Probucol attenuates lipopolysaccharide-induced leukocyte recruitment and inflammatory hyperalgesia: effect on NF-кB activation and cytokine production.

Probucol 4,4'- (Isopropylidenedithio)bis(2,6-di-tert-butylphenol) is a synthetic molecule clinically used for prevention and treatment of hypercholesterolemia and atherosclerosis. Recent studies have shown that the beneficial effects of probucol mainly derive from its anti-inflammatory and antioxidant properties. Gram-negative bacteria are common infectious agents and their wall components, e.g. lipopolysaccharide (LPS), are important elicitors of inflammation. LPS is sensed by tissue resident cells and it triggers a Toll-like receptor 4/MyD88-dependent signaling cascade resulting in endothelial activation, leukocyte recruitment and nociception. Therefore the present study aimed to investigate the anti-inflammatory and analgesic effects of probucol in models of LPS-induced acute inflammation. Probucol at 0.3-30mg/kg was administrated to male Swiss mice per oral 1h before intraplantar or intraperitoneal lipopolysaccharide stimulus. Probucol at 3mg/kg reduced lipopolysaccharide-induced mechanical and thermal hyperalgesia. These effects were accompanied by reduced leukocyte influx and cytokine production in both paw skin and peritoneum exudate. Unexpectedly, probucol did not alter lipopolysaccharide-induced tissue oxidative stress at anti-inflammatory /analgesic dose. On the other hand, probucol inhibited lipopolysaccharide-induced nuclear factor kappa B (NF-кB) activation in paw tissue as well as NF-кB activity in cultured macrophages in vitro, reinforcing the inhibitory effect of probucol over the NF-кB signaling pathway. In this sense, we propose that probucol acts on resident immune cells, such as macrophages, targeting the NF-кB pathway. As a result, it prevents the amplification and persistence of the inflammatory response by attenuating NF-кB-dependent cytokine production and leukocyte recruitment explaining its analgesic effects as well.

Probucol attenuates overt pain-like behavior and carrageenan-induced inflammatory hyperalgesia and leukocyte recruitment by inhibiting NF-кB activation and cytokine production without antioxidant effects.

OBJECTIVE AND DESIGN: This study aimed to evaluate the effect of probucol in inflammatory hyperalgesia and leukocyte recruitment in mice. TREATMENT: Probucol at 0.3-3 mg/kg was administrated per oral 1 h before inflammatory stimulus.Author: Kindly check and confirm the affiliation 1 have been correctly processed or not and amend if necessary.Thank you. We have corrected affiliation 1. We added the information to the appropriate boxes. However the state and the postal code are in a different order when compared to the other affiliations. METHODS: Overt pain-like behaviors were determined by the number of abdominal writhings induced by phenyl-p-benzoquinone and acetic acid. Mechanical and thermal hyperalgesia induced by carrageenan were determined using an electronic anesthesiometer and hot plate apparatus, respectively. Leukocyte recruitment was evaluated by direct count or by determination of myeloperoxidase and N-acetylglucosaminidase activities. Antioxidant ability was determined by measurement of GSH levels, ABTS and FRAP assays. Cytokine production and NF-кB activation were evaluated by ELISA. Data were analyzed by ANOVA followed by Tukey's post-hoc. p < 0.05 was considered significant. RESULTS: Probucol reduced overt pain-like behavior, and carrageenan-induced mechanical and thermal hyperalgesia. These effects were accompanied by reduced leukocyte influx in both paw skin and peritoneum exudate. Probucol did not alter carrageenan-induced tissue antioxidant capacity at anti-inflammatory/analgesic dose. On the other hand, probucol inhibited carrageenan-induced IL-1ß, TNF-α and CXCL1 production as well as NF-кB activation. CONCLUSION: Probucol presents analgesic and anti-inflammatory activities by employing mechanisms other than its antioxidant properties. These mechanisms involve targeting of pro-inflammatory cytokines and NF-кB activation.

Succinobucol, a Non-Statin Hypocholesterolemic Drug, Prevents Premotor Symptoms and Nigrostriatal Neurodegeneration in an Experimental Model of Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by non-motor and motor disabilities. This study investigated whether succinobucol (SUC) could mitigate nigrostriatal injury caused by intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in mice. Moreover, the effects of SUC against MPTP-induced behavioral impairments and neurochemical changes were also evaluated. The quantification of tyrosine hydroxylase-positive (TH+) cells was also performed in primary mesencephalic cultures to evaluate the effects of SUC against 1-methyl-4-phenylpyridinium (MPP+) toxicity in vitro. C57BL/6 mice were treated with SUC (10 mg/kg/day, intragastric (i.g.)) for 30 days, and thereafter, animals received MPTP infusion (1 mg/nostril) and SUC treatment continued for additional 15 days. MPTP-infused animals displayed significant non-motor symptoms including olfactory and short-term memory deficits evaluated in the olfactory discrimination, social recognition, and water maze tasks. These behavioral impairments were accompanied by inhibition of mitochondrial NADH dehydrogenase activity (complex I), as well as significant decrease of TH and dopamine transporter (DAT) immunoreactivity in the substantia nigra pars compacta and striatum. Although SUC treatment did not rescue NADH dehydrogenase activity inhibition, it was able to blunt MPTP-induced behavioral impairments and prevented the decrease in TH and DAT immunoreactivities in substantia nigra (SN) and striatum. SUC also suppressed striatal astroglial activation and increased interleukin-6 levels in MPTP-intoxicated mice. Furthermore, SUC significantly prevented the loss of TH+ neurons induced by MPP+ in primary mesencephalic cultures. These results provide new evidence that SUC treatment counteracts early non-motor symptoms and neurodegeneration/neuroinflammation in the nigrostriatal pathway induced by intranasal MPTP administration in mice by modulating events downstream to the mitochondrial NADH dehydrogenase inhibition.

Protective effect and mechanism of probucol in the treatment of spinal cord injury.

To investigate the effects of probucol on the treatment of spinal cord injury in rat, 80 rats were randomly divided into two groups of 40: a group treated with probucol and a control group. Allen's method was used to establish a rat model of spinal cord injury. After establishment, probucol (500 mg·kg(-1)·day(-1)) was intraperitoneally injected into the treatment group rats for 1 week, while the same amount of saline was used to treat the control group. On days 1, 7, 14, 21, and 28 after treatment, the function of rats' spinal cord was evaluated according to the Bresnahan locomotor rating scale. Serum protein and mRNA levels of the cytokines [interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and interleukin (IL)-17] were measured using enzyme-linked immunosorbent assay and quantitative polymerase chain reaction, respectively. Protein levels of IFN-γ, TNF-α, IL-17, and the downstream markers signal transducer and activator of transcription (STAT)-1 and STAT-3 were measured using western blot. In addition, the oxidative stress-related parameters, superoxide dismutase (SOD) and malondialdehyde (MDA), were also measured. It was found that compared to control group, rats from the treatment group had significantly lower levels of IFN-γ, TNF-α, and IL-17 (P < 0.05) on days 1 and 7, as well as lower MDA levels and higher SOD activity on days 7, 21, and 28 (P < 0.05). In summary, probucol improved the recovery of locomotion function after spinal cord injury in rats through downregulation of inflammation and upregulation of anti-oxidative activity.

Probucol increases striatal glutathione peroxidase activity and protects against 3-nitropropionic acid-induced pro-oxidative damage in rats.

Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disease characterized by symptoms attributable to the death of striatal and cortical neurons. The molecular mechanisms mediating neuronal death in HD involve oxidative stress and mitochondrial dysfunction. Administration of 3-nitropropionic acid (3-NP), an irreversible inhibitor of the mitochondrial enzyme succinate dehydrogenase, in rodents has been proposed as a useful experimental model of HD. This study evaluated the effects of probucol, a lipid-lowering agent with anti-inflammatory and antioxidant properties, on the biochemical parameters related to oxidative stress, as well as on the behavioral parameters related to motor function in an in vivo HD model based on 3-NP intoxication in rats. Animals were treated with 3.5 mg/kg of probucol in drinking water daily for 2 months and, subsequently, received 3-NP (25 mg/kg i.p.) once a day for 6 days. At the end of the treatments, 3-NP-treated animals showed a significant decrease in body weight, which corresponded with impairment on motor ability, inhibition of mitochondrial complex II activity and oxidative stress in the striatum. Probucol, which did not rescue complex II inhibition, protected against behavioral and striatal biochemical changes induced by 3-NP, attenuating 3-NP-induced motor impairments and striatal oxidative stress. Importantly, probucol was able to increase activity of glutathione peroxidase (GPx), an enzyme important in mediating the detoxification of peroxides in the central nervous system. The major finding of this study was that probucol protected against 3-NP-induced behavioral and striatal biochemical changes without affecting 3-NP-induced mitochondrial complex II inhibition, indicating that long-term probucol treatment resulted in an increased resistance against neurotoxic events (i.e., increased oxidative damage) secondary to mitochondrial dysfunction. These data appeared to be of great relevance when extrapolated to human neurodegenerative processes involving mitochondrial dysfunction and indicates that GPx is an important molecular target involved in the beneficial effects of probucol.

Effects of lifestyle modifications on cognitive impairments in a mouse model of hypercholesterolemia.

Epidemiological studies indicate that high midlife plasma cholesterol levels increases the risk of Alzheimer's disease. Moreover, middle-aged familial hypercholesterolemia (FH) subjects show a particularly high incidence of mild cognitive impairments (MCI). These evidence points to hypercholesterolemia as one of the modifiable risk factors focused on prevention/treatment of cognitive deterioration. The present study draws a comparison between pharmacological (lipid-lowering drug probucol) and non-pharmacological (voluntary running wheel, RW) approaches for the management of hypercholesterolemia and cognitive impairments associated with the low-density lipoprotein receptor-deficient (LDLr(-/-)) mice, a well-established rodent model of FH. We also investigated whether exposure to environmental enrichment (EE), a feasible option to increase physical activity in young mice cohort, from birth to adolescence (PN45) yields long-term behavioral changes in adult LDLr(-/-) mice (PN90). We observed that both probucol and RW significantly decreased total and non-HDL plasma cholesterol levels in LDLr(-/-) mice. Notably, only physical exercise mitigated the spatial memory deficits of LDLr(-/-) mice. In addition, we showed that exposure to EE from birth until the adolescence did not mitigate the spatial memory deficits of adult LDLr(-/-) mice in the object location task, although it induced persistent anxyolitic-like effects in the open field arena. Collectively, our results emphasize the advantages physical exercise, in comparison to lipid-lowering drugs, for the management of cognitive deficits associated with FH.

Probucol affords neuroprotection in a 6-OHDA mouse model of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic nigrostriatal neurons. Although the etiology of the majority of human PD cases is unknown, experimental evidence points to oxidative stress as an early and causal event. Probucol is a lipid-lowering phenolic compound with anti-inflammatory and antioxidant properties that has been recently reported as protective in neurotoxicity and neurodegeneration models. This study was designed to investigate the effects of probucol on the vulnerability of striatal dopaminergic neurons to oxidative stress in a PD in vivo model. Swiss mice were treated with probucol during 21 days (11.8 mg/kg; oral route). Two weeks after the beginning of treatment, mice received a single intracerebroventricular (i.c.v.) infusion of 6-hydroxydopamine (6-OHDA). On the 21st day, locomotor performance, striatal oxidative stress-related parameters, and striatal tyrosine hydroxylase and synaptophysin levels, were measured as outcomes of toxicity. 6-OHDA-infused mice showed hyperlocomotion and a significant decrease in striatal tyrosine hydroxylase (TH) and synaptophysin levels. In addition, 6-OHDA-infused mice showed reduced superoxide dismutase activity and increased lipid peroxidation and catalase activity in the striatum. Notably, probucol protected against 6-OHDA-induced hyperlocomotion and striatal lipid peroxidation, catalase upregulation and decrease of TH levels. Overall, the present results show that probucol protects against 6-OHDA-induced toxicity in mice. These findings may render probucol as a promising molecule for further pharmacological studies on the search for disease-modifying treatment in PD.

Probucol, a lipid-lowering drug, prevents cognitive and hippocampal synaptic impairments induced by amyloid ß peptide in mice.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by synaptic loss and cognitive impairments. The presence of extracellular senile plaques (mainly composed of amyloid-ß (Aß) peptide) is an important molecular hallmark in AD and neuronal damage has been attributed, at least in part, to Aß-mediated toxicity. Although the molecular mechanisms involved in the pathogenesis of AD are not yet completely understood, several lines of evidence indicate that oxidative stress and cholesterol dyshomeostasis play crucial roles in mediating the synaptic loss and cognitive deficits observed in AD patients. This study evaluated the effects of Probucol, a phenolic lipid-lowering agent with anti-inflammatory and antioxidant properties, on biochemical parameters related to oxidative stress and synaptic function (hippocampal glutathione and synaptophysin levels; glutathione peroxidase, glutathione reductase and acetylcholinesterase activities; lipid peroxidation), as well as on behavioral parameters related to the cognitive function (displaced and new object recognition tasks) in Aß-exposed mice. Animals were treated with a single intracerebroventricular (i.c.v.) injection of aggregated Aß(1-40) (400 pmol/site) and, subsequently, received Probucol (10 mg/kg, i.p.) once a day, during the following 2 weeks. At the end of treatments, Aß(1-40)-exposed animals showed a significant impairment on learning-memory ability, which was paralleled by a significant decrease in hippocampal synaptophysin levels, as well as by an increase in hippocampal acetylcholinesterase activity. Importantly, Probucol treatment blunted the deleterious effects of Aß(1-40) on learning-memory ability and hippocampal biochemistry. Although Aß(1-40) treatment did not change hippocampal glutathione levels and glutathione peroxidase (GPx) and glutathione reductase (GR) activities, Aß(1-40)-exposed animals showed increased hippocampal lipid peroxidation and this event was completely blunted by Probucol treatment. These findings reinforce and extend the notion of the hazardous effects of Aß(1-40) toward hippocampal synaptic homeostasis and cognitive functions. In addition, the present results indicate that Probucol is able to counteract the cognitive and biochemical impairments induced by i.c.v. Aß(1-40) administration in mice. The study is the first to report the protective effects of Probucol (a "non-statin cholesterol-lowering drug") against Aß(1-40)-induced synaptic and behavioral impairments, rendering this compound a promising molecule for further pharmacological studies on the search for therapeutic strategies to treat or prevent AD.

Estudo piloto do papel do probucol na proteção da lesão pulmonar induzida pela administração de doxorrubicina em ratos: análise comparativa entre microscopia óptica e microscopia eletrônica / Pilot study of probucol protection on pulmonary injury induced by doxorubicin in rats: comparison analysis between optic and eletronic microscopy

Objetivo: Estudar o papel do probucol na lesão pulmonar obtida pela administração de doxorrubicina em ratos. Método: foi realizado um estudo piloto experimental, onde o probucol foi testado como protetor da injúria pulmonar obtida pela administração de doxorrubicina em ratos. Resultados: Na análise comparativa dos grupos, estudados por microscopia óptica, não houve diferença significativa de critérios previamente definidos, exceto pelo edema pleural (p < 0,05). Já na microscopia eletrônica, a agressão da doxorrubicina foi identificada através da desorganização estrutural. No grupo que recebeu probucol e doxorrubicina, não foi observada a mesma desorganização (p < 0,05). Conclusões: os resultados deste estudo piloto sugerem que o probucol exerceu um efeito protetor no tecido pulmonar agredido pela doxorrubicina e que a microscopia eletrônica é mais sensível na identificação de critérios de injúria pulmonar decorrente da exposição à doxorrubicina (AU)

Objective: To study the role of probucol in the pulmonary injury caused by doxorubicin in rats. Methods: An experimental study was carried out to verify where the probucol was protective of the pulmonary injury caused by the administration of doxorubicin in rats. Results: In the comparative analysis of the groups studied by optic microscopy, it did not have significant difference in pre-definite criterions, except for pleural edema (p < 0,05). In eletronic microscopy, the aggression of the doxorubicin was indicated through the structural disorganization. In the group that received probucol and doxorubicin was not observed the same disorganization (p < 0,05). Conclusion: The results suggest that the probucol was effective in the protection of pulmonary injury caused by doxorubicin and that the eletronic microscopy is more sensitive for pre-definite criterions of pulmonary injury (AU)

Role of probucol in inhibiting intimal hyperplasia after coronary stent implantation: a randomized study.

BACKGROUND: Oxygen-free radicals can stimulate smooth muscle cell proliferation and may therefore be involved in the genesis of in-stent restenosis. Thus, treatment with probucol, a potent antioxidant agent that has been shown to reduce restenosis after balloon angioplasty, may be an effective strategy to prevent intimal hyperplasia after stenting. METHODS: In a prospective double-blind study, 59 patients submitted to coronary stent implantation were randomly assigned to treatment with either probucol (1 g/d) or placebo, starting two weeks before the procedure and continued for 6 months. The primary end point was the intimal hyperplasia volume at 6 months measured by intravascular ultrasound (IVUS) imaging. RESULTS: Of the 59 randomized patients, 54 underwent successful stent implantation, completed the follow-up period, and underwent repeat angiography, 6.1 +/- 1.1 months after the procedure. Volumetric IVUS analysis revealed similar intimal hyperplasia volumes (403 +/- 26.7 mm3 for probucol vs 44.8 +/- 28.3 mm3 for placebo) and percent volume obstruction of the lumen (30.4% +/- 14.5% for probucol versus 30.7% +/- 17.2% for placebo) in both groups. In addition, quantitative coronary angiography showed no differences in late loss (1.0 +/- 0.8 mm vs 1.1 +/- 0.8 mm), loss index (0.5 +/- 0.4 for both groups), or angiographic restenosis rates (19.4% vs 18.5%) between the probucol and placebo groups, despite the observation of significant changes in the lipid profile and in the plasma antioxidant defenses in patients receiving probucol. CONCLUSIONS: Treatment with the antioxidant probucol failed to reduce neointimal formation after coronary stent implantation as assessed by IVUS volumetric analysis.

Avanços terapêuticos em cardiologia: parte 6; hipolipemiantes / Therapeutic development in cardiology

Os autores chamam a atençäo para a necessidade de as lipoproteínas LDL e VLDL serem reduzidas para níveis normais principalmente naqueles pacientes portadores de doença coronária ou que já submeteram-se à cirurgia de revascularizaçäo. Também enfatizam que ao lado da dieta, três säo as principais drogas usadas: gemfibrosil, para reduzir VLDL; inibidores da HMG GoA redutase para diminuir os níveis de LDL e o probucol como antioxidante

A controlled trial of pravastatin vs probucol in the treatment of primary hypercholesterolemia.

We compared the safety, tolerability and efficacy of the HMGCoA reductase inhibitor pravastatin and probucol in the treatment of patients with primary hypercholesterolemia using an active, drug controlled, double blind, randomized, double placebo design. Patients were included if LDL-C levels after a minimum of six weeks on an AHA phase I diet were greater than 150 mg/dL and triglycerides were less than 350 mg/dL. Included patients were randomly assigned to either pravastatin 40 mg pm or probucol 500 mg bi. They also received matching placebos for each drug. The active drug period lasted 16 weeks, during which the patients were seen at 4, 8, 12 and 16 weeks after baseline. There were no significant differences in baseline values between both treatment groups. Significantly lower values of total cholesterol and LDL-C were observed with pravastatin as compared to probucol. While a non significant increase of HDL-C was observed with pravastatin, a remarkable and statistically significant decrease was observed with probucol. A large dispersion of triglycerides levels was observed with both drugs and no statistically significant changes were demonstrated. Both pravastatin and probucol were well tolerated: only minimal clinical and laboratory changes, not considered to have been drug-related, were observed. No changes, considered drug-related, were observed in the cristalline lens. This study shows an overall superiority of pravastatin over probucol with significant larger decreases of total cholesterol and LDL-C and a better effect on HDL-C.

[Effects of lovastatin and probucol on lipoprotein fractions in patients with hypercholesterolemia. A Brazilian multicenter study]. / Efeito da lovastatina e do probucol sobre as frações lipídicas de indivíduos com hipercolesterolemia. Estudo multicêntrico brasileiro.

PURPOSE: The changes in lipoproteins induced by lovastatin (L) and probucol (P) were compared in patients with primary hypercholesterolemia. METHODS: After a six-week period of screening, during which patients were maintained on lipid-lowering diet, they were administered placebo for four weeks. Those patients, whose total cholesterol (TC) remained above 250 mg/dl were eligible for active treatment. Thirty-one patients were administered L and P for 12 weeks. The initial dosage of L was 20 mg daily and it was titrated up to 40 mg daily at the end of the fifth week of treatment, whenever total cholesterol levels remained above 200 mg/dl; P was administered at a dosage of 500 mg b.i.d. through 12 weeks. Lipid analyses (TC, triglycerides-Tg, high-density cholesterol (HDL-C) non HDL cholesterol, low-density cholesterol (LDL-C) very low-density cholesterol (VLDL-C) and the ratios CT/HDL-C and laboratory safety measurements were performed during placebo period and at the end of the 5th and 12th weeks of active treatment. Clinical and ophthalmological evaluations were performed and eventual adverse reactions were recorded on different occasions. RESULTS: 1) L induced decrease of TC, LDL-C/HDL-C of 27.9, 34.1, 32.2, 30.9 and 36.5% respectively. These reductions were significantly more pronounced than those induced by P (21.7, 23.8, 24.5, 11.3 and 13.4% respectively); 2) L induced an increase of HDL-C of 6.8%, while P induced a reduction of HDL-C of 6.9%; 3) 54.8% and 51.6% of the patients treated with L showed reductions of the ratios TC/HDL-C and LDL-C/HDL-C respectively. The patients who were administered P showed decrease in those indices of 15.7% and 13.1% respectively; 4) L was associated with 77.4% and 77.3% of excellent and good responses for TC and LDL-C. Regular and poor responses were more frequently observed during the treatment with P (39.4% each); 5) the incidence of adverse reactions was low and tolerability was considered good for both drugs. CONCLUSION: Lovastatin was more effective in the reduction of atherogenic lipoprotein fraction and in the increase of the protective one, with more pronounced reduction of the risk indices. They suggest that with the administration of L, that leads to an appropriate normalization of TC and LDL-C levels, greater benefits on morbidity and mortality of coronary disease can be achieved.

Efeito da lovastina e do probucol sobre as fraçöes lipídicas de indivíduos com hipercolesterolemia: estudo multicêntrico brasileiro / Effects of lovastatin and probucol on lipoprotein fractions in patients with primary hypercholesterolemia: a Brazilian multicenter study

Objetivo Comparar efeitos da administração de lovastatina e de probucol nas frações lipoprotéicas em indivíduos com hipercolesterotemia primária. Métodos Sessenta e nove pacientes que mantidos com dieta adequada e por quatro semanas sob uso de placebo (PLAC) permaneceram com colesterolemia total (CT) acima de 250 mg/dl. Lovastatina foi administrada a 31 pacientes na dose de 20 mg/dia, sendo aumentada para 40 mg/dia se ao final da 5a semana de tratamento os valores da CT se mantivessem acima de 200 mg/dl. Probucol prescrito a 38 pacientes na dose de 500 mg, duas vezes ao dia. O estudo foi realizado por 12 semanas. Dosagens de colesterolemia total (CT), trigliceridemia (TG), HDL-C, colesterol não HDL, LDL-C, VLDL-C e relações CT/ HDL-C e LDL-C/HDL-C e exames laboratoriais de controle foram feitos em PLAC, na 5a e 12a semanas de tratamento. Foram realizados também exames clínico e oftalmológico e anotados os eventuais efeitos adversos. Resultados A lovastatina provocou reduções de CT, LDL-C, colesterol não HDL e das relações CT/HDL-C e LDL-C/HDL-C respectivamente de 27,9,34,1,3,2,30,9 e 36,5%, significativamente mais acentuadas que as induzidas por probucol, (respectivamente 21,7, 23,8, 24,5, 11,3 e 13,4%); a lovastatina foi responsável pela elevação dos valores de HDL-C em 6,8%, enquanto que probucol provocou redução de 6,9%; 5,8% e 51,6% dos sob uso de lovastatina tiveram respectivamente redução das relações CT/HDL-C e LDL-C/HDL-C. Sob efeito de probucol, essas reduções ocorreram, respectivamente, em 15,7% e 13,1%; a lovastatina foi responsável por 77,4% e 77,3% das respostas ótimas e boas para CT e LDL-C. As respostas regulares e precárias foram mais freqüentemente observadas com o uso do probucol (39,4% cada); a freqüência dos efeitos adversos foi baixa e a tolerância satisfatória para as duas drogas. Conclusão A lovastatina foi mais eficaz para a redução dos níveis sangüíneos das frações aterogênicas e para a elevação da fração protetora, com redução mais acentuada dos índices de risco. Com seu uso, permitindo atingir mais facilmente os níveis ideais de CT e LDL-C, deverá ocorrer maior benefício sobre a morbidade e mortalidade por doença arterial coronariana

Purpose The changes in lipoproteins induced by lovastatin (L) and probucol (P) were compared in patients with primary hypercholesterolemia. Methods—After a six-week period of screening, during which patients were maintained on lipid-lowering diet, they were administered placebo for four weeks. Those patients. whose total cholesterol (TC) remained above 250 mg/dl were eligible for active treatment. Thirty-one patients were administered L and P for 12 weeks. The initial dosage of L was 20 mg daily and it was titrated up to 40 mg daily at the end of the fifth week of treatment, whenever total cholesterol levels remained above 200 mg/dl; P was administered at a dosage of 500 mg b.i.d. through 12 weeks. Lipid analyses (TC, triglycerides-Tg, high-density cholesterol (HDL-C) non HDL cholesterol, low-density cholesterol (LDL-C) very lowdensity cholesterol (VLDL-C) and the ratios CT/HDL-C and laboratory safety measurements were performed during placebo period and at the end of the 5th and 12th weeks of active treatment. Clinical and ophthalmological evaluations were performed and eventual adverse reactions were recorded on different occasions. Results—1) L induced decrease of TC, LDL-C/HDL-C of 27.9,34.1,32.2,30.9 and 36.5% respectively. These reductions were significantly more pronounced than those induced by P (21.7, 23.8, 24.5, 11.3 and 13.4% respectively); 2) L induced an increase of HDL-C of 6.8%, while P induced a reduction of HDL-C of 6.9%; 3) 54.8% and 51.6 % of the patients treated with L showed reductions of the ratios TC/HDL-C and LDL-C/HDL-C respectively The patients who were administered P showed decrease in those indices of 15.7% and 13.1% respectively; 4) L was associated with 77.4% and 77.3% of excellent and good responses for TC and LDL-C. Regular and poor responses were more frequently observed during the treatment with P (39.4% each); 5) the incidence of adverse reactions was low and tolerability was considered good for both drugs. Conclusion Lovastatin was more effective in the reduction of atherogenic lipoprotein fraction and in the increase of the protective one, with more pronounced reduction of the risk indices. They suggest that with the administration of L, that leads to an approapriate normalization of TC and LDL-C levels, greater benefits on morbidity and mortality of coronary disease can be achieved

[Pravastatin vs. probucol in the treatment of hypercholesterolemia. A double-blind study]. / Pravastatina vs. probucol en el tratamiento de la hipercolesterolemia. Estudio doble ciego.

This 16-week, double-blind study compared the efficacy and safety of pravastatin, a new HMG-CoA reductase inhibitor, with probucol in the treatment of hyperlipidemia in 26 patients at the Instituto Nacional de Cardiología "Ignacio Chávez" in Mexico City. Patients had to have a low-density lipoprotein-cholesterol (LDL-C) level in the 75th (or greater) percentile for age and sex greater than 150 mg/ on 2 occasions, and a triglyceride level less than 350 mg/dl. The patients, aged 21 to 75 years, were randomly assigned to receive either pravastatin, 40 mg once daily at bedtime (n = 15), or probucol, 500 mg twice daily (n = 11). Complete lipid profiles were obtained at 4-week intervals. By the end of the study, mean changes in total cholesterol (CT) and LDL-C in the pravastatin group were -28% and -37%, respectively, p less than 0.001 vs baseline. In the pravastatin group, there was a mean increment in HDL-cholesterol (HDL-C) of 9% and consequently a significant reduction in the LDL-C/HDL-C ratio. However, in the probucol group HDL-C levels dropped -21%, p less than 0.01, and no significant change in the LDL-C/HDL-C ratio was observed, accounting for the significant difference in LDL-C/HDL-C ratios between the 2 groups. Both drugs were well tolerated. One pravastatin patient discontinued because of adverse effects (nausea/vomiting and mild muscle pain). These results suggest that once daily administration of pravastatin is an effective therapy for hypercholesterolemia and that it produces a more favorable response in LDL-C/HDL-C ratio than probucol.