Succinate Treatment Research Articles

Discontinuation symptoms and taper/poststudy-emergent adverse events with desvenlafaxine treatment for major depressive disorder

The objective of this study was to assess discontinuation symptoms with desvenlafaxine (administered as desvenlafaxine succinate) treatment for major depressive disorder. Data were analyzed from nine 8-week, double-blind (DB), placebo-controlled studies of desvenlafaxine (50, 100, 200, or 400 mg/day; placebo, n = 319; desvenlafaxine, n = 578) and a relapse-prevention study [12-week, open-label (OL) 200 or 400 mg/day desvenlafaxine (n = 373); 6-month DB placebo (n = 73) or desvenlafaxine (n = 118)]. Rates of taper/poststudy-emergent adverse events were summarized. Discontinuation-Emergent Signs and Symptoms (DESS) checklist scores were analyzed in treatment completers at the end of OL and DB treatment. The most common (> or = 5%) taper/poststudy-emergent adverse events among desvenlafaxine patients were dizziness, nausea, headache, irritability, diarrhea, anxiety, abnormal dreams, fatigue, and hyperhidrosis. In the short-term studies, the highest DESS scores observed for desvenlafaxine groups occurred at first assessment after discontinuation of all active treatment (1.9-5.7). Desvenlafaxine 50- and 100-mg/day groups had significantly increased scores versus placebo (P values < or = 0.028). DESS scores increased significantly for patients discontinuing 12-week, OL desvenlafaxine 200 and 400 mg/day doses compared with those continuing desvenlafaxine (P values < or = 0.022). After the 6-month DB phase, DESS scores increased significantly compared with placebo for patients discontinuing 400 mg/day only (P = 0.029). In conclusion, cessation of desvenlafaxine use is associated with discontinuation symptoms after both short-term and long-term treatment.

The role of the GPR91 ligand succinate in hematopoiesis

Regulation of cellular metabolism by the citric acid cycle occurs in the mitochondria. However, the citric acid cycle intermediate succinate was shown recently to be a ligand for the G-protein-coupled receptor GPR91. Here, we describe a role for succinate and its receptor in the stimulation of hematopoietic progenitor cell (HPC) growth. GPR91 mRNA and protein expression were detected in human bone marrow CD34+ progenitor cells, as well as in erythroid and megakaryocyte cultures and the erythroleukemic cell line TF-1. Treatment of these cell cultures with succinate resulted in increased proliferation rates. The proliferation response of TF-1 cells was pertussis toxin (PTX)-sensitive, suggesting a role for Gi signaling. Proliferation was also blocked when TF-1 cells were transfected with small interfering RNA specific for GPR91. Succinate stimulated activation of the Erk MAPK pathway and inositol phosphate accumulation in a PTX-sensitive manner. Pretreatment of TF-1 cells with the Erk1/2 kinase (MEK) inhibitor PD98059 blocked the proliferation response. Succinate treatment additionally protected TF-1 cells from cell death induced by serum deprivation. Finally, in vivo administration of succinate was found to elevate the levels of hemoglobin, platelets, and neutrophils in a mouse model of chemotherapy-induced myelosuppression. These results suggest that succinate-GPR91 signaling is capable of promoting HPC development.

Glucocorticoid binding and cytolethal responsiveness of hairy-cell and chronic lymphocytic leukaemia.

The glucocorticoid binding properties and cytolethal responsiveness of leukaemic cells were studied in vitro in seven patients with hairy-cell leukaemia (HCL) and five with chronic lymphocytic leukaemia (CLL). Substantial levels of glucocorticoid binding were detected both in whole cell and cytosol preparations from all patients although the level of binding by HCL cells always exceeded that of CLL cells (P less than 0.05). In both leukaemic cell types the uptake and binding of prednisolone in vitro was significantly greater than that of dexamethasone (P less than 0.05). CLL cells showed a variable dose-related cytolethal response to methylprednisolone sodium succinate (MPSS) treatment in vitro although cytolytic effects were not marked in the usual pharmacological dose range (10(-5)-10(-6)M). Treatment of CLL patients with conventional doses of prednisone for extended periods or high intravenous infusions of MPSS over shorter periods had no consistent effect on the in-vitro level of steroid binding or the cytolethal responsiveness of CLL cells to glucocorticoid treatment. Although HCL cells proved highly resistant to the cytolethal effects of MPSS in vitro, the substantial binding of glucocorticoids by leukaemic cells from all HCL patients indicates the potential value of steroid therapy in this disease should be explored further.

Reduction of anxiety symptoms in patients with major depressive disorder treated with Desvenlafaxine Succinate: A pooled analysis

Objective:To assess the efficacy of desvenlafaxine succinate (DVS) treatment in reducing symptoms of anxiety in patients with major depressive disorder (MDD).Methods:Data were pooled from 7 randomized, double-blind, placebo-controlled, 8-week DVS trials. All studies enrolled adult outpatients with DSM-IV MDD. Patients were excluded if an anxiety disorder was the primary diagnosis. Eligible patients were randomly assigned to treatment with 100–400 mg/d DVS (n=1186) or placebo (n=797) for 8 weeks. The primary efficacy outcomes in this analysis were the 17-item Hamilton Rating Scale for Depression (HAM-D17) item 10 (Anxiety/Psychic) and the Covi Anxiety total score (measured in 6 of the 7 trials). Patients with a Covi Anxiety score >9 or whose Covi score exceeded their Raskin Depression total score were not enrolled. Changes from baseline were analyzed using a mixed-effects model for repeated measures (MMRM) analysis, which included the fixed, categorical effects of treatment, protocol, visit, and the treatment-by-visit interaction, as well as the continuous, fixed covariate of baseline score. Secondary analyses evaluated changes from baseline to end point using analysis of covariance (ANCOVA, using last-observation-carried-forward [LOCF] and observed cases [OC] analyses).Results:Improvement from baseline at week 8, the study end point, was significantly greater for the DVS group than for the placebo group on both the HAM-D17 Anxiety/Psychic item and Covi Anxiety total scores in both the MMRM and ANCOVA (LOCF and OC) analyses.Conclusion:In this pooled analysis, DVS was significantly superior to placebo in the treatment of anxiety symptoms associated with depression.

Efficacy and Tolerability of Desvenlafaxine Succinate Treatment for Menopausal Vasomotor Symptoms

To compare efficacy and safety of desvenlafaxine succinate (desvenlafaxine) with placebo for the treatment of vasomotor symptoms. This randomized, double-blind, placebo-controlled trial enrolled 707 healthy, postmenopausal women experiencing 50 or more moderate-to-severe hot flushes per week. Participants randomly received desvenlafaxine 50, 100, 150, or 200 mg or placebo daily. Trial duration was 52 weeks. Primary outcomes were change from baseline in average daily number of moderate-to-severe hot flushes and in daily hot flush severity score at weeks 4 and 12. Six hundred twenty women with an average of 11 moderate-to-severe hot flushes per day at baseline completed at least one on-therapy evaluation for primary efficacy end points; 519 participants completed 12 weeks of treatment, and 368 completed the study. Desvenlafaxine 100 mg/d achieved a significantly greater reduction compared with placebo in average daily number of hot flushes at weeks 4 (P=.013) and 12 (P=.005), reaching a 64% decrease from baseline at week 12, and the 75% responder rate was significantly higher for desvenlafaxine 100 mg (50%) compared with placebo (29%; P=.003; number needed to treat=4.7) at week 12. Average daily severity of hot flushes was significantly lower in the desvenlafaxine 100-mg group compared with placebo at week 12 (P=.020). Desvenlafaxine-treated women reported significantly more treatment-emergent adverse events than placebo-treated women during the first week of therapy only. Desvenlafaxine is an effective nonhormonal treatment for vasomotor symptoms in postmenopausal women. Its tolerability profile is consistent with that of other serotonin-norepinephrine reuptake inhibitors. ClinicalTrials.gov, www.clinicaltrials.gov, NCT00421031 I.

Comparison of the efficacy and tolerability of solifenacin succinate with or without previous use of trospium chloride

Overactive bladder syndrome (OBS) is described as urinary urgency with or without incontinence, usually with increased daytime frequency and nocturia in the absence of another identifiable pathological process. Nowadays and despite other alternative therapies, the mainstay of OBS is still the pharmacological approach, mainly with anti-muscarinic drugs. To compare the efficacy of a 30-day solifenacin succinate (5 mg OD) treatment with or without previous medication with trospium chloride, a prostective open, two-arm, parallel group study was conducted for 5 weeks in 40 patients with OBS. The primary endpoint was patient self-assessment of improvement after 30 days of medication. Secondary endpoints included the reduction of the daily number of voids and urgency or involuntary leakage episodes. Adverse reactions and therapeutic stoppage were also evaluated. To be included in the trospium chloride treatment group, patients were required to have been treated with such drug for 1 to 6 months before the present study. Evaluation and efficacy assessment were accomplished using a 3-day bladder diary and an urgency severity scale (USS). Safety assessment was done by recording all the patients' complaints after starting medication. A total of 40 patients were enrolled for this study, 19 without previous medication and 21 who had already tried trospium chloride. Two patients from the non-previous medication group were excluded. Globally, there was a statistically significant reduction for the USS (2.73-->1.73), the daily number of voids (9.5-->7.0), of urgency episodes (9.1-->4.0) and of involuntary leakage episodes (3.6-->1.0) over the 24 h. Six patients had no improvement, four from the previous trospium chloride group and two from the non-previous medication group. Three patients reported side effects, two cases of dry mouth and one case of constipation. One patient dropped out of the treatment due to an unspecified intolerance. Solifenacin succinate 5 mg seems to be effective concerning patients' self-assessment of improvement and decrease in the mean number of daily voids, urgency episodes and incontinence episodes. This was reported both in patients who have already been medicated with trospium chloride and those who have never taken any kind of medication. Regarding side effects, solifenacin is quite well-tolerated in both groups.

Metoprolol succinate, a selective beta-adrenergic blocker, has no effect on insulin sensitivity.

Insulin resistance is a risk factor for cardiovascular disease. Therapies to lower blood pressure should not decrease insulin sensitivity. Some b-adrenergic blocking agents can have an adverse effect on insulin sensitivity. This study examined the effect of extended-release metoprolol succinate on insulin sensitivity. Nondiabetics with hypertension (N=30) were started on (or changed to) hydrochlorothiazide (HCTZ) 12.5 mg daily for 14 days. Patients with blood pressure>140/90 mm Hg while taking HCTZ alone underwent an insulin clamp procedure to quantify insulin sensitivity. Metoprolol succinate treatment was begun at 50 mg daily and titrated to a dose that lowered blood pressure to <140/90 mm Hg. Following 12 weeks of metoprolol succinate plus HCTZ therapy, the insulin clamp procedure was repeated. On metoprolol succinate plus HCTZ treatment, there were no significant changes in insulin clamp measures of insulin sensitivity. Plasma cholesterol and low-density lipoprotein cholesterol decreased significantly on metoprolol succinate plus HCTZ. When b-blocker therapy is considered, metoprolol succinate can be used to treat hypertension without adverse metabolic effects.

Beta blocker effects on plasma homocysteine levels in patients with hypertension

Recent studies have shown that hyperhomocysteinemia might play a role in the pathogenesis of hypertension. The effects of antihypertensive agents on plasma homocysteine levels have not been tested extensively. We investigated the effects of beta-blocker therapy on homocysteine levels in patients with hypertension. In the study, 120 patients with newly diagnosed hypertension were enrolled. All patients received metoprolol succinate 100 mg/day initially. If blood pressure was above normal on the 15th day of follow-up, the metoprolol dosage was doubled. Before initiation of the antihypertensive medication and after the fourth month of treatment, homocysteine levels were measured. Of the 120 patients enrolled, 39 could not complete the study. Homocysteine levels decreased significantly by the end of the fourth month when compared with basal values (13.5 ± 4.5 μmol/l versus 12.4 ± 4.9 μmol/l; P = 0.001). There was no relation between homocysteine level and blood pressure control. There was a significant decrease in homocysteine levels in the women treated in this study ( P = 0.001); however, this effect was absent in men ( P = 0.185). We demonstrate that metoprolol succinate treatment significantly decreases plasma homocysteine levels in patients with hypertension, especially in women.

Improved quality of life in patients with overactive bladder symptoms treated with solifenacin

To assess the effect of solifenacin succinate treatment on quality of life (QoL) measured in clinical trials in patients with overactive bladder (OAB). QoL data using the King's Health Questionnaire (KHQ) were analysed from two phase-3, 12-week studies (1984 patients) and a long-term extension of these studies (1637 patients) where patients received solifenacin for up to an additional 40 weeks (i.e. a 52-week exposure to solifenacin). The 12-week studies were multinational, multicentre, randomized, double-blind, and placebo-controlled. The 10 domains from the KHQ evaluated were general health perception, incontinence impact, role limitations, physical limitations, social limitations, personal relationships, emotions, sleep/energy, severity measures, and symptom severity. Changes from baseline to endpoint in QoL variables were assessed by analysis of variance, and from pooled outcomes of the 12-week studies by analysis of covariance. Descriptive statistics were used to evaluate data in the extension study. In the two 12-week studies (1033 and 857 patients), those receiving once-daily solifenacin had statistically significantly better QoL than those on placebo. Changes in the KHQ were statistically significantly (P < 0.05) different from placebo for both solifenacin 5 and 10 mg once daily on five of the 10 KHQ domains in each of the studies. Pooled data from the two 12-week studies showed statistically significant (P < 0.05) differences from placebo for both solifenacin doses in nine of the 10 domains. Improvements in QoL scores for solifenacin were 35-48% in nine of the 10 domains for the 1347 patients providing QoL data in the extension study. About two-thirds of this overall improvement occurred during the original 12-week study, with an additional third reported during the extension, with an improvement in QoL over time in patients treated with solifenacin. Results from the KHQ in study participants in the two double-blind studies showed that solifenacin significantly improved the QoL in patients with OAB symptoms after 12 weeks of treatment, with further improvements during long-term administration up to 1 year. Clinical trial outcomes show a favourable balance of efficacy and tolerability with solifenacin; the present report further supports this efficacy and tolerability by providing evidence for both short- and long-term improvements in QoL.

Vitamin E succinate and cancer treatment: a vitamin E prototype for selective antitumour activity.

Great hope has been given to micronutrients as anticancer agents, since they present natural compounds with beneficial effects for normal cells and tissues. One of these is vitamin E (VE), an antioxidant and an essential component of biological membranes and circulating lipoproteins. In spite of a number of epidemiological and intervention studies, little or no correlation between VE intake and incidence of cancer has been found. Recent reports have identified a redox-silent analogue of VE, α-tocopheryl succinate (α-TOS), as a potent anticancer agent with a unique structure and pharmacokinetics in vivo. α-TOS is highly selective for malignant cells, inducing them into apoptotic death largely via the mitochondrial route. The molecule of α-TOS may be modified so that analogues with higher activity are generated. Finally, α-TOS and similar agents are metabolised to VE, thereby yielding a compound with a secondary beneficial activity. Thus, α-TOS epitomises a group of novel compounds that hold substantial promise as future anticancer drugs. The reasons for this optimistic notion are discussed in the following paragraphs.

Effect of glutathione depletion on sites and topology of superoxide and hydrogen peroxide production in mitochondria.

In this work, the topology of mitochondrial O2(-)(radical) and H2O2 generation and their interplay with matrix GSH in isolated heart mitochondria were examined. We observed that complex I releases O2(-)(radical) into the matrix (where it is converted to H2O2 by Mn-SOD) but not into the intermembrane space. No free radical generation was observed from complex II, but succinate treatment caused H2O2 generation from the matrix through a reverse electron flow to complex I. Complex III was found to release O2(-)(radical) into the matrix and into the intermembrane space. Antimycin, which increases steady-state levels of UQO>- (ubisemiquinone at the Qo site) in complex III, enhanced both H2O2 generation from the matrix and O2(-)(radical) production from the intermembrane space. On the other hand, myxothiazol, which inhibits UQO>- formation, completely inhibited antimycin induced O2(-)(radical) toward the intermembrane space and inhibited H2O2 generation from the matrix by 70%. However, myxothiazol alone enhanced H2O2 production from complex III, suggesting that other components of complex III besides the UQO- can cause O2(-)(radical) generation toward the matrix. As expected, mitochondrial GSH was found to modulate H2O2 production from the matrix but not O2- generation from the intermembrane space. Low levels of GSH depletion (from 0-40%, depending on the rate of H2O2 production) had no effect on H2O2 diffusion from mitochondria. Once this GSH depletion threshold was reached, GSH loss corresponded to a linear increase in H2O2 production by mitochondria. The impact of 50% mitochondrial GSH depletion, as seen in certain pathological conditions in vivo, on H2O2 production by mitochondria depends on the metabolic state of mitochondria, which governs its rate of H2O2 production. The greater the rate of H2O2 generation the greater the effect 50% GSH depletion had on enhancing H2O2 production.

The effect of zinc supply and succinate treatment on plant growth and mineral uptake in pea plant

The influence of succinate treatment on Zn toxicity was investigated using plant growth and mineral uptake as stress indicators. Pea plants (Pisum sativum L., cv. Citrine) were treated with various Zn concentrations (0.67 to 700 muM Zn) in the presence and absence of 0.2 mM Na-succinate. Plants pre-treated with succinate and then exposed to Zn exhibited higher dry root, stem and leaf weight than the plants treated with Zn alone. An increase in Zn supply resulted in a decrease in the concentrations of Ca, Mg, P in the roots and an increase of Ca and N levels in the stems and leaves. The amount of Zn in the roots, stems and leaves increased with greater Zn rates. The succinate treatment increased P in the roots but did not affect the Ca, N and Mg contents in Zn-treated plants. Most of the Zn taken up was retained in the roots after succinate treatment. The ameliorative effect of succinate on plant growth could be due to a lower Zn translocation in the leaves and stems and increased Zn accumulation in the roots. Lower Zn translocation in aboveground parts seemed to result from Zn complexing by organic anion in the roots. This probably caused less Zn transport to the stems and leaves and suggested that succinate has potential for complexing with Zn and may play a role in tolerance to high Zn levels.

INFLUENCE OF SUCCINATE ON ZINC TOXICITY OF PEA PLANTS

The response of pea plants (Pisum sativum, cv. Citrine) to various zinc (Zn) concentrations (0.67 to 1000 μM Zn) in the presence and absence of succinate (200 μM Na-succinate) were investigated. Treatment of pea plants alone with excess of Zn reduced plant growth, chlorophyll content and induced alterations in the structure of the chloroplast, resulting mainly in decreased granal thylakoids. The photochemical activity of photosystem II estimated by the ratios Fv/Fm and Fv/Fo was less affected by Zn treatment. The presence of succinate lead to an increase in plant growth and chlorophyll content, improved chloroplast structure of and recovered photosystem II activity in Zn-treated plants. This stimulation was accompanied by an increased zinc root concentration and a decreased zinc shoot concentration. The higher root zinc concentration and decreased zinc translocation from root to shoot by succinate treatment suggest that succinate facilitates the formation of metal-succinate complexes in the roots and may play a role in zinc accumulation.These results provide indirect evidence for a possible role of succinate in Zn-resistance of plants.

RRR-α-tocopheryl succinate induction of prolonged activation of c-jun amino-terminal kinase and c-jun during induction of apoptosis in human MDA-MB-435 breast cancer cells

We have demonstrated that RRR-alpha-tocopheryl succinate (10 microg/mL vitamin E succinate (VES) treatment of estrogen receptor-negative MDA-MB-435 human breast cancer cells induces 9, 19, 51, and 72% apoptotic cells on days 1-4, respectively, after treatment, which involves transforming growth factor-beta signaling. Here, we show that VES-triggered apoptosis of MDA-MB-435 cells induced prolonged elevated expression of c-jun mRNA and protein (neither of which was caused by major increases in stability) and also induced enhanced activator protein-1 (AP-1) binding to the consensus DNA oligomer. Furthermore, VES treatments resulted in increased AP-1 transactivation activity, as measured with an AP-1 promoter/luciferase reporter construct and by the measurement of increased mRNA expression of the AP-1-dependent endogenous gene collagenase. Evidence of VES-induced involvement of the c-jun amino-terminal kinase in these AP-1-dependent events was suggested by data showing prolonged activity of this kinase, as measured by a kinase assay using glutathione S-transferase-c-jun as the substrate. The c-jun-dependent transcriptional activity was verified by cotransfection of a chimeric transcription factor having a galactose 4 DNA-binding domain coupled with the transactivation domain of c-jun plus the reporter plasmid 5X GAL4-luciferase. MDA-MB-435 cells infected with an adenovirus expression vector containing the TAM-67 sequence for dominant/negative-acting mutant c-jun or transiently transfected with c-jun antisense exhibited a 50-77% reduction in VES-mediated apoptosis as compared with control adenovirus-infected or control sense oligomer-transfected cells.

Modulation of TCDD-induced fetotoxicity and oxidative stress in embryonic and placental tissues of C57BL/6J mice by vitamin E succinate and ellagic acid

The ability of vitamin E succinate and ellagic acid to modulate 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD)-induced developmental toxicity and oxidative damage in embryonic/fetal and placental tissues was studied in C57BL/6J mice. Vitamin E succinate (100 mg/kg per day) and ellagic acid(6 mg/kg per day) were administered by gavage to groups of pregnant mice on days 10, 11 and 12 of gestation and 40 mg vitamin E succinate/kg or 3 mg ellagic acid/kg on day 13 of gestation. A number of animals from the vitamin E succinate and ellagic acid treated groups also received 30 μg TCDD/kg on day 12 of gestation, 2 h prior to vitamin E succinate or ellagic acid treatment. Groups of treated animals were terminated on day 14 of gestation, and the biomarkers of oxidative stress, including superoxide anion production and the induction of lipid peroxidation and DNA-single strand breaks (SSB), were determined in whole embryonic and placental tissues homogenates. Groups of treated animals were also killed on day 18 of gestation for investigation of the fetotoxic and teratogenic effects as well as effects on the placentae. Vitamin E succinate and ellagic acid significantly decreased TCDD-induced fetal growth retardation fetal death and placental weight reduction, with no significant ameliorating effects on TCDD-induced malformations including cleft palate and hydronephrosis. Vitamin E succinate treatment resulted in decreases of 77–88%, 70–87%, and 21–47% in the production of superoxide anion, lipid peroxidation and DNA-SSB, respectively, in embryonic and placental tissues, while ellagic acid caused 47–98%, 79–93%, and 37–53% decreases, respectively, in these parameters. These results indicate that TCDD-induced fetal death and fetal and placental weight reductions in C57BL/6J mice may be due to oxidative damage induced by TCDD, and ellagic acid and vitamin E succinate provide protection against those effects. Ellagic acid provided better protection than vitamin E succinate against TCDD-induced fetal growth retardation and increases in lipid peroxidation in embryonic and placental tissues.

Effect of vitamin E and indomethacin treatment on adenylate cyclase activity, PGE 2 and cAMP levels in murine melanoma cells

Malignant murine melanoma (BL6) cells cultured in vitro were supplemented with indomethacin (0.15 μM) and varying levels (1–10 μg/ml) of vitamin E succinate. The effect of combined indomethacin and vitamin E succinate treatment on the growth as well as the levels of adenylate cyclase activity, prostaglandin E 2 (PGE 2) and cyclic adenosine monophosphate (cAMP) were determined in these cells. BL6 cells supplemented with 0.15 μM indomethacin and 1–10 μg/ml vitamin E succinate showed a significant ( P ≤ 0.05) decrease in growth at 1 μg/ml vitamin E succinate, while at 3–10 μg/ml, no significant increase or decrease in growth was observed when compared to control cultures (OE). Results from studies of adenylate cyclase activity in BL6 cells showed no significant increase or decrease in enzyme activity, nor were the levels of PGE 2 and cAMP affected when the cells were supplemented with 0.15 μM indomethacin and 1–10 μg/ml vitamin E succinate.

Increased sensitivity to mechanical ventilation after surfactant inactivation in young rabbit lungs.

To study the individual and combined effects of surfactant inactivation and mechanical ventilation on pulmonary microvascular permeability and lung compliance. Prospective, controlled trial. An isolated, perfused, lung model of surfactant inactivation and mechanical ventilation at 15, 30, and 45 cm H2O peak inspiratory pressure was developed in young (4 to 6 wks) New Zealand white rabbits. Laboratory of a university-affiliated medical school. Isolated, perfused lungs were prepared for measurement of the capillary filtration coefficient before and after one of four interventions: instillation of dioctyl succinate, a surfactant inactivator, without ventilation (group 1); ventilation without dioctyl succinate at 15, 30, or 45 cm H2O peak inspiratory pressure (group 2); ventilation after dioctyl succinate pretreatment at 15, 30, or 45 cm H2O peak inspiratory pressure (group 3); and control lungs without dioctyl succinate or ventilation (group 4). A significant increase in the capillary filtration coefficient was noted after dioctyl succinate treatment alone, after ventilation alone at 45 cm H2O peak inspiratory pressure, and after dioctyl succinate plus ventilation at 15, 30, and 45 cm H2O peak inspiratory pressure. Dioctyl succinate plus ventilation produced a significantly greater increase in the capillary filtration coefficient than ventilation alone at 15 and 45 cm H2O peak inspiratory pressure. These data suggest that ventilation after surfactant inactivation is more injurious to the pulmonary microvasculature than ventilation alone, and that generalized lung overdistention is not the primary mechanism for microvascular injury in the diseased, noncompliant lung. The increases seen in the capillary filtration coefficient in postventilated surfactant inactivated lungs, even at low-ventilation pressures, suggest that low peak inspiratory pressures do not overdistend the dioctyl succinate-treated lung.

Effect of vitamin E succinate and a cAMP-Stimulating agent on the expression of c-myc, N-myc and H-ras in murine neuroblastoma cells

d-Alpha-tocopheryl succinate (vitamin E succinate) at a concentration of 11.3 μM inhibited growth and reduced the expression of c-myc, N-myc and H-ras specific mRNAs in murine neuroblastoma cells (NBP2) in culture. R020-1724 [4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone], an inhibitor of cyclic AMP phosphodiesterase, also inhibited growth and reduced the expression of these oncogenes. Vitamin E succinate treatment caused the formation of two c-myc related transcripts of 1.9 and 3.7 kb; however, R020-1724 treatment did not. These results suggest that the inhibition of growth is sufficient to reduce the expression of c-myc, N-myc and H-ras in NB cells in culture, but it is not sufficient to produce two c-myc related transcripts.

RRR‐α‐tocopheryl succinate enhances t cell mitogen‐induced proliferation and reduces suppressor activity in spleen cells derived from AEV‐infected chickens

RRR-alpha-tocopheryl succinate was demonstrated to be a potent in vitro modulator of retrovirus-induced immune abnormalities. Spleen cells from avian erythroblastosis virus (AEV)-infected chickens exhibit suppressed T cell mitogen-induced proliferative responses and elevated levels of suppressor T cell activity. In vitro addition of RRR-alpha-tocopheryl succinate resulted in amelioration of these abnormalities. Antioxidants including Trolox (a water-soluble analogue of RRR-alpha-tocopherol with antioxidant properties) and a combination of butylated hydroxyanisole and butylated hydroxytoluene were able to restore immune functions to levels similar to those achieved with RRR-alpha-tocopheryl succinate treatment. Aspirin, an irreversible inhibitor of cyclooxygenase activity, was capable of ameliorating some of the AEV-induced immune dysfunctions. These studies suggest a role for the antioxidant functions of RRR-alpha-tocopheryl succinate in modulation of retrovirus-induced immune abnormalities.

Decreased expressions of c-myc and H-ras oncogenes in vitamin E succinate induced morphologically differentiated murine B-16 melanoma cells in culture

Treatment of B-16 melanoma cells in culture with d-alpha-tocopheryl succinate (vitamin E succinate) at concentrations of 11.3 and 15.1 microM inhibited growth and induced cell differentiation in culture. Vitamin E succinate treatment decreased the levels of c-myc and H-ras specific mRNAs in melanoma cells. Similar results were obtained by the vitamin retinoic acid and the nonvitamin agents R020-1724 (4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone), an inhibitor of cyclic nucleotide phosphodiesterase (0.72 mM), and sodium butyrate (1 mM), which induced differentiation and (or) inhibited growth of melanoma cells in culture. The extent of inhibition of c-myc mRNA was greater than that of H-ras mRNA. These results indicate that vitamin E succinate induced reduction of the levels of c-myc and H-ras mRNAs is related to growth inhibition of melanoma cells in culture.