativa (p < 0,000 1) en un 10,4 %. (En el chequeo intermedio realizado a las 4 semanas, los cambios inducidos por ambos medicamentos sobre el perfil de los lípidos del suero eran ya significativos, siendo el efecto de la atorvastatina similar al obtenido a las 8 semanas, mientras que el policosanol continuó incrementando su efecto a lo largo del tratamiento. Tanto el policosanol como la simvastatina fueron bien tolerados. La atorvastatina incremento significativamente (p < 0,01) la CPK y la ALAT mientras que el policosanol disminuyó estos valores (p < 0,01) en relación a los basales, pero los individuales permanecieron dentro del intervalo normal. Seis pacientes resultaron baja del estudio debido a eventos adversos, todos del grupo de la atorvastatina . De 17 pacientes que reportaron EA durante el estudio, tres fueron del grupo policosanol y 14 del grupo atorvastatina (p < 0,01), que reportaron un total de 4 y 23 AE, respectivamente. La atorvastatina (10 mg/d) por 8 semanas fue más efectiva que el policosanol en igual dosis para reducir LDL-C y TC en pacientes con hipercolesterolemia tipo II, pero similarmente efectivos para reducir las concentraciones en suero de TG , LDL - C/HDL - C y CT/HDL - C. El policosanol, pero no la atorvastatina fue efectivo en el incremento de la concentraci ón en el suero de HDL - C. El policosanol fue mejor tolerado que la atorvastatina de acuerdo con los indicadores bioquímicos de seguridad y el reporte de EA.

Background: Drugs inhibiting cholesterol biosynthesis may affect bone metabolism through inhibition of the mevalonate pathway resulting in the inhibition of protein prenylation required for osteoclast activity. D-003 is a mixture of high molecular weight aliphatic primary acids purified from sugar-cane (Saccharum officinarum) wax, with cholesterol-lowering effects demonstrated in experimental and clinical studies. D-003 inhibits cholesterol biosynthesis through indirect regulation of HMG-CoA reductase activity. A previous study demonstrated that D-003 prevented bone loss and bone resorption on ovariectomy-induced osteoporosis in rats. Corticosteroid-induced osteoporosis is the result of changes affecting calcium homeostasis, but the hallmark of corticosteroid-induced bone loss is the direct effects on bone cells, such as inhibition of osteoblastogenesis, promotion of apoptosis of osteoblasts and osteocytes, and decrease in bone formation. Objective: To determine whether D-003 could prevent the bone loss induced with prednisolone in Sprague-Dawley rats. Methods: Rats were randomly distributed in five groups (ten rats per group): a sham-operated control and four groups orally treated with prednisolone 6 mg/kg for 80 days; a positive control orally treated with vehicle; and three groups orally treated with D-003 at 5, 25 and 200 mg/kg, respectively. Rats were killed, bones removed and histological variables of bone resorption and formation studied for histomorphometry. Results: Compared with the sham group, prednisolone significantly (p < 0.01) reduced trabecular bone volume (TBV), while D-003 significantly (p < 0.001) and dose-dependently prevented the prednisolone-induced reduction of TBV. Treatment with prednisolone lowered (p < 0.001) trabecular thickness (TbTh) and number (TbN), while increasing (p < 0.001) the gap between trabeculae. D-003 (5, 25 and 200 mg/kg/day) significantly (p < 0.001) and dose-dependently prevented the reduction of TbTh and TbN and the increase of trabecular gap induced with prednisolone. Treatment with prednisolone increased both the surface and number of osteoclasts compared with sham (p < 0.001). D-003 (5–200 mg/day), however, prevented this effect (p < 0.001 for all comparisons). D-003 also prevented (p < 0.001) the reduction of osteoblast surface (ObS/BS) induced by prednisolone. Osteonecrotic areas were observed in all positive controls, but in none of the sham animals. Positive controls showed hypertrophy of bone marrow adipocytes and lipid-laden pluripotential stromal cells in bones. A significant and dose-dependent reduction of the frequency of animals showing prednisolone-induced osteo-necrosis was observed across the doses of D-003 (5, 25 and 200 mg/kg) investigated here. Conclusions: D-003 (5, 25 and 200 mg/kg) prevented trabecular bone loss and femoral neck osteonecrosis induced with prednisolone in Sprague Dawley rats, also increasing osteoblast surface and reducing bone resorption parameters. These results suggest that D-003 could be useful for managing corticosteroid-induced osteoporosis.

D-003 is a cholesterol-lowering agent that is isolated and purified from sugarcane wax and has concomitant antiplatelet effects.To evaluate lipid profile responses to different doses of D-003 in patients with type II hypercholesterolaemia.An 8-week, double-blind, placebo-controlled, parallel-group clinical study.After concluding a 5-week diet-only baseline period, 55 patients were randomly allocated to receive either placebo or D-003 at 5, 10, 20 or 40mg once daily with their evening meal for 8 weeks. An interim check-up was performed at week 4. The primary efficacy variable was the reduction of serum low-density lipoprotein-cholesterol (LDL-C) from baseline compared with placebo. Drug safety and tolerability were assessed on the basis of changes in physical, haematological and blood biochemical indicators and on questioning about adverse experiences (AEs).After 8 weeks of therapy, D-003 significantly lowered (p0.0001 vs baseline and placebo) serum LDL-C in a dose-related manner, with reductions of 20.5-26.1% from the lowest to the highest dose investigated. At study completion, 43 of 44 (97.7%) randomised patients treated with D-003 reached LDL-C reductions15% compared with baseline, while 30 of 44 patients (68.2%) reached LDL-C targets according to their individual global coronary risk status. Decreases in total cholesterol (TC) and the ratios of TC/high-density lipoprotein-cholesterol (HDL-C) and LDL-C/HDL-C were also significant (p0.0001) and dose related. Changes in LDL-C, TC and both ratios were significant from the interim check-up. D-003 significantly increased HDL-C values (11.7-16.7%), but the increase was not dose related. No significant changes in lipid profile variables were observed with placebo. D-003 was well tolerated. The treatment did not affect any physical, haematological or blood safety indicators. All included patients completed the study. Four patients reported mild AEs during the study: headache (one patient treated with placebo and one treated with D-003 20 mg/day), insomnia (one patient treated with D-003 5 mg/day) and polyuria (one patient treated with D-003 40 mg/day).D-003 was effective in dose dependently reducing LDL-C in patients with type II hypercholesterolaemia, as documented by average percentage reductions and the percentage of patients achieving decreases15% from baseline and LDL-C goals. The treatment was well tolerated by patients and did not affect any safety indicator. Further studies corroborating these results and exploring the effect of lower doses of D-003 and a longer treatment duration must be carried out, however, before definitive conclusions can be reached. These results encourage continuing clinical investigation on this drug.

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).

Background: Policosanol is a cholesterol-lowering drug purified from sugar cane wax that consists of a mixture of higher aliphatic primary alcohols. D-003 is a mixture of long-chain aliphatic primary acids isolated from the same source with experimentally proven cholesterol-lowering effects. Objective: The present study was undertaken to compare the cholesterol-lowering effects of D-003 and policosanol in normocholesterolemic New Zealand rabbits. In addition, the effects of the 2 drugs on levels of plasma circulating endothelial cells (PCEC) before and after citrate-induced endothelial damage were compared. Methods: Animals were randomly distributed to 3 experimental groups: 1 control and 2 treatment groups. Rabbits in the treatment groups received orally administered policosanol or D-003 daily at 5 mg/kg, the lowest effective dose of policosanol in this model, for 30 days. Results: After 15 days of treatment, both D-003 and policosanol significantly ( P P P P P P P P P Conclusions: D-003 administered orally at 5 mg/kg for 30 days to normocholesterolemic rabbits induced more beneficial changes in serum LDL-C levels than policosanol at the same dose. In addition, a slightly greater beneficial effect on HDL-C levels and PCEC count was noted with D-003 versus policosanol. Although D-003 was more effective than policosanol in these experimental conditions, additional comparative studies that include a wide dose range of both drugs must be conducted before definitive conclusions can be made about the comparative cholesterol-lowering effects of D-003.

Objectives The goal of the present study was to evaluate the effects of D-003 (5 to 200 mg/kg) administered orally for 30 days on the serum lipid profile of normocholesterolemic New Zealand rabbits as well as the effects of treatment withdrawal for the following 30 days. Background D-003 is a mixture of higher primary aliphatic acids; octacosanoic acid is its major component. Methods Thirty-five animals were adapted to experimental conditions for 15 days and then randomized to 5 study groups: a control group, which received only orally equivalent volumes of the vehicle, and 4 groups treated with the various doses of D-003 (5, 25, 100, or 200 mg/kg). Results After 30 days of treatment, D-003 significantly ( P P Conclusions Results of this study suggest that D-003 has reversible cholesterol-lowering effects characterized by a dosedependent reduction of TC and LDL-C values accompanied by a non-dose-dependent increase in HDL-C levels.

Osteonecrosis (ON) is characterized through the impairment of osseous blood flow that leads to the collapse of femur head. Corticoid-induced ON in rats and lipopolysaccharide (LPS)-induced in rabbits are useful models to assess the efficacy of potential treatments on this disease. D-003 inhibits the mevalonate pathway, lipid peroxidation and prevents osteoporosis in rats through increasing the osteoclast apoptosis. This study investigated the effects of D-003 on corticoid- and LPS-induced ON in rats and rabbits. Corticoid-induced ON: Rats were randomized into five groups. A negative control and four groups treated with prednisolone 6 mg/Kg: a positive control and three treated with D-003 (5, 25 and 200 mg/Kg) for 80 days. All positive controls presented ON areas. D-003 significantly reduced the numbers and proportions of ON lesions, as compared to the positive control group. LPS-induced ON in rabbits: Rabbits were randomized into five groups: a negative control and four injected with a single intra-venous injection of LPS (10 μg/Kg) including a positive control and three with D-003 (5, 25 and 200 mg/Kg) for 30 days. ON was seen in all positive controls. The incidence of ON and the number of ON lesions in the groups treated with D-003 (25 and 200 mg/Kg) was significantly lower compared to the positive controls. LPS injection significantly increased the size of bone marrow fat cells in positive controls and such increase was significantly decreased by D-003. In conclusion, D-003 reduced ON lesions in corticoid-and LPS-induced ON and also the size of bone marrow fat cells in rabbits with LPS.

The aim of this study was to conduct a randomized, double-blind and placebo-controlled study to investigate the effects of D-004, a lipid extract of the Roystonea regia fruit that prevents testosterone- and phenylepinephrine-induced prostate hyperplasia in rodents, on plasma oxidative markers in healthy men. We enrolled male volunteers (20–55 years) in good health and without lower urinary tract symptoms. Thirty-four eligible participants were randomized to placebo or D-004 (320 mg) capsules administered daily for 6 weeks. An interim check-up and a final visit were conducted after 3 and 6 weeks of therapy, respectively. Physical examinations were performed at each visit, and laboratory tests were performed at baseline and at treatment completion. Oxidative variables included plasma malondialdehyde (MDA), total hydroxyperoxides (TOH), sulphydryl (SH) groups and total antioxidant status (TAS). We assessed treatment compliance and addressed adverse experiences (AEs) at weeks 3 and 6. At week 6, with D-004, the mean reductions of plasma MDA (26.7%), TOH (18.8%) and SH groups (31.6%), and the mean increase of TAS (35.3%) were significantly different from those of placebo (P < 0.001 for plasma TAS, P < 0.0001 for all other comparisons). D-004 did not differ from the placebo in safety indicators. There were two withdrawals (both in the D-004 group), with one due to dyspepsia (the only AE during the trial). In conclusion, D-004 displayed antioxidant effects on plasma oxidative markers in healthy men, which was consistent with findings from laboratory experimental studies.

Antiplatelet therapy, including aspirin, is recommended to lower the vascular risk in patients with intermittent claudication. Policosanol has increased walking distances in these patients, probably because of its antiplatelet effects, but the effect of shorter treatment has not been studied. This double-blind study compared the effects of policosanol 10 mg/d and aspirin 100 mg/d for 10 weeks on walking distances in claudicants. Thirty-nine patients were randomized to policosanol or aspirin. Walking distances on a treadmill were assessed before and after treatment. Policosanol significantly increased the initial and absolute claudication distances, while aspirin changed neither variable. Policosanol, not aspirin, significantly lowered serum low-density lipoprotein-cholesterol and total cholesterol while raising high-density lipoprotein-cholesterol. In conclusion, treatments of policosanol, not aspirin, for 10 weeks significantly increased walking distances, but modestly, in contrast with previous results. Therefore, the duration of treatments at the doses tested was too short for meaningful effects on the treadmill test.

D-002 is a mixture of higher aliphatic primary alcohols purified from beeswax with antioxidant effects. Acute hepatotoxicity induced with CCl4 in rats has been related to increased hepatic lipid peroxidation and prevented with some antioxidants. This study investigated whether D-002 could prevent the acute CCl4-induced hepatotoxicity in rats. Animals were randomly distributed into four groups: a negative control treated orally with the vehicle and three groups injected with CCl4 (1 mL/kg) and treated orally either with the vehicle (positive control) or with D-002 (25 and 100 mg/kg). Eighteen hours after CCl4 dosing, rats were anesthetized, and livers were removed for histopathological studies. Some portions were taken and homogenized for assessing malondialdehyde (MDA) concentrations. Positive, but not negative, controls showed ballooned cells, swollen hepatocytes, and lipid-included hepatocytes, as well as necrotic areas and inflammatory infiltrates. D-002 (25 and 100 mg/kg) dose-dependently and significantly (P < .01) decreased the frequency of all abnormal liver cell types and increased that of normal hepatocytes compared with the positive controls, not showing necrotic areas or inflammatory infiltrates. D-002 dose-dependently decreased hepatic MDA levels, but only in the highest dose group were these levels significantly lower than in the positive control. In conclusion, D-002 effectively prevented the histological liver disturbances and lowered MDA levels, a marker of cellular lipid peroxidation, in rats treated with CCl4. Since increased liver lipid peroxidation has been postulated as a cause of CCl4-induced liver damage in rats, the preventive effects of D-002 could be due to its antioxidant action, but such a proposal still requires further research.

D-003 is a mixture of very-high-molecular-weight aliphatic primary acids purified from sugar-cane (Saccharum officinarum L.) wax, in which octacosanoic acid is the most abundant component. Previous experimental studies have shown that D-003 not only shows cholesterol-lowering and anti-platelet effects, but also reduces thromboxane B2 and increases prostacyclin levels. It acts by inhibiting cholesterol biosynthesis. The positioning of a non-occlusive silicone collar around the rabbit carotid artery results in the formation of a neointima. Collars were placed around the left carotid for 15 days. The contralateral artery was sham-operated. We included three experimental groups: A control group received vehicle, and two others received D-003 at 5 and 25 mg/kg until sacrificed. Samples of arteries were examined by light microscopy. To evaluate intimal thickening the cross-sectional areas of intima and media were measured. Neointima was significantly reduced in D-003-treated animals compared with controls. Furthermore, the circulating endothelial cell has been studied in this experimental model with endothelium damage. The results demonstrate the protective effect of D-003 on vascular endothelium of the studied rabbits. It is concluded that the protective effect of D-003 against neointima formation and circulating endothelial cells in this experimental model could represent potential beneficial pleiotropic effects in the anti-atherogenic profile of this substance, beyond its cholesterol-lowering and anti-platelet effects independently demonstrated.

Background: Policosanol is a mixture of higher aliphatic primary alcohols purified from sugar-cane wax. The mixture has cholesterol-lowering efficacy, its specific effects being to reduce serum total (TC) and low-density lipoprotein cholesterol (LDL-C), and to increase high-density lipoprotein cholesterol (HDL-C). The effects of policosanol on triglycerides (TG) are modest and inconsistent. Omega-3 fatty acids (FA) from fish oil protect against coronary disease, mainly through antiarrhythmic and antiplatelet effects. Omega-3 FA also have lipid-modifying effects, mostly relating to TG reduction. Thus, potential benefits could be expected from combined therapy with omega-3 FA and policosanol. Objective: To investigate whether combined therapy with omega-3 FA + policosanol offers benefits compared with omega-3 FA + placebo with respect to the lipid profile of patients with type II hypercholesterolaemia. Methods: This randomised, double-blind study was conducted in 90 patients with type II hypercholesterolaemia. After 5 weeks on a cholesterol-lowering diet, patients were randomised to omega-3 FA + placebo, omega-3 FA + policosanol 5 mg/day or omega-3 FA + policosanol 10 mg/day for 8 weeks. Omega-3 FA was supplied as 1g capsules (two per day); placebo and policosanol were provided in tablet form. Physical signs and laboratory markers were assessed at baseline and after 4 and 8 weeks on therapy. Drug compliance and adverse experiences (AEs) were assessed at weeks 4 and 8. The primary efficacy variable was LDL-C reduction; other lipid profile markers were secondary variables. Results: After 8 weeks, omega-3 FA + policosanol 5 and 10 mg/day, but not omega-3 FA + placebo, significantly reduced LDL-C by 21.1% and 24.4%, respectively (both p < 0.0001). Omega-3 FA + policosanol 5 mg/day also significantly lowered TC (12.7%; p < 0.01) and TG (13.6%; p < 0.05), and significantly increased HDL-C (+14.4%; p < 0.001). Omega-3 FA + policosanol 10 mg/day significantly decreased TC (15.3%; p < 0.001) and TG (14.7%; p < 0.01), and significantly increased HDL-C (+15.5%; p < 0.0001). Omega-3 FA + placebo significantly reduced TG (14.2%; p < 0.05) but had no significant effect on other lipid profile variables. The proportion of randomised patients in the omega-3 FA + policosanol 5 or 10 mg/day groups that achieved LDL-C targets or reductions ≥15% was significantly greater than in the omega-3 FA + placebo group (p < 0.001). Combined therapy with omega-3 FA + policosanol 5 or 10 mg/day resulted in significantly greater changes in LDL-C, TC and HDL-C than treatment with omega-3 FA + placebo, but did not modify the TG response compared with the omega-3 FA + placebo group. Four patients (two in the omega-3 FA + placebo group and two in the omega-3 FA + policosanol 10 mg/day group) withdrew from the study; none of these withdrawals was due to AEs. Two patients reported mild AEs, namely nausea/headache (one in the omega-3 FA + placebo group) and heartburn (one in the omega-3 FA + policosanol 5 mg/day group). Conclusions: Policosanol 5 or 10 mg/day administered concomitantly with omega-3 FA 1 g/day improved LDL-C, TC and HDL-C, maintained the reduction in TG attributable to omega-3 FA monotherapy, and was well tolerated. Treatment with omega-3 FA + policosanol could be useful for regulating lipid profile in patients with type II hypercholesterolaemia, but further studies involving larger sample sizes are needed before definitive conclusions can be drawn.

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 occuring in older Cuban patients treated with policosanol in routine clinical practice. Methods: All patients aged ≥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), penumonia (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.

Background: Policosanol is a mixture of high-molecular-weight aliphatic primary alcohols isolated from sugarcane wax with cholesterol-lowering and antiplatelet effects. Omega-3 fatty acids (FA) from fish oil can protect against coronary disease. An antiarrhythmic mechanism is emerging as the most convincing explanation for omega-3 FA cardiovascular protection, but triglyceride (TG)-lowering effects and inhibition of platelet function could play a role. In view of the effects of policosanol and omega-3 FA on lipid profile and platelet function, potential benefits of combined therapy were expected. Objective: To investigate whether combined therapy with policosanol and omega-3 FA would offer some benefit, compared with policosanol or omega-3 FA alone, on serum lipid profile and platelet aggregation in rabbits. Methods: Male rabbits were randomly distributed in four groups (n = 9 per group). A control group received vehicle, one group was treated with policosanol 5 mg/kg and one with omega-3 FA (eicosapentaenoic acid; EPA [47.0%], docosahexaenoic acid; DHEA [41%]) 250 mg/kg, and the fourth received policosanol 5 mg/kg + omega-3 FA 250 mg/kg. Treatments were orally administered for 60 days. Bodyweight, food consumption and animal behaviour were recorded daily. Lipid profile, platelet aggregation and other blood tests were performed at baseline and study completion. Results: Policosanol significantly lowered low-density lipoprotein cholesterol (LDL-C) [42.7%; p < 0.01] and total cholesterol (TC) [29.4%; p < 0.05], increased high-density lipoprotein cholesterol (HDL-C) [15.4%; p < 0.05], but left TG levels unchanged. Omega-3 FA significantly lowered TG (47.1%; p < 0.05), but left TC, LDL-C and HDL-C unchanged. Combined therapy decreased LDL-C (38.7%; p < 0.05), TC (28.0%; p < 0.01) and TG (50.7%; p < 0.05), and increased HDL-C (15.4%; p < 0.05). Changes in TC, LDL-C and HDL-C obtained with combined therapy were greater (p < 0.05) than those with omega-3 FA, but similar to those with policosanol, whereas the opposite applied to TG reduction. No significant changes in lipid profile were observed in the control group. Policosanol and omega-3 FA significantly (p < 0.05) but moderately inhibited platelet aggregation induced with arachidonic acid (13.3% and 12.4%, respectively); combined therapy achieved greater inhibition (23.9%; p < 0.05). All groups showed similar food consumption and bodyweight gain. No toxic signs were observed in any animal. Conclusion: Concurrent therapy with policosanol 5 m/kg and omega-3 FA 250 mg/kg lowered LDL-C, TC and TG and increased HDL-C. All treatments inhibited platelet aggregation, but better effects were observed with policosanol + omega-3 FA compared with either treatment alone. Combined therapy was well tolerated. These results suggest that treatment with policosanol + omega-3 FA could be useful for regulating lipid profile and inhibiting platelet aggregation, but conclusive demonstration of such effects requires further experimental and clinical studies.

Background: D-003 is a mixture of long-chain aliphatic primary acids purified from sugar cane wax with cholesterol-lowering and preventive effects on lipoprotein lipid peroxidation (LP) proven in experimental and clinical studies. Objectives: To investigate if D-003 favourably modifies LP markers on older individuals. Methods: This double-blinded, randomized, placebo-controlled study investigated the effects of D-003 (5 and 10 mg/d) administered for 8 weeks on serum LP markers of older individuals. We assessed the effects of D-003 on LP of LDL as primary variable, while effects on plasma total antioxidant status (TAS), malondialdehyde (MDA) levels and plasma antioxidant enzyme activities were also investigated. We investigated the effects on lipid profile. Fifty-one older individuals (40 women, 11 men) were randomized to placebo or D-003 (5 or 10 mg/d), tablets being taken once a day with evening meal for 8 weeks. Laboratory tests and physical examination were performed at baseline and after 4 and 8 weeks on therapy, whereas compliance and adverse experiences (AE) were assessed at weeks 4 and 8. Results: D-003 (5 and 10 mg/d) significantly increased (p < 0.05 and p < 0.01) lag phase by 24.7 % and 29.3 %, respectively, while decreased propagation rate (p< 0.05) by 22.7 % (5 mg/d) and 25.8 % (10 mg/d). D-003 (5 and 10 mg/d) increased (p < 0.01) TAS by 17.7% and 23.0%, respectively, but only the changes achieved with 10 mg/d were different from placebo (p < 0.05). D-003 at 10 mg/d, not at 5 mg/d, significantly lowered (p < 0.05) plasma levels of thiobarbituric acid reactive substances (TBARS). D-003 (5 or 10 mg/d) did not modify superoxide dismutase (SOD) and GPX (glutathione peroxidase) activities. Also, D-003 (5 and 10 mg/d) reduced significantly low-density lipoprotein-cholesterol (LDL-C), total cholesterol (TC), and increased high-density lipoprotein-cholesterol (HDL-C). D-003 (10 mg/d) also reduced modestly, but significantly triglycerides. No significant changes of LP or lipid profile occurred in placebo. Treatment was well tolerated. D-003 did not impair safety indicators. No subject withdrew from the study. Only 3 subjects (2 placebo, 1 D-003 5 mg/d) reported AE: the two placebo patients reported insomnia and acidity, respectively, while that treated with D-003 referred acidity. Conclusions: D-003 (5 and 10 mg/d) administered for 8 weeks to older subjects effectively prevented LP in older and favourable modified lipid profile parameters. The present results add new data on the antioxidant effects of D-003, including demonstration on a new population subset. However, this aspect deserves further investigation including studies with larger sample sizes, doses and treatment duration.

Background: D-003 is a mixture of long-chain aliphatic primary acids isolated from sugar-cane wax and having cholesterol-lowering effects and a safety profile that have been proven in animals and in previous clinical studies in healthy volunteers. Lovastatin, the first member of the statin class, is an effective and well tolerated cholesterol-lowering drug. Some lovastatin-related adverse effects have been reported, and preclinical assessment has shown that the rabbit is the most sensitive species to lovastatin toxicity. Objective: To compare the cholesterol-lowering effects and toxicity pattern of D-003 and lovastatin in normocholesterolaemic rabbits. Methods: In order to study cholesterol-lowering effects, rabbits were randomly distributed into three groups (eight animals/group): one control group, only receiving the vehicle, and two groups treated with D-003 or lovastatin at 5 and 10 mg/kg/day, respectively. All treatments were orally administered for 30 days. To study toxicity, rabbits were distributed into four groups (six animals/group): one control group and three groups treated with D-003 200 and 400 mg/kg, respectively, or lovastatin 100 mg/kg. Results: After 30 days, D-003 5 mg/kg and lovastatin 10 mg/kg significantly (p < 0.05) and similarly lowered serum total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) levels versus baseline. D-003, but not lovastatin, increased high-density lipoprotein-cholesterol (HDL-C) significantly (p < 0.05), whereas only lovastatin decreased (p < 0.05) triglycerides. Low doses of both drugs did not change safety indicators. D-003 (200 and 400 mg/kg) and lovastatin (100 mg/kg) administered for 10 days reduced TC and LDL-C levels significantly (p < 0.05). HDL-C values increased significantly (p < 0.05) with D-003, but were unchanged with lovastatin. Neither treatment affected triglycerides. No significant changes in lipid profile were observed in the control groups of the two series. Lovastatin 100 mg/kg impaired bodyweight gain and food consumption versus the controls, while D-003 did not. Lovastatin 100 mg/kg increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT ) values (p < 0.05 versus baseline and controls) and liver weight (p < 0.05 versus controls). D-003 200 or 400 mg/kg did not affect AST, ALT or liver weight. Lovastatin 100 mg/kg, but not D-003 200 or 400 mg/kg, induced typical hepatocellular and renal tubular necrosis in the rabbits. Conclusions: D-003 5 mg/kg/day administered orally for 30 days to normocholesterolaemic rabbits lowered LDL-C and TC, as did lovastatin 10 mg/ kg. D-003 was more effective in increasing HDL-C, while lovastatin was more effective in lowering triglycerides. Administration of higher doses for 10 days did not show D-003-related toxicity, but did demonstrate the typical pattern of lovastatin-induced toxicity in rabbits.

D-003 is a mixture of high-molecular-weight aliphatic primary acids purified from sugar cane wax with antiplatelet and cholesterol-lowering effects. Cardiac lesions induced by isoproterenol (ISO) are characterized by myocardial necrosis and exudative infiltration. The objective of this study was to determine whether D-003 shows protective effects against ISO-induced myocardial necrosis in rats. Effects of orally administered single doses of D-003 (25-400 mg/kg) and acetylsalicylic acid (ASA, 30 mg/kg), as well as repeated doses of D-003 (5-200 mg/kg), on characteristic markers of ISO-induced myocardial necrosis in rats were investigated. D-003 administered as single doses dose-dependently decreased necrosis area, percent of infarct area, and the presence of polymorphonuclear cells (PMNs) in myocardial tissue, but only the reductions induced by 200 and 400 mg/kg were significant. Oral acute treatment with ASA also decreased necrosis area and percent of infarct area, but the occurrence of PMNs was unchanged. D-003 administered repeatedly for 10 days also decreased all myocardial necrosis indicators in a dose-dependent manner, with results effective from 25 mg/kg to the highest dose tested, indicating that the repeated dose scheme was more effective to prevent the damage. It is concluded that D-003 shows a protective effect on the myocardial necrosis induced by ISO in rats.

Background: Policosanol is a cholesterol-lowering drug purified from sugarcane (Saccharum officinarum, L.) wax. Beneficial pleiotropic effects of policosanol, such as inhibition of the susceptibility of low density lipoprotein to lipid peroxidation, have been shown. Policosanol has a good safety profile and well tolerated and, to date, no drug-related adverse effects have been demonstrated. Specifically, policosanol has not been shown to affect liver function or to increase liver enzyme levels in experimental or clinical studies. Aim: This study was conducted to determine whether policosanol prevents liver damage induced by carbon tetrachloride (CCl4) in rats, since this model has been associated with an increased rate of lipid peroxidation. Methods: Male Sprague-Dawley rats were randomised to four experimental groups: negative controls (no CCl4 or policosanol, group 1); positive controls (CCl4 but no policosanol, group 2); policosanol 25 mg/kg (group 3) and policosanol 100 mg/kg (group 4). Acute liver injury was induced in groups 2, 3 and 4 by CCl4 suspended in olive oil and administered at a dose of 1590 mg/kg via intraperitoneal injection. Eighteen hours after CCl4 dosing, the rats were anaesthetised and their livers removed for histopathological studies. Results: Policosanol 25 and 100 mg/kg dose dependently and significantly (p < 0.01) decreased the percentage of ballooned cells and hepatocytes with lipid inclusions and increased the percentage of normal hepatocytes compared with positive controls. The percentage inhibition of the occurrence of ballooned cells and hepatocytes with lipids was marked, reaching 71 and 49%, respectively, with the higher dose (100 mg/kg). The percentage of swollen hepatocytes was unchanged by policosanol compared with positive controls. No histological alterations in liver sections were found in the negative control group. Necrotic areas and inflammatory infiltrates were observed in the liver of seven of eight (87.5%) animals in the positive control group. However, only one of eight (12.5%) animals treated with policosanol 25 mg/kg and none (0%) treated with the higher dose (100 mg/kg) showed such a pattern. Conclusions: Policosanol protected against the histological changes characteristic of CCl4-induced hepatic injury in rats, a model of hepatotoxicity in which the process of lipid peroxidation plays a role. Further studies aimed at demonstrating the connection between such hepatoprotective and antioxidant effects of policosanol must be initiated.