A randomized, double-blind, placebo-controlled phase 2 study to assess safety, tolerability, and efficacy of RT001 in patients with amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: RT001 is a deuterated synthetic homologue of linoleic acid, which makes membrane polyunsaturated fatty acids resistant to lipid peroxidation, a process involved in motor neuron degeneration in amyotrophic lateral sclerosis (ALS). METHODS: We conducted a randomized, multicenter, placebo-controlled clinical trial. Patients with ALS were randomly allocated to receive either RT001 or placebo for 24 weeks. After the double-blind period, all patients received RT001 during an open-label phase for 24 weeks. The primary outcome measures were safety and tolerability. Key efficacy outcomes included the ALS Functional Rating Scale (ALSFRS-R), percent predicted slow vital capacity, and plasma neurofilament light chain concentration. RESULTS: In total, 43 patients (RT001 = 21; placebo = 22) were randomized. RT001 was well tolerated; one patient required dose reduction due to adverse events (AEs). Numerically, there were more AEs in the RT001 group compared to the placebo group (71% versus 55%, p = 0.35), with gastrointestinal symptoms being the most common (43% in RT001, 27% in placebo, p = 0.35). Two patients in the RT001 group experienced a serious AE, though unrelated to treatment. The least-squares mean difference in ALSFRS-R total score at week 24 of treatment was 1.90 (95% confidence interval = -1.39 to 5.19) in favor of RT001 (p = 0.25). The directions of other efficacy outcomes favored RT001 compared to placebo, although no inferential statistics were performed. CONCLUSIONS: Initial data indicate that RT001 is safe and well tolerated. Given the exploratory nature of the study, a larger clinical trial is required to evaluate its efficacy.

An expanded access protocol of RT001 in amyotrophic lateral sclerosis-Initial experience with a lipid peroxidation inhibitor.

INTRODUCTION/AIMS: Lipid peroxidation is thought to play a biologically important role in motor neuron death in amyotrophic lateral sclerosis (ALS). 11,11 Di-deuterated linoleic ethyl ester (RT001) prevents lipid peroxidation in cellular and mitochondrial membranes. Herein we report on the use of RT001 under expanded access (EA). METHODS: We provided RT001 to patients with ALS via EA at a single site. The starting dose was 2.88 g/day, which was increased to to 8.64 g/day as tolerated. Participants were not eligible for alternative clinical trials. Participants were followed for adverse events and pharmacokinetic (PK) parameters were measured approximately 3 months after RT001 initiation. RESULTS: Sixteen participants received RT001 (5.6 ± 1.6 g/day; dose range, 1.92 to 8.64 g/day) for a mean period of 10.8 ± 7.1 months. After 3 months of treatment, PK studies showed that RT001 was absorbed, metabolized, and incorporated into red blood cell membranes at concentrations expected to be therapeutic based on in vitro models. The most common adverse events were gastrointestinal, including diarrhea, which occurred in 25% of the participants, and were considered possibly related to RT001. One participant (6%) discontinued due to an adverse event. Ten serious adverse events occurred: these events were recognized complications of ALS and none were attributed to treatment with RT001. DISCUSSION: RT001 was administered safely to a small group of people living with ALS in the context of an EA protocol. Currently, there is an ongoing randomized, double-blind, controlled study of RT001 in ALS.

Effect of a Novel Omega-3 and Omega-6 Fatty Acid Supplement on Dry Eye Disease: A 3-month Randomized Controlled Trial.

SIGNIFICANCE: Supplementing diet with a novel combination of omega-3 and omega-6 fatty acids significantly improved symptoms in extremely symptomatic participants with dry eye disease (DED). PURPOSE: This study aimed to determine the effect of daily intake of a novel combination of essential fatty acids on signs and symptoms of DED. METHODS: Participants with moderate to severe DED were enrolled in a prospective, randomized, double-masked parallel group study. Participants ingested either the treatment supplement containing omega-3 and omega-6 fatty acids (1200 mg eicosapentaenoic acid, 300 mg docosahexaenoic acid, 150 mg γ-linoleic acid) or the placebo (coconut and olive oil) daily for 3 months. To determine compliance, Omega-3 Index blood tests were conducted. At baseline and at 1 and 3 months, the following assessments were conducted: Ocular Surface Disease Index (OSDI) questionnaire and Symptom Assessment Questionnaire in Dry Eye, noninvasive tear breakup time, tear meniscus height, tear osmolarity, ocular redness, surface staining, Schirmer test, and meibography. RESULTS: Fifty participants (mean ± standard deviation baseline OSDI score, 52.2 ± 16.5) completed the study: 24 randomized to treatment and 26 randomized to placebo. Although there was an improvement in OSDI score at 3 months for both groups (treatment: -13.4 points, P = .003; placebo: -7.8 points, P = .02), participants with baseline OSDI scores >52 demonstrated an even larger significant improvement in symptoms with the treatment at 3 months compared with baseline (n = 13, -20.8 points, P = .002). There were no significant changes in any of the ocular assessments at 1 or 3 months (all P > .05). After 3 months, Omega-3 Index increased by 34% in the treatment group (baseline, 5.3 ± 0.8; 3 months, 8.0 ± 2.1; P < .001) and did not change in the placebo group (baseline, 4.8 ± 0.8; 3 months, 4.8 ± 0.6; P = .95). CONCLUSIONS: Supplementation with eicosapentaenoic acid, docosahexaenoic acid, and γ-linoleic acid resulted in a significant and clinically meaningful improvement of dry eye symptoms in extremely symptomatic participants with DED (OSDI ≥52).

Sequential Intercellular Delivery Nanosystem for Enhancing ROS-Induced Antitumor Therapy.

Despite recent advances in enhancing photodynamic therapy efficacy, high-efficiency reactive oxygen species (ROS)-based therapy approach, especially in malignancy tumor treatment, remains challenging. Relieving the hypoxia of tumor tissue has been considered to be an attractive strategy for enhancing ROS-based treatment effect. Nevertheless, it is frequently neglected that the hypoxic regions are usually located deep in the tumors and therefore are usually inaccessible. To address these limitations, herein we constructed a sequential intercellular delivery system (MFLs/LAOOH@DOX) that consists of a membrane fusion liposomes (MFLs) doped with linoleic acid hydroperoxide (LAOOH) in the lipid bilayer and antitumor doxorubicin (DOX) encapsulated inside. In this report, LAOOH, one of the primary products of lipid peroxidation in vivo, was selected as ROS-generated agent herein, which depends on Fe2+ rather than oxygen and other external stimuli to produce ROS. Upon the enhanced permeation and retention effect, MFLs/LAOOH@DOX first fused with tumor cell membranes in the perivascular region in synchrony with selective delivery of LAOOH into the plasma membrane and the on-demand intracellular release of DOX. By hitchhiking with extracellular vesicles, LAOOH, as a cell membrane natural ingredient, spread gradually to neighboring cells and throughout the entire tumor eventually. Combined with subsequent administration of nano Fe3O4, ROS was specifically generated on the tumor cell membrane by LAOOH throughout the tumor tissues. This study offers a new method to enhance ROS-based antitumor treatment efficiency.

Randomized, clinical trial of RT001: Early signals of efficacy in Friedreich's ataxia.

BACKGROUND: RT001 is a deuterated ethyl linoleate that inhibits lipid peroxidation and is hypothesized to reduce cellular damage and recover mitochondrial function in degenerative diseases such as Friedreich's ataxia. OBJECTIVE: To evaluate the safety, pharmacokinetics, and preliminary efficacy of RT001 in Friedreich's ataxia patients. DESIGN/METHODS: We conducted a phase I/II double-blind, comparator-controlled trial with 2 doses of RT001 in Friedreich's ataxia patients (9 subjects each cohort). Subjects were randomized 2:1 to receive either RT001 (1.8 or 9.0 g/day), or a matching dose of nondeuterated ethyl linoleate as comparator for 28 days. The primary endpoints were safety, tolerability, and pharmacokinetic analysis. Secondary endpoints included cardiopulmonary exercise testing and timed 25-foot walk. RESULTS: Nineteen patients enrolled in the trial, and 18 completed all safety and efficacy measurements. RT001 was found to be safe and tolerable, with plasma levels approaching saturation by 28 days. One subject with a low body mass index experienced steatorrhea taking a high dose and discontinued the study. Deuterated arachidonic acid (a brain-penetrant metabolite of RT001) was found to be present in plasma on day 28. There was an improvement in peak workload in the drug group compared to placebo (0.16 watts/kg; P = 0.008), as well as an improvement trend in peak oxygen consumption (change of 0.16 L/min; P = 0.116), and in stride speed (P = 0.15). CONCLUSIONS: RT001 was found to be safe and tolerable over 28 days, and improved peak workload. Further research into the effect of RT001 in Friedreich's ataxia is warranted. © 2018 International Parkinson and Movement Disorder Society.

Evening primrose oil and labour, is it effective? A randomised clinical trial.

The purpose of the present study was to evaluate the effects of evening primrose oil (EvPO) on the duration of pregnancy and labour. The study was performed as a triple blind placebo controlled randomised clinical trial on nulliparous low-risk women with a certain gestational age of 40 weeks of pregnancy and a Bishop score of less than 4. In the case group (EvPO group), EvPO capsules were administered, 1000 mg, twice daily, for 7 days, and in the control group, placebo was administered similarly. The women of the two groups were followed up to delivery. In total, 80 women finished the study (40 in each group). The women of the two groups did not have significant differences according to age, BMI, Bishop Score at the beginning of the study, gestational age at entering the study, employment status and education level, the number of capsules used and duration of using medications. There was no significant difference between the two groups according to gestational age at delivery, need for induction or augmentation of labour, duration of different stages of labour, neonatal weight and Apgar scores, and the indications for hospital admission. Impact statement What is already known on this subject? Evening primrose oil has been used for the treatment of systemic disorders, which are accompanied with chronic inflammation such as atopic dermatitis, rheumatoid arthritis and psoriasis. Also, it has been proposed for some women's health conditions including breast pain (mastalgia), symptoms of premenstrual syndrome and menopausal symptoms, cervical ripening and induction or augmentation of labour. What do the results of this study add? Evening primrose oil does not have any impact on Bishop Score and the duration of different stages of labour. What are the implications of these findings for clinical practice and/or further research? According to the present study and the other performed studies, there is not enough evidence confirming effectiveness of Evening primrose oil for cervical ripening and duration of labour. It is suggested that pending further data its usage should be limited to experimental RCTs and its use in clinical practice should be prevented. Also, different routes of administration and different dosages should be investigated.

The Use of Evening Primrose Oil for Cervical Ripening in Low-Risk Women with Term Pregnancy: A Randomized Double-Blinded Controlled Trial.

BACKGROUND: Several methods have been developed for cervical ripening. The data regarding the efficiency of evening primrose oil (EPO) are inconsistent. The purpose of this study was to investigate the outcomes of EPO use on cervical ripening in low-risk women with term pregnancy. PATIENTS AND METHODS: Low-risk term pregnant women referred to the obstetrics clinic of Imam Hossein Hospital in Tehran who were eligible according to the inclusion were randomized either to the case or control group. The case group received 1,000 mg vaginal EPO capsule, and the other group received a vaginal placebo capsule daily, similar to the original drug. The primary outcome was Bishop score, while the duration of labor phases and the inducing procedures were the secondary outcomes. RESULTS: Forty-eight participants were randomized to each group and were considered for data analysis. Although Bishop score was not statistically different before the intervention, it was significantly higher in case group compared to the placebo group after the intervention (EPO = 5.83 ± 1.68, placebo = 5.19 ± 1.52, p value = 0.002). Four participants in the case group and two in the control group underwent cesarean section (p value = 0.677). The need for labor induction was significantly higher in the placebo group than EPO group (oxytocin injection: 10.4% vs. 31.3%, p value = 0.012, amniotomy: 75% vs. 41.7, p value = 0.001). CONCLUSION: The vaginal use of EPO could be considered as a safe and efficient approach for cervical ripening in low-risk term pregnant women.Es wurden verschiedene Methoden zur Zervixreifung entwickelt. Die Daten zur Wirksamkeit von Nachtkerzenöl (evening primrose oil, EPO) sind uneinheitlich. Mit dieser Studie sollen die Ergebnisse der Anwendung von EPO zur Zervixreifung bei Frauen mit niedrigem Risiko und termingerechter Schwangerschaft untersucht werden.Schwangere Frauen mit niedrigem Risiko und termingerechter Schwangerschaft, die in die Geburtsklinik des Imam-Hossein-Krankenhauses in Teheran eingewiesen wurden und gemäss den Einschlusskriterien für die Teilnahme infrage kamen, wurden randomisiert der Fall- oder der Kontrollgruppe zugewiesen. Die Fallgruppe erhielt 1.000 mg EPO als Vaginalkapseln, während die andere Gruppe täglich eine vaginale Placebokapsel erhielt, die dem Originalpräparat ähnelte. Primäres Zielkriterium war der Bishop-Score und sekundäre Zielkriterien waren die Dauer der Wehenphasen sowie die Verfahren zur Geburtseinleitung.Jeder Gruppe wurden randomisiert 48 Teilnehmerinnen zugewiesen und bei der Datenanalyse berücksichtigt. Während vor der Intervention kein statistisch signifikanter Unterschied im Bishop-Score bestand, fiel dieser nach der Intervention in der Fallgruppe signifikant höher aus als in der Placebogruppe (EPO = 5,83 ± 1,68, Placebo = 5,19 ± 1,52, p-Wert = 0,002). Bei vier Teilnehmerinnen in der Fallgruppe und zwei in der Kontrollgruppe wurde ein Kaiserschnitt durchgeführt (p-Wert = 0,677). Die Notwendigkeit einer Weheneinleitung war in der Placebogruppe signifikant höher als in der EPO-Gruppe (Oxytocin-Injektion: 10,4% vs. 31,3%, p-Wert = 0,012, Amniotomie: 75% vs. 41,7%, p-Wert = 0,001).Die vaginale Anwendung von EPO kann als sicherer und wirksamer Ansatz zur Zervixreifung bei Frauen mit niedrigem Risiko und termingerechter Schwangerschaft angesehen werden.

Comparative study on bruise reduction treatments after bruise induction using the pulsed dye laser.

BACKGROUND: Several bruise reduction methods have been suggested to decrease postprocedure ecchymoses. Comparing the effectiveness of common bruise reduction therapies provides better evidence of the efficacy of bruise reduction techniques. OBJECTIVE: To compare the effectiveness of cold compresses, hydrogen peroxide, over-the-counter bruise serum, and pulsed dye laser (PDL) in minimizing the time required for bruise resolution. METHODS: Seventeen patients aged 22 to 51 (mean 28) with Fitzpatrick skin types I to IV underwent bruise induction with a PDL to produce five 2- by 2-cm zones of bruising on the lower abdomen. Excluding the control, bruises were randomly treated using a cold compress, bruise serum, 3% hydrogen peroxide-soaked gauze, or PDL. Subjects and two blinded physician evaluators evaluated bruise severity and graded it on a visual analog scale on days 0, 3, and 7. RESULTS: Treatment did not result in statistically significantly shorter bruise resolution time than in controls. PDL-treated bruises took a statistically significantly longer time to resolve than controls. CONCLUSION: Our study showed no significant difference in cold compress, hydrogen peroxide, and over-the-counter serum in reducing time to bruise resolution. PDL therapy resulted in greater bruise severity scores and increased time to bruise resolution when used soon after bruise induction.

Double blind trial of a deuterated form of linoleic acid (RT001) in Friedreich ataxia.

OBJECTIVES: Friedreich ataxia is (FRDA) an autosomal recessive neurodegenerative disorder associated with intrinsic oxidative damage, suggesting that decreasing lipid peroxidation (LPO) might ameliorate disease progression. The present study tested the ability of RT001, a deuterated form of linoleic acid (D2-LA), to alter disease severity in patients with FRDA in a double-blind placebo-controlled trial. METHODS: Sixty-five subjects were recruited across six sites and received either placebo or active drug for an 11-month study. Subjects were evaluated at 0, 4, 9, and 11 months, with the primary outcome measure being maximum oxygen consumption (MVO2) during cardiopulmonary exercise testing (CPET). A key secondary outcome measure was a composite statistical test using results from the timed 1-min walk (T1MW), peak workload, and MVO2. RESULTS: Forty-five subjects completed the protocol. RT001 was well tolerated, with no serious adverse events related to drug. Plasma and red blood cell (RBC) membrane levels of D2-LA and its primary metabolite deuterated arachidonic acid (D2-AA) achieved steady-state concentrations by 4 months. No significant changes in MVO2 were observed for RT001 compared to placebo. Similarly, no differences between the groups were found in secondary or exploratory outcome measures. Post hoc evaluations also suggested minimal effects of RT001 at the dosages used in this study. INTERPRETATIONS: The results of this study provide no evidence for a significant benefit of RT001 at the dosages tested in this Friedreich ataxia patient population.

Temozolomide-fatty acid conjugates for glioblastoma multiforme: In vitro and in vivo evaluation.

Glioblastoma multiforme (GBM) is the deadliest brain tumor with a poor prognosis and limited therapeutic options. Temozolomide (TMZ) is the first-line chemotherapeutic agent used for the treatment of GBM; however, it suffers from several limitations, including short half-life, rapid metabolism, <1% brain bioavailability, methyl guanine methyl transferase (MGMT) based chemoresistance, and hematological toxicities. Several approaches have been adopted to overcome these limitations, particularly by using nanotechnology-based systems, but its physicochemical properties make TMZ challenging to load into these nanocarriers. In the current research, we conjugated TMZ with different fatty acids, i.e., linoleic acid (LA), oleic acid (OA), and palmitic acid (PA), to obtain TMZ-fatty acid conjugates, which are comparatively hydrophobic, less prone to degradation and potent. These conjugates were thoroughly characterized using 1H NMR spectroscopy, high-resolution mass spectrometry (HR-MS), and reverse phase-high performance liquid chromatography (RP-HPLC). The synthesized conjugates, namely Temozolomide-oleic acid (TOA,6R1), Temozolomide-linoleic acid (TLA, 6R2), and Temozolomide-palmitic acid (TPA, 6R3), showed an IC50 of 101.4, 67.97, and 672.04 µM, respectively in C6 cells and 428.257, 366.43 and 413.69 µM, respectively in U87-MG cells. On the other hand, the free TMZ showed an IC50 of >1000 µM and 564.23 µM in C6 and U87-MG, respectively. Further, the in vivo efficacy of the TMZ-fatty acid conjugates was evaluated in the C6-induced orthotropic rat glioblastoma model, wherein the TMZ-fatty acid conjugate showed improved survival rate (1.6 folds) and overall health of the animals. Collectively, the conjugation of fatty acids with TMZ improves its anticancer potential against glioblastoma multiforme (GBM).

Nitro-oleic acid inhibits angiotensin II-induced hypertension.

RATIONALE: Nitro-oleic acid (OA-NO(2)) is a bioactive, nitric-oxide derived fatty acid with physiologically relevant vasculoprotective properties in vivo. OA-NO(2) exerts cell signaling actions as a result of its strong electrophilic nature and mediates pleiotropic cell responses in the vasculature. OBJECTIVE: The present study sought to investigate the protective role of OA-NO(2) in angiotensin (Ang) II-induced hypertension. METHODS AND RESULTS: We show that systemic administration of OA-NO(2) results in a sustained reduction of Ang II-induced hypertension in mice and exerts a significant blood pressure lowering effect on preexisting hypertension established by Ang II infusion. OA-NO(2) significantly inhibits Ang II contractile response as compared to oleic acid (OA) in mesenteric vessels. The improved vasoconstriction is specific for the Ang II type 1 receptor (AT(1)R)-mediated signaling because vascular contraction by other G-protein-coupled receptors is not altered in response to OA-NO(2) treatment. From the mechanistic viewpoint, OA-NO(2) lowers Ang II-induced hypertension independently of peroxisome proliferation-activated receptor (PPAR)gamma activation. Rather, OA-NO(2), but not OA, specifically binds to the AT(1)R, reduces heterotrimeric G-protein coupling, and inhibits IP(3) (inositol-1,4,5-trisphosphate) and calcium mobilization, without inhibiting Ang II binding to the receptor. CONCLUSIONS: These results demonstrate that OA-NO(2) diminishes the pressor response to Ang II and inhibits AT(1)R-dependent vasoconstriction, revealing OA-NO(2) as a novel antagonist of Ang II-induced hypertension.

Histopathological study of evening primrose oil effects on experimental diabetic neuropathy.

UNLABELLED: Diabetic polyneuropathy is a serious complication of diabetes mellitus and the most frequent neuropathy worldwide. AIM: This study was designed to investigate the possible beneficial effects of evening primrose oil (EPO) on histopathological changes of sciatic nerves in streptozotocin-induced diabetic rats. MATERIALS AND METHODS: The rats were randomly allotted into three experimental groups: A (control), B (diabetic untreated), and C (diabetic treated with EPO); each group contained 10 animals. Groups B and C received streptozotocin (STZ) to induce diabetes. The rats in group C were given EPO for 2 weeks after 6 weeks of STZ injection. Blood and tissue samples were obtained for biochemical and histopathological investigation. RESULTS: STZ-treated diabetic rats showed reduction of the size of islets of Langerhans, fatty degeneration in the pancreatic acini with dilation, irregularity, and increased thickness of blood vessels. Electron micrography of sciatic nerves of diabetic rats showed multiple vaculations and partial separation of myelinated nerve fibers with axonal atrophy, endoneural edema, and increased collagen fibers. Compared with diabetic rats, EPO induced partial recovery from diabetes-induced pancreatic and nerve damage. CONCLUSIONS: Histologic evaluation of the tissues in diabetic animals treated with EPO showed fewer morphologic alterations with significant decrease of myelin breakdown. Furthermore, the ultrastructural features of axons showed partial improvement. It is believed that further preclinical research into the utility of EPO may indicate its usefulness as a potential treatment on peripheral neuropathy in STZ-induced diabetic rats.

Antihypertension Nanoblockers Increase Intratumoral Perfusion of Sequential Cytotoxic Nanoparticles to Enhance Chemotherapy Efficacy against Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC), one of the worst prognosis types of tumors, is characterized by dense extracellular matrix, which compresses tumor vessels and forms a physical barrier to inhibit therapeutic drug penetration and efficacy. Herein, losartan, an antihypertension agent, is applied as a tumor stroma modulator and developed into a nanosystem. A series of lipophilic losartan prodrugs are constructed by esterification of the hydroxyl group on losartan to fatty acids. Based on the self-assembly ability and hydrodynamic diameter, the losartan-linoleic acid conjugate is selected for further investigation. To improve the stability in vivo, nanoassemblies are refined with PEGylation to form losartan nanoblocker (Los NB), and administered via intravenous injection for experiments. On murine models of pancreatic cancer, Los NB shows a greater ability to remodel the tumor microenvironment than free losartan, including stromal depletion, vessel perfusion increase, and hypoxia relief. Furthermore, Los NB pretreatment remarkably enhances the accumulation and penetration of 7-ethyl-10-hydroxycamptothecin (SN38)-loaded nanodrugs (SN38 NPs) in tumor tissues. Expectedly, overall therapeutic efficacy of SN38 NPs is significantly enhanced after Los NB pretreatment. Since losartan is one of the most commonly used antihypertension agents, this study may provide a potential for clinical transformation in stroma-rich PDAC treatment.

Self-Deliverable Peptide-Mediated and Reactive-Oxygen-Species-Amplified Therapeutic Nanoplatform for Highly Effective Bacterial Inhibition.

An "antibiotic-free strategy" provides a viable option to address bacterial infections, especially for the "superbug" challenge. However, the undesirable antibacterial activity of antibiotic-free agents hinders their practical applications. In this study, we developed a combination antibacterial strategy of coupling peptide-drug therapy with chemodynamic therapy (CDT) to achieve the effective bacterial inhibition. An amphiphilic oligopeptide (LAOOH-OPA) containing a therapeutic unit of D(KLAK)2 peptide and a hydrophobic linoleic acid hydroperoxide (LAHP) was designed. The positively charged D(KLAK)2 peptide with an α-helical conformation enabled rapid binding with microbial cells via electrostatic interaction and subsequent membrane insertion to deactivate the bacterial membrane. When triggered by Fe2+, moreover, LAHP could generate singlet oxygen (1O2) to elicit lipid bilayer leakage for enhanced bacteria inhibition. In vitro assays demonstrated that the combination strategy possessed excellent antimicrobial activity not only merely toward susceptible strains (Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli) but also toward methicillin-resistant Staphylococcus aureus (MRSA). On the mouse skin abscess model induced by S. aureus, self-assembled LAOOH-OPA exhibited a more significant bacteria reduction (1.4 log10 reduction) in the bioburden compared to that of the standard vancomycin (0.9 log10 reduction) without apparent systemic side effects. This combination antibacterial strategy shows great potential for effective bacterial inhibition.

Bovine milk fat enriched in conjugated linoleic and vaccenic acids attenuates allergic dermatitis in mice.

BACKGROUND: Orally administered milk fat enriched in conjugated linoleic acid (CLA) and trans-vaccenic acid (VA) ('enriched milk fat'), produced by supplementing the diet of pasture-fed cows with fish and sunflower oil, has been shown previously to suppress the development of allergic airway disease in mice. OBJECTIVE: To investigate whether topical or oral application of enriched milk fat and its two major fatty acids cis-9, trans-11 CLA (c9,t11-CLA) and VA inhibit allergic dermatitis in mice. METHODS: Allergic dermatitis was induced in C57BL/6 mice by epicutaneous sensitization of tape-stripped skin with ovalbumin (OVA). Enriched milk fat and its two major fatty acids were either topically applied to the OVA-sensitized skin, or orally fed to mice by supplementation of the diet. Blood and skin tissues were collected for analysis after the third skin sensitization. RESULTS: Both topical and oral administration of enriched milk fat and its two major fatty acids led to significant suppression of allergic dermatitis as evidenced by reduced clinical and histological scores of affected skins, infiltration of inflammatory cells, and circulating allergen-specific IgE levels, compared with treatment with normal milk fat or the base control diet. C9,t11-CLA and VA individually inhibited multiple facets of allergic dermatitis when topically applied, and their combination produced a strong additive effect. CONCLUSION AND CLINICAL RELEVANCE: Enriched milk fat, and its two major fatty acids c9,t11-CLA and vaccenic acid attenuate allergic dermatitis in mice.

Effect of evening primrose oil and ω-3 polyunsaturated fatty acids on the cardiovascular risk of celecoxib in rats.

Experimental data raised the specter of increased cardiovascular risk with selective cyclooxygenase-2 inhibitors. The study aimed to investigate the cardiovascular risk caused by celecoxib by studying its effect on blood pressure (BP) and thrombogenesis in rats. We tested the possible protective effects of evening primrose oil (EPO) or ω-3 polyunsaturated fatty acids (n-3 PUFAs). Male Wistar rats were assigned to the following groups: vehicle, celecoxib, celecoxib/n-3 PUFAs, celecoxib/EPO, n-3 PUFAs, and EPO. The rats were treated with celecoxib (20 mg·kg(-1)·d(-1)) by gastric gavage for 6 weeks. The mean BP was recorded, and blood samples were collected for testing prothrombin time and activated partial thromboplastin time. Platelet aggregation assay and collagen-induced platelet consumption test were used as models of thrombogenesis. Celecoxib increased the BP without affecting coagulation parameters and accelerated thrombogenesis by increasing platelet aggregation and collagen-induced thrombocytopenia. EPO and n-3 PUFAs decreased the celecoxib-induced elevation in BP. Although EPO significantly decreased platelet aggregation and collagen-induced thrombocytopenia, n-3 PUFAs did not. Celecoxib elevated BP and increased the risk of thrombogenesis in rats. A combination of celecoxib and the selected natural supplements is suggested as a novel approach to minimize cardiovascular risk caused by celecoxib.

A Systematic Review and Meta-Analysis of the Efficacy of Evening Primrose Oil for Mastalgia Treatment.

Mastalgia, or breast pain, is common among women which can lead to significant impairment in daily living. Hence, finding an effective treatment that can alleviate the symptom is very important. Thus, we carry out this study to determine the efficacy of evening primrose oil (EPO) for mastalgia treatment in women. The review included published randomised clinical trials that evaluated EPO used for treating mastalgia against a placebo or other treatments, irrespective of the blinding procedure, publication status, or sample size. Two independent authors screened the titles and abstracts of the identified trials; full texts of relevant trials were evaluated for eligibility. Two reviewers independently extracted data on the methods, interventions, outcomes, and risk of bias. The random-effects model was used for estimating the risk ratios and mean differences with 95% confidence intervals. Thirteen trials with 1752 randomised patients were included. The results showed that EPO has no difference to reduce breast pain compared to topical NSAIDS, danazol, or vitamin E. The number of patients who achieved pain relief was no different compared to the placebo or other treatments. The EPO does not increase adverse events, such as nausea, abdominal bloating, headache or giddiness, increase weight gain, and altered taste compared to a placebo or other treatments. EPO is a safe medication with similar efficacy for pain control in women with mastalgia compared to a placebo, topical NSAIDS, danazol, or vitamin E.

A first-in-human phase I/Ib dose-escalation clinical trial of the autophagy inducer ABTL0812 in patients with advanced solid tumours.

BACKGROUND: ABTL0812 is an autophagy inducer that promotes cancer cell death by activation of cytotoxic autophagy selectively in tumour cells. ABTL0812 induces endoplasmic reticulum stress and blocks the Akt-mTOR axis; both actions converge to activate a robust and sustained autophagy leading to cancer cell death. Preclinical data supported the initiation of clinical trials in patients with cancer. PATIENTS AND METHODS: This first-in-human trial consisted of an escalation phase (3 + 3 design), followed by an expansion phase, to assess safety and tolerability of ABTL0812. Secondary objectives were determining the recommended phase II dose (RP2D), clinical antitumour activity, pharmacokinetics (PK) and pharmacodynamics (PD). RESULTS: A total of 29 patients were enrolled and treated; fifteen patients were treated in four escalation dosing cohorts (ranging from 500 mg once a day to 2000 mg twice a day) and fourteen in the expansion phase (dosed with 1300 mg three times a day). No maximum tolerated dose was attained, and RP2D was determined by PK/PD modelling. Most drug-related adverse events were gastrointestinal grade I-II. Correlation between drug levels and pAkt/Akt ratio was found. Two cases of long-term (>1 year) stable disease were observed. CONCLUSIONS: ABTL0812 is safe and has an acceptable tolerability profile, allowing a long-term oral dosing. RP2D of 1300 mg three times a day was determined according to PK/PD modelling, and preliminary antitumour efficacy was observed. CLINICAL TRIAL REGISTRATION NUMBER: NCT02201823.

Development of a novel self-microemulsifying drug delivery system for reducing HIV protease inhibitor-induced intestinal epithelial barrier dysfunction.

The development of HIV protease inhibitors (PIs) has been one of the most significant advances of the past decade in controlling HIV infection. Unfortunately, the benefits of HIV PIs are compromised by serious side effects. One of the most frequent and deleterious side effects of HIV PIs is severe gastrointestinal (GI) disorders including mucosal erosions, epithelial barrier dysfunction, and leak-flux diarrhea, which occurs in 16-62% of patients on HIV PIs. Although the underlying mechanisms behind HIV PI-associated serious adverse side effects remain to be identified, our recent studies have shown that activation of endoplasmic reticulum (ER) stress response plays a critical role in HIV PI-induced GI complications. The objective of this study was to develop a novel self-microemulsifying drug delivery system (SMEDDS) using various antioxidants as surfactants and cosurfactants to reduce the GI side effects of the most commonly used HIV PI, ritonavir. The biological activities of this SMSDDS of ritonavir were compared with that of Norvir, which is currently used in the clinic. Rat normal intestinal epithelial cells (IEC-6) and mouse Raw 264.7 macrophages were used to examine the effect of new SMEDDS of ritonavir on activation of ER stress and oxidative stress. Sprague-Dawley rats and C57/BL6 mice were used for pharmacokinetic studies and in vivo studies. The intracellular and plasma drug concentrations were determined by HPLC analysis. Activation of ER stress was detected by Western blot analysis and secreted alkaline phosphatase (SEAP) reporter assay. Reactive oxygen species (ROS) was measured using dichlorodihydrofluorescein diacetate as a probe. Cell viability was determined by Roche's cell proliferation reagent WST-1. Protein levels of inflammatory cytokines (TNF-alpha and IL-6) were determined by enzyme-linked immunosorbent assays (ELISA). The intestinal permeability was assessed by luminal enteral administration of fluorescein isothiocyanate conjugated dextran (FITC-dextran, 4 kDa). The pathologic changes in intestine were determined by histological examination. The results indicated that incorporation of antioxidants in this new SMEDDS not only significantly reduced ritonavir-induced ER stress activation, ROS production and apoptosis in intestinal epithelial cells and macrophages, but also improved the solubility, stability and bioavailability of ritonavir, and significantly reduced ritonavir-induced disruption of intestinal barrier function in vivo. In conclusion, this new SMEDDS of ritonavir has less GI side effects compared to Norvir. This new SMEDDS can be used for other HIV PIs and any insoluble antiviral drug with serious GI side effects.