Probucol attenuates NF-κB/NLRP3 signalling and augments Nrf-2 mediated antioxidant defence in nerve injury induced neuropathic pain.

Neuroinflammation is one of the most significant pathological drivers following nerve injury which along with immune cell activation, oxidative stress and other associated molecular mechanisms contribute to development of neuropathic pain characterized by hyperalgesia and allodynia. In the current study we have investigated the pharmacological effect of probucol (prb) using chronic constriction injury (CCI) of sciatic nerve induced neuropathic pain (NP) model in rats. CCI of sciatic nerve resulted in marked decrease in pain threshold along with perturbations in anti-oxidant defence, enhanced inflammatory mediators and abnormal foot posture. Administration of prb at the doses of 8 and 16 mg/kg, p.o. for 14 days significantly attenuated the behavioural, biochemical and functional deficits following CCI of sciatic nerve. To further explore the molecular mechanisms of prb, we assessed the post treatment levels of inflammatory and oxidative stress markers like NLRP3 inflammasome, NF-κB and associated proinflammatory molecules such as IL-1 ß, TNF-α & IL-6 along with Nrf-2 and HO-1. Our findings demonstrated that CCI induced changes in levels of these markers were dose dependently reversed by administration of prb. Of note, at molecular level the elevated expression of transcription factors such as NF-κB which is crucial for Nlrp3 activation and diminished levels of Nrf-2 were manifested following CCI induction, these changes were markedly reversed with 14 days treatment of prb at both the doses. Our findings highlighted the dual pharmacological effect of prb, anti-inflammatory and anti-oxidant via modulation of NF-κB/NLRP3 signalling and Nrf-2 pathway in attenuation of CCI of sciatic nerve induced NP.

Ten-year clinical outcomes of polymer-free versus durable polymer new-generation drug-eluting stent in patients with coronary artery disease with and without diabetes mellitus : Results of the Intracoronary Stenting and Angiographic Results: Test Efficacy of Sirolimus- and Probucol- and Zotarolimus-Eluting Stents (ISAR-TEST 5) trial.

BACKGROUND: Very long-term outcomes according to diabetic status of patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) with new-generation drug-eluting stents (DES) are scant. Both, the durable polymer zotarolimus-eluting stent (DP-ZES), the first DES to gain FDA-approval for specific use in patients with diabetes mellitus, and the polymer-free sirolimus- and probucol-eluting stent (PF-SES), with a unique design that enables effective drug release without the need of a polymer offer the potential to enhance clinical long-term outcomes especially in patients with diabetes mellitus. METHODS: We investigate 10-year clinical outcomes of the prespecified subgroups of patients with and without diabetes mellitus, randomly assigned to treatment with PF-SES versus DP-ZES in the ISAR-TEST 5 trial. The primary endpoint of interest was major adverse cardiac events (MACE), defined as the composite of all-cause death, any myocardial infarction or any revascularization. Further endpoints of interest were cardiac death, myocardial infarction related to the target vessel and target lesion revascularization as well as the individual components of the primary composite endpoint and the incidence of definite or probable stent thrombosis at 10 years. RESULTS: This analysis includes a total of 3002 patients randomly assigned to PF-SES (n = 2002) or DP-ZES (n = 1000). Prevalence of diabetes mellitus was high and comparable, 575 Patients (28.7%) in PF-SES group and 295 patients (29.5%) in DP-ZES group (P = 0.66). At 10 years 53.5% of patients with diabetes mellitus and 68.5% of patients without diabetes mellitus were alive. Regarding major adverse cardiac events, PF-SES as compared to DP-ZES showed comparable event rates in patients with diabetes mellitus (74.8% vs. 79.6%; hazard ratio 0.86; 95% CI 0.73-1.02; P = 0.08) and in patients without diabetes (PF-SES 62.5% vs. DP-ZES 62.2%; hazard ratio 0.99; 95% CI 0.88-1.11; P = 0.88). CONCLUSION: At 10 years, both new-generation DES show comparable clinical outcome irrespective of diabetic status or polymer strategy. Event rates after PCI in patients with diabetes mellitus are considerable higher than in patients without diabetes mellitus and continue to accrue over time. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00598533, Registered 10 January 2008, https://clinicaltrials.gov/ct2/show/NCT00598533?term=NCT00598533 Kaplan-Meier estimates of endpoints of interest for patients with vs. without diabetes mellitus treated with PF-SES vs. DP-ZES. Bar graphs: Kaplan-Meier estimates as percentages. PF-SES: polymer-free sirolimus-eluting stent; DP-ZES: durable polymer zotarolimus-eluting stent; DM: diabetes mellitus. Comparison of event rates of individual endpoints in patients with and without diabetes mellitus treated with PF-SES vs. DP-ZES all without statistically significant differences. Comparison of event rates of individual endpoints in overall patients with vs. without diabetes mellitus significantly different (P ≤ 0.01 for all comparisons).

Probucol Trial for Secondary Prevention of Atherosclerotic Events in Patients with Coronary Heart Disease (PROSPECTIVE).

AIMS: Although intensive statin therapy reduced cardiovascular risks, cardiovascular events have not been completely prevented. Probucol is a potent antioxidant and reduces tendon xanthomas in familial hypercholesterolemia patients despite reduction of high-density lipoprotein (HDL)-cholesterol (HDL-C). We investigated whether probucol can reduce cardiovascular events on top of conventional lipid-lowering therapy in patients with coronary heart disease (CHD). METHODS: PROSPECTIVE is a multicenter, randomized, prospective study that recruited 876 Japanese patients with CHD and dyslipidemia with a low-density lipoprotein (LDL)-cholesterol (LDL-C) level of ≥ 140 mg/dL without medication or those treated with lipid-lowering drugs. Lipid-lowering agents were administered during the study period in the control group (n=438), and probucol 500 mg/day was added to lipid-lowering therapy in the probucol group (n=438). Patients were randomly assigned to two treatment groups by adjusting the LDL-C level and presence of diabetes and hypertension and followed up for more than 3 years. The primary end point was a composite of cerebrovascular and cardiovascular events (cardiovascular disease death including sudden death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, hospitalization for heart failure, or coronary revascularization). The secondary end point was carotid intima-media thickness in a subset of patients. RESULTS: The incidence of the primary end point showed a trend to be lower in the probucol group compared with that in the control group despite reduced HDL-C without serious adverse events. Anti-atherogenic effects of probucol may be attributed to its potent antioxidative function and enhancement of reverse cholesterol transport. CONCLUSION: Since there was no statistical significance between the probucol and control groups despite a marked reduction of HDL-C, further studies on the clinical outcomes of probucol on top of conventional therapy may be necessary in the future (UMIN000003307).

Effect of Probucol and/or Cilostazol on Carotid Intima Media Thickness in Patients with Coronary Heart Disease: A Randomized, Multicenter, Multinational Study.

AIM: In a prospective randomized multinational open blinded endpoint study, the long-term effects of probucol or probucol and cilostazol with statin on carotid mean intima media thickness (IMT) were evaluated for the first time. METHODS: Hypercholesterolemic patients with coronary artery disease were randomized to three groups and received study drugs for 3 years: the control with statin alone; the probucol group with statin and probucol; and the combo group with statin, probucol, and cilostazol. Primary efficacy endpoint was changes of mean carotid IMT at 3 years. Biomarkers, major adverse cerebro-cardiovascular events (MACCEs) and safety were secondary endpoints. RESULTS: Two hundred eighty-one patients were randomized into three groups. All three groups showed significant regression of carotid IMT at 3 years compared with baseline. Decrease in mean carotid IMT was significantly greater in the combo group than in the control group at 1 year. However, there were no significant differences in changes of mean carotid IMT between groups at 3 years (control; -0.12±0.36 mm vs. probucol; -0.11 ±0.32 mm vs. combo; -0.16±0.38 mm). MACCEs were frequent in the control group, but the difference was not significant (control; 10.8% vs. probucol; 4.4% vs. combo; 6.9%, p=0.35). Probucol and cilostazol were well tolerated in long-term treatment without serious drug-related adverse reactions. CONCLUSION: Probucol or probucol and cilostazol with statin did not reduce carotid IMT in comparison with statin alone in this study. However, the clinical outcome of probucol-based treatment with current standard statin treatment may need further studies.

Analysis of the effect of probucol-mecobalamin tablets combination on oxidative stress in patients with diabetic peripheral neuropathy.

OBJECTIVE: This research aimed to observe the effect of probucol combined with mecobalamin tablets on oxidative stress in patients with diabetic peripheral neuropathy (DPN). METHODS: In this prospective study, 104 patients with DPN who were treated in our hospital were included, from August 2018 to January 2020. They were divided into groups of combination (n = 52) and control (n = 52) by using a random number table. All patients took mecobalamin tablets after meals for 3 months (1 tablet/time, 3 times/d). On this basis, patients in the combination group took probucol for 3 months (4 tablets/time, 2 times/d). The observation indicators were the Toronto Clinical Scoring System (TCSS)(symptom, sensory, and reflex scores), nerve conduction velocity[sensory nerve conduction velocity (SNCV) and motor nerve conduction velocity(MNCV) of the common peroneal nerve and median nerve], oxidative stress indicators[superoxide dismutase(SOD), malondialdehyde(MDA), glutathione peroxidase(GSH-Px) and catalase(CAT)], clinical efficacy and adverse reactions. RESULTS: There was no significant difference in the symptom scores, sensory scores, reflex scores, and total scores between the two groups before treatment (p > 0.05), while these four indicators of the combination group were significantly lower than that in the control group after treatment (p < 0.05). These four indicators of the two groups after treatment were significantly lower than before treatment (p < 0.05). There was no significant difference in the SNCV and NMCV of the common peroneal nerve and median nerve between the two groups before treatment (p > 0.05), while the indicators of the combination group were significantly higher than that of the control group (p < 0.05) after treatment, and these indicators of the two groups after treatment were significantly higher than that before treatment (p < 0.05). There was no significant difference in SOD, MDA, GSH-Px, and CAT between the two groups before treatment (p > 0.05). After treatment, the SOD, GSH-Px, and CAT in the combination group were significantly higher than that in the control group (p < 0.05), while the MDA in the combination group was significantly lower than that in the control group (p < 0.05). After treatment, the SOD, GSH-Px, and CAT in the two groups were significantly higher than that before treatment (p < 0.05), while the MDA was lower (p < 0.05). The clinical efficacy of the combination group was significantly better than that of the control group (94.23 % vs 78.85 %, p＜0.05) after treatment. There was no significant difference in the incidence of total adverse reactions between the two groups (3.85 % vs 5.77 %, p > 0.05). CONCLUSION: The therapeutic effect of probucol combined with mecobalamin tablets for patients with DPN was significant, which could effectively improve the oxidative stress response of patients and was worthy of clinical promotion.

Bile acid bio-nanoencapsulation improved drug targeted-delivery and pharmacological effects via cellular flux: 6-months diabetes preclinical study.

The antilipidemic drug, probucol (PB), has demonstrated potential applications in Type 2 diabetes (T2D) through its protective effects on pancreatic ß-cells. PB has poor solubility and bioavailability, and despite attempts to improve its oral delivery, none has shown dramatic improvements in absorption or antidiabetic effects. Preliminary data has shown potential benefits from bile acid co-encapsulation with PB. One bile acid has shown best potential improvement of PB oral delivery (ursodeoxycholic acid, UDCA). This study aimed to examine PB and UDCA microcapsules (with UDCA microcapsules serving as control) in terms of the microcapsules' morphology, biological effects ex vivo, and their hypoglycemic and antilipidemic and anti-inflammatory effects in vivo. PBUDCA and UDCA microcapsules were examined in vitro (formulation studies), ex vivo and in vivo. PBUDCA microcapsules exerted positive effects on ß-cells viability at hyperglycemic state, and brought about hypoglycemic and anti-inflammatory effects on the prediabetic mice. In conclusion, PBUDCA co-encapsulation have showed beneficial therapeutic impact of dual antioxidant-bile acid effects in diabetes treatment.

Polymer-functionalized mesoporous carbon nanoparticles on overcoming multiple barriers and improving oral bioavailability of Probucol.

Oral administration of nanoparticles is extremely limited due to the two processes of mucus permeation and epithelial absorption, which requires completely opposite surface properties of the nanocarriers. To tackle the contradiction, we developed a rational strategy to modify the surface of mesoporous carbon nanoparticles with chitosan concealed by a hydrophilic N-(2-hydroxypropyl) methacrylamide copolymer (pHPMA) layer. Probucol (PB) with the low poor permeability and solubility was loaded in optimal nanocarriers to realize the high loading efficacy and controlled release. The pHPMA polymer is a hydrophilic "mucus-inert" material, which could be dissociable from the surface of nanoparticles in the mucus, thus promoting their mucus permeation and causing exposure of chitosan in transepithelial transport. The swelling effect of chitosan under acidic conditions allowed regulation of PB release behavior. In conclusion, the mucus-permeable nanocarrier could effectively overcome multiple gastrointestinal absorption barriers and the oral bioavailability of PB-loaded HCMCN was 2.76-fold that of commercial preparation.

Bile acid-polymer-probucol microparticles: protective effect on pancreatic ß-cells and decrease in type 1 diabetes development in a murine model.

Studies in our laboratory have shown potential applications of the anti-atherosclerotic drug probucol (PB) in diabetes due to anti-inflammatory and ß-cell protective effects. The anti-inflammatory effects were optimized by incorporation of the anti-inflammatory bile acid, ursodeoxycholic acid (UDCA). This study aimed to test PB absorption, tissue accumulation profiles, effects on inflammation and type 1 diabetes prevention when combined with UDCA. Balb/c mice were divided into three equal groups and gavaged daily PB powder, PB microcapsules or PB-UDCA microcapsules for one week, at a constant dose. Mice were injected with a single dose of intraperitoneal/subcutaneous alloxan to induce type-1 diabetes and once diabetes was confirmed, treatments were continued for 3 days. Mice were euthanized and blood and tissues collected for analysis of PB and cytokine levels. The PB-UDCA group showed the highest PB concentrations in blood, gut, liver, spleen, brain, and white adipose tissues, with no significant increase in pancreas, heart, skeletal muscles, kidneys, urine or feces. Interferon gamma in plasma was significantly reduced by PB-UDCA suggesting potent anti-inflammatory effects. Blood glucose levels remained similar after treatments, while survival was highest among the PB-UDCA group. Our findings suggest that PB-UDCA resulted in best PB blood and tissue absorption and reduced inflammation.

Co-treatment with probucol does not improve lung pathology in hydroxypropyl-ß-cyclodextrin-treated Npc1-/- mice.

We previously reported the altered pulmonary function and pathology found in the mouse model of infantile Niemann-Pick C1 disease, the Npc1-/- mouse. Despite its salutary properties on brain and liver parameters, we did not find efficacious effects of hydroxypropyl-ß-cyclodextrin (HPBCD) on pulmonary pathology. Since we had previously shown the beneficial effects of probucol on the somatic phenotype in the Npc1-/- mice, we have now studied the effects of combined therapy with HPBCD and probucol on the lung with mostly negative results. Body weight and lung weight for body weight were increased in parallel while inspiratory capacity for body weight was markedly decreased. Other physical, biochemical, and pulmonary function parameters were not much changed. There were trends towards improved lung elastance (p = 0.09) and compliance (p = 0.07).

Probucol Self-Emulsified Drug Delivery System: Stability Testing and Bioavailability Assessment in Human Volunteers.

BACKGROUND: Self-Emulsifying Drug Delivery System (SEDDS), if taken orally, is expected to self-emulsify in GIT and improve the absorption and bioavailability. Probucol (PB) is a highly lipophilic compound with very low and variable bioavailability. OBJECTIVE: The objectives of this study were to examine the stability and conduct bioavailability of the prepared Probucol Self-Emulsified Drug Delivery System (PBSEDDS) in human volunteers. METHODS: The methods included preparation of different PBSEDDS using soybean oil (solvent), Labrafil M1944CS (surfactant) and Capmul MCM-C8 (co-surfactant). The formulations were characterized in vitro for spontaneity of emulsification, droplet size, turbidity and dissolution in water after packing in HPMC capsules. The optimized formulations were evaluated for stability at different storage temperatures and human bioavailability compared with the drug dissolved in soybean oil (reference). RESULTS: The results showed that formulations (F1-F4) were stable if stored at 20 °C. The mean (n=3) pharmacokinetic parameters for stable formulations were: The Cmax, 1070.76, 883.16, 2876.43, 3513.46 and 1047.37 ng/ml; the Tmax, 7.93, 7.33, 3.96, 3.67 and 4.67 hr.; the AUC (0-t), 41043.41, 37763.23, 75006.26, 46731.36 and 26966.43 ng.hr/ml for F1, F2, F3, F4 and reference, respectively. The percentage relative bioavailability was in this order: F3> F4> F1> F2>. CONCLUSION: In conclusion, the PBSEDDS formulations were stable at room temperature. F4 showed the highest Cmax and the shortest Tmax. All the formulations showed significant enhancement of bioavailability compared with the reference. The results illustrated the potential use of SEDDS for the delivery of probucol hydrophobic compound.

Eudragit®-based microcapsules of probucol with a gut-bacterial processed secondary bile acid.

AIM: Deoxycholic acid (DCA) has improved gliclazide oral absorption, while Eudragit® (ED) polymers have improved formulation stability of antidiabetic drugs. The aim of the study is to test if DCA and ED encapsulation will optimize the release and stability of the potential antidiabetic drug probucol (PB). MATERIALS & METHODS: The PB formulations were prepared using ED polymers and DCA, and formulations were analyzed for their rheological and biological properties. RESULTS: Rheological properties and size distribution were similar among all groups. ß-cell survival and biological activities were best with NM30D microcapsules. The inflammatory profile and oxidative stress effects of microcapsules remained similar among all groups. CONCLUSION: ED NM30D and DCA incorporation can exert positive and stabilizing effects on PB oral microcapsules.

Sodium alginate capsulation increased brain delivery of probucol and suppressed neuroinflammation and neurodegeneration.

AIM: To enhance the bioavailability and brain uptake of probucol and examine whether it attenuates neuroinflammation and neurodegeneration by utilizing a sodium alginate nanoencapsulation technique. MATERIALS & METHODS: Wild-type mice were given either low-fat standard chow, high-fat (HF) diet to induce neuroinflammation and neurodegeneration, HF diet supplemented with nanocapsuled probucol at a concentration of 0.1% (w/w), HF diet supplemented with noncapsulated probucol at the same concentration of 0.1%, or HF diet supplemented with noncapsulated probucol at higher concentration (1%) for 24 weeks. RESULTS & CONCLUSION: The nanoencapsulation increased the plasma and brain concentration of probucol significantly compared with the mice that was given the same dosage of probucol without capsulation, and significantly suppressed the neuroinflammation and neurodegeneration.

Antidepressant Effects of Probucol on Early-Symptomatic YAC128 Transgenic Mice for Huntington's Disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a trinucleotide expansion in the HD gene, resulting in an extended polyglutamine tract in the protein huntingtin. HD is traditionally viewed as a movement disorder, but cognitive and neuropsychiatric symptoms also contribute to the clinical presentation. Depression is one of the most common psychiatric disturbances in HD, present even before manifestation of motor symptoms. Diagnosis and treatment of depression in HD-affected individuals are essential aspects of clinical management in this population, especially owing to the high risk of suicide. This study investigated whether chronic administration of the antioxidant probucol improved motor and affective symptoms as well as hippocampal neurogenic function in the YAC128 transgenic mouse model of HD during the early- to mild-symptomatic stages of disease progression. The motor performance and affective symptoms were monitored using well-validated behavioral tests in YAC128 mice and age-matched wild-type littermates at 2, 4, and 6 months of age, after 1, 3, or 5 months of treatment with probucol (30 mg/kg/day via water supplementation, starting on postnatal day 30). Endogenous markers were used to assess the effect of probucol on cell proliferation (Ki-67 and proliferation cell nuclear antigen (PCNA)) and neuronal differentiation (doublecortin (DCX)) in the hippocampal dentate gyrus (DG). Chronic treatment with probucol reduced the occurrence of depressive-like behaviors in early- and mild-symptomatic YAC128 mice. Functional improvements were not accompanied by increased progenitor cell proliferation and neuronal differentiation. Our findings provide evidence that administration of probucol may be of clinical benefit in the management of early- to mild-symptomatic HD.

The biological effects of the hypolipidaemic drug probucol microcapsules fed daily for 4 weeks, to an insulin-resistant mouse model: potential hypoglycaemic and anti-inflammatory effects.

Probucol (PB) is an hypolipidaemic drug with potential antidiabetic effects. We showed recently using in vitro studies that when PB was incorporated with stabilising lipophilic bile acids and microencapsulated using the polymer sodium alginate, the microcapsules showed good stability but poor and irregular PB release. This suggests that PB microcapsules may exhibit better release profile and hence better absorption, if more hydrophilic bile acids were used, such as ursodeoxycholic acid (UDCA). Accordingly, this study aimed to produce PB-UDCA microcapsules and examine PB absorption and antidiabetic effects in our mouse-model of insulin-resistance and diabetes (fed high-fat diet; HFD). The study also aimed to examine the effects of the microcapsules on the bile acid profile. Healthy mice (fed low-fat diet; LFD) were used as control. Seventy mice were randomly allocated into seven equal groups: LFD, HFD given empty microcapsules, HFD given metformin (M), HFD given standard-dose probucol (PB-SD), HFD given high-dose probucol (PB-H), HFD given UDCA microcapsules and HFD given PB-UDCA microcapsules. Blood glucose (BG), inflammatory biomarkers (TNF-α, IFN-γ, IL-1ß, IL-6, IL-10, IL-12 and IL-17), plasma cholesterol, non-esterified fatty acids and triglycerides were analysed together with plasma bile acid and probucol concentrations. PB-UDCA microcapsules reduced BG in HFD mice, but did not reduce inflammation or improve lipid profile, compared with positive control (HFD) group. Although PB-UDCA microcapsules did not exert hypolipidaemic or antiinflammatory effects, they resulted in significant hypoglycaemic effects in a mouse model of insulin resistance, which suggests potential applications in insulin-resistance and glucose haemostasis.

Propensity score matched all comers population treated with ultra-thin strut bare metal and sirolimus-probucol coated drug-eluting stents of identical stent architecture.

OBJECTIVE: The objective of this study was to compare the safety and efficacy of a polymer-free sirolimus coated, ultrathin strut drug eluting stent (PF-SES) to its uncoated bare-metal stent (BMS) platform of identical stent architecture. BACKGROUND: Recently published randomized trials comparing BMS to DES with a focus on shortened dual-antiplatelet therapy reported incidences of stent thrombosis (ST) and bleeding complications (LEADERS FREE) in favor of drug eluting stents (DES). METHODS: Data of previously published large-sale, international, single-armed, multicenter, observational studies of ultra-thin PF-SES, and BMS were propensity score (PS) matched for selected lesion morphological and cardiovascular risk factors to compare target lesion revascularization (TLR), myocardial infarction, cardiac death, major adverse cardiac events (MACE), bleeding complications and ST rates. Primary endpoint in both studies was TLR at 9 months. RESULTS: At 9 months the rates of TLR was significantly lower in the PF-SES group as compared with patients treated with the BMS analogue of identical stent design (1.4% vs. 4.6%, P = 0.005). Likewise the 9-month MACE rates were lower in the PF-SES group (3.2% vs. 8.7%, P = 0.001) whereas there were no differences in the accumulated ST rates (0.5% vs. 1.5%, P = 0.109). Overall accumulated bleeding incidences (BARC 1-5) were not significantly different between PF-SES and BMS patients (1.8% vs. 2.7%, p = 0.388). CONCLUSIONS: PF-SES are superior over analogue BMS of identical stent architecture in daily clinical routine with lower rates of TLR and MACE in a PS-matched, unselected patient population without differences in accumulated ST rates and bleeding frequencies given the currently favored postprocedural comedication (ClinicalTrials.gov Identifier NCT02629575).

Effect of different polysorbates on development of self-microemulsifying drug delivery systems using medium chain lipids.

The primary objective of this study was to develop lipid-based self-microemulsifying drug delivery systems (SMEDDS) without using any organic cosolvents that would spontaneously form microemulsions upon dilution with water. Cosolvents were avoided to prevent possible precipitation of drug upon dilution and other stability issues. Different polysorbates, namely, Tween 20, Tween 40, Tween 60, and Tween 80, were used as surfactants, and Captex 355 EP/NF (glycerol tricaprylate/caprate) or its 1:1 mixture with Capmul MCM NF (glycerol monocaprylocaprate) were used as lipids. Captex 355-Tween-water ternary phase diagrams showed that oil-in-water microemulsions were formed only when the surfactant content was high (80-90%) and the lipid content low (10-20%). Thus, mixtures of Tweens with Captex 355 alone were not suitable to prepare SMEDDS with substantial lipid contents. However, when Captex 355 was replaced with the 1:1 mixture of Captex 355 and Capmul MCM, clear isotropic microemulsion regions in phase diagrams with sizes in the increasing order of Tween 20 < Tween 40 < Tween 60 < Tween 80 were obtained. Tween 80 had the most profound effect among all surfactants as microemulsions were formed with lipid to surfactant ratios as high as 7:3, which may be attributed to the presence of double bond in its side chain that increased the curvature of surfactant layer. Thus, lipid-surfactant mixtures containing 1:1 mixture of medium chain triglyceride (Captex 355) and monoglyceride (Capmul MCM) and as low as 30% Tween 80 were identified as organic cosolvent-free systems for the preparation of SMEDDS. Formulations with a model drug, probucol, dispersed spontaneously and rapidly upon dilution with water to form microemulsions without any drug precipitation.

Polymer-free dual drug-eluting stents evaluated in a porcine model.

BACKGROUND: Although drug-eluting stents have dramatically reduced the rates of restenosis and target lesion revascularization, they are associated with stent thrombosis (ST), a catastrophic event likely due to delayed endothelialization and chronic inflammation caused by the polymer and the metal scaffolds. To increase the safety and efficacy of stents, polymer-free dual drug-eluting stents (DDES) have been developed. METHODS: A total 160 stents (Bare-metal stents (BMS), polymer-free probucol stents (PrES), sirolimus-eluting stents (SES) and DDES) were randomly implanted in the coronary arteries of 80 pigs. 14, 28, 90 and 191 days after implantation, QCA and OCT evaluations were performed in 20 pigs respectively, and the arteries were harvested for scanning electron microscope (SEM), histomorphology, histopathology analyses and for the relative expression of CD31, CD34 and CD133 on mRNA and protein levels. RESULTS: At the 14-day time point, there were significant differences in the strut rate coverage (p = 0.011), with greater coverage in the PrES than in the SES group (53.2%vs. 20.3%, p = 0.002). As well, there were no significant differences in the expression of CD31, CD34 and CD133 between groups in mRNA and protein level. CONCLUSIONS: DDES were as safe as BMS and SES, but they did not further improve the endothelialization of the stented coronary arteries in the porcine model.

Five-year follow-up of polymer-free sirolimus- and probucol-eluting stents versus new generation zotarolimus-eluting stents in patients presenting with st-elevation myocardial infarction.

BACKGROUND: Patients with ST-segment elevation myocardial infarction (STEMI) undergoing drug-eluting stent (DES) implantation are at increased risk of late adverse events, partly explained by an exaggerated inflammatory reaction to durable-polymer stent coatings. OBJECTIVES: We sought to investigate whether implantation of polymer-free DES would reduce this risk. METHODS: In the ISAR-TEST 5 (the Intracoronary Stenting and Angiographic Results: Test Efficacy of Sirolimus- and Probucol- and Zotarolimus-Eluting Stents) trial, patients were randomly allocated to receive a polymer-free sirolimus- and probucol-eluting stent or a new generation durable-polymer zotarolimus-eluting stent. We analyzed late clinical outcomes in the subgroup of patients presenting with STEMI. The primary endpoint was the combined incidence of cardiac death, target vessel-related myocardial infarction or target lesion revascularization at 5 years. RESULTS: 311 patients with STEMI were randomized to receive sirolimus- and probucol-eluting stents (n = 215) or zotarolimus-eluting stents (n = 96). At 5 years, there was no difference in the incidence of the primary endpoint in patients treated with sirolimus- and probucol-eluting stents versus zotarolimus-eluting stents (18.3% versus 20.1% respectively, hazard ratio = 0.87, 95% CI, 0.50-1.51; P = 0.62). Rates of the individual components of the primary endpoint were also comparable in both groups. The incidence of definite/probable stent thrombosis was 1.4% versus 1.0% respectively (hazard ratio = 1.35, 95% CI, 0.14-12.94, P = 0.80). CONCLUSIONS: Long-term outcomes of patients with STEMI treated with polymer-free sirolimus- and probucol-eluting stents versus durable-polymer zotarolimus-eluting stents were similar. Stent thrombosis rates were low and comparable in both treatment groups, with no events beyond 12 months. CLINICAL TRIAL REGISTRATION: Registered at ClinicalTrials.gov (Identifier NCT 00598533) © 2016 Wiley Periodicals, Inc.