Effect of a sulforaphane supplement on muscle soreness and damage induced by eccentric exercise in young adults: A pilot study.

OBJECTIVE: Excessive exercise increases the production of reactive oxygen species in skeletal muscles. Sulforaphane activates nuclear factor erythroid 2-related factor 2 (Nrf2) and induces a protective effect against oxidative stress. In a recent report, sulforaphane intake suppressed exercise-induced oxidative stress and muscle damage in mice. However, the effect of sulforaphane intake on delayed onset muscle soreness after eccentric exercise in humans is unknown. We evaluated the effect of sulforaphane supplement intake in humans regarding the delayed onset muscle soreness (DOMS) after eccentric exercise. RESEARCH METHODS & PROCEDURES: To determine the duration of sulforaphane supplementation, continuous blood sampling was performed and NQO1 mRNA expression levels were analyzed. Sixteen young men were randomly divided into sulforaphane and control groups. The sulforaphane group received sulforaphane supplements. Each group performed six set of five eccentric exercise with the nondominant arm in elbow flexion with 70% maximum voluntary contraction. We assessed muscle soreness in the biceps using the visual analog scale, range of motion (ROM), muscle damage markers, and oxidative stress marker (malondialdehyde; MDA). RESULTS: Sulforaphane supplement intake for 2 weeks increased NQO1 mRNA expression in peripheral blood mononuclear cells (PBMCs). Muscle soreness on palpation and ROM were significantly lower 2 days after exercise in the sulforaphane group compared with the control group. Serum MDA showed significantly lower levels 2 days after exercise in the sulforaphane group compared with the control group. CONCLUSION: Our findings suggest that sulforaphane intake from 2 weeks before to 4 days after the exercise increased NQO1, a target gene of Nrf2, and suppressed DOMS after 2 days of eccentric exercise.

Sulforaphane-cisplatin combination inhibits the stemness and metastatic potential of TNBCs via down regulation of sirtuins-mediated EMT signaling axis.

BACKGROUND: Sulforaphane (SFN) is a naturally occurring organosulfur compound found in cruciferous vegetables such as broccoli, brussels sprouts and cabbage. SFN is known for its multiple therapeutic properties, such as HDAC inhibitory, chemo preventive and anti-cancer effects. Cisplatin (CIS) has limited effect against metastatic triple-negative breast cancer (TNBC). Additionally, CIS impose severe side effects to normal cells, and later TNBC cells develops resistance. Studies suggest that the overexpression of sirtuins (SIRTs) promotes CIS resistance and metastasis by activating epithelial-to-mesenchymal transition (EMT) pathway in TNBC. PURPOSE: In view of the above information, we investigated the therapeutic efficacy of SFN, in combination with CIS against TNBC metastasis and CIS resistance. METHODS: The anti-cancerous effect of SFN-CIS combination on human TNBC cell lines was demonstrated by utilizing MTT assay and, apoptosis and cell cycle assay followed by FACS analysis. The synergistic effect of SFN-CIS combination on the experimental metastasis was demonstrated by utilizing migration, invasion, chemotaxis, mammosphere and colony formation assay on human TNBC MDA-MB-231 and MDA-MB-468 cells. The role of SIRTs-mediated EMT signaling axis in the metastasis and chemoresistance was investigated by western blotting technique as well as sirtuin activity tests. This was further validated by using Chromatin immunoprecipitation (ChIP) analysis. RESULTS: We found that SFN-CIS combination synergistically inhibits cellular growth of MDA-MB-231 and MDA-MB-468 cells. More importantly, SFN was found to protect normal kidney cells from CIS-induced toxicity. Further, SFN-CIS combination was found to synergistically inhibit metastatic-events via significantly altering EMT markers which was further associated with the suppression of SIRTs functions in TNBC cells. ChIP analysis validated that SFN-CIS combination suppresses EMT mechanism through altered chromatin modifications at E-cadherin promoter resulting in its re-expression. CONCLUSION: The results of the current study suggests that CIS when supplemented with SFN, inhibits metastasis and stemness potential of TNBC cells by down regulating SIRTs-mediated EMT cascade. Overall this study affirms that, this novel combination could be a promising strategy against SIRT-mediated TNBC metastasis and CIS-resistance.

Dietary polyacetylene falcarinol upregulated intestinal heme oxygenase-1 and modified plasma cytokine profile in late phase lipopolysaccharide-induced acute inflammation in CB57BL/6 mice.

Unlike polyphenols, which are widely available in the diet, polyacetylenes are available only from the Apiaceae family vegetables, including carrot, parsnip, fennel, celery, and many herbs (parsley, lovage, etc). The aim of this study was to investigate the hypothesis that polyacetylene falcarinol (FA) reduces intestinal inflammation and examine its similarity of effect to isothiocyanate R-sulforaphane during the late phase of acute inflammation. To this end, 3-month-old male CB57BL/6 mice were fed twice daily for 1 week with 5 mg/kg of FA, sulforaphane, or vehicle before receiving an intraperitoneal injection of 5 mg/kg endotoxin (lipopolysaccharide [LPS]) to induce modest acute inflammation. The expression of intestinal and hepatic heme oxygenase-1 at the mRNA and protein levels, circulating cytokines, as well as intestinal and mesenteric n-6 and n-3 fatty acid lipid mediators was compared 24 hours after LPS administration to examine its effects on the late phase of inflammation. Intestinal nuclear factor (erythroid-derived 2)-like 2 target enzyme heme oxygenase-1 was upregulated 8.42-fold at the mRNA level and 10.7-fold at the protein level by FA-supplemented diet. However, the FA-supplemented diet produced a unique type-2 plasma cytokine skew after LPS treatment. Plasma cytokines interleukin (IL)-4, IL-13, IL-9, and IL-10 were upregulated, reflecting the cytokine profile of reduced type 1 inflammation. A detailed lipidomic analysis of n-6 and n-3 fatty acid pro- and anti-inflammatory pathways in the mesentery and intestinal mucosa showed that FA diet was more similar to the control groups than to other LPS treated groups. In this study, we demonstrated that FA-supplemented diet produced a unique immunomodulatory effect not observed with sulforaphane in late phases of inflammation. These results support the hypothesis that FA may have role as a dietary immunosuppressant in patients with inflammatory gastrointestinal as well as other inflammatory disorders that may be alleviated by increasing consumption of carrot or other FA-containing food sources.

The lab oddity prevails: discovery of pan-CDK inhibitor (R)-S-cyclopropyl-S-(4-{[4-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)sulfoximide (BAY 1000394) for the treatment of cancer.

Lead optimization of a high-throughput screening hit led to the rapid identification of aminopyrimidine ZK 304709, a multitargeted CDK and VEGF-R inhibitor that displayed a promising preclinical profile. Nevertheless, ZK 304709 failed in phase I studies due to dose-limited absorption and high inter-patient variability, which was attributed to limited aqueous solubility and off-target activity against carbonic anhydrases. Further lead optimization efforts to address the off-target activity profile finally resulted in the introduction of a sulfoximine group, which is still a rather unusual approach in medicinal chemistry. However, the sulfoximine series of compounds quickly revealed very interesting properties, culminating in the identification of the nanomolar pan-CDK inhibitor BAY 1000394, which is currently being investigated in phase I clinical trials.

BAY 1000394, a novel cyclin-dependent kinase inhibitor, with potent antitumor activity in mono- and in combination treatment upon oral application.

Deregulated activity of cyclin-dependent kinases (CDK) results in loss of cell-cycle checkpoint function and increased expression of antiapoptotic proteins, which has been directly linked to the molecular pathology of cancer. BAY 1000394 inhibits the activity of cell-cycle CDKs CDK1, CDK2, CDK3, CDK4, and of transcriptional CDKs CDK7 and CDK9 with IC(50) values in the range between 5 and 25 nmol/L. Cell proliferation was inhibited at low nanomolar concentration in a broad spectrum of human cancer cell lines. In cell-based assays, the inhibition of phosphorylation of the CDK substrates retinoblastoma protein, nucleophosmin, and RNA polymerase II was shown. Cell-cycle profiles were consistent with inhibition of CDK 1, 2, and 4 as shown in cell-cycle block and release experiments. The physicochemical and pharmacokinetic properties of BAY 1000394 facilitate rapid absorption and moderate oral bioavailability. The compound potently inhibits growth of various human tumor xenografts on athymic mice including models of chemotherapy resistance upon oral dosing. Furthermore, BAY 1000394 shows more than additive efficacy when combined with cisplatin and etoposide. These results suggest that BAY 1000394 is a potent pan-CDK inhibitor and a novel oral cytotoxic agent currently in phase I clinical trials.

Using synthesized onion lachrymatory factor to measure age-related decreases in reflex-tear secretion and ocular-surface sensation.

PURPOSE: To use synthesized onion lachrymatory factor (SOLF) to investigate age-related changes in reflex-tear secretion and ocular-surface sensation. METHODS: We separated 91 healthy volunteers into four groups: groups A, age 20-29 years; B, 30-39; C, 40-49; and D, older than 50 years. We exposed one eye of each subject to SOLF and measured the elapsed time until the subject's limit of irritation tolerance (TLI) was reached and an increase in the tear meniscus radius (DeltaR). After the SOLF stimulus, corneal sensitivity was examined by Cochet-Bonnet esthesiometry (CB), and reflex-tear secretion was examined by the Schirmer I-test (ST). RESULTS: TLI was significantly shorter in group A than in the other groups (P < 0.0001), and the groups B and D also differed significantly from each other (P = 0.0013). The increase in DeltaR was significantly greater in group A than in group C (P = 0.0306) or D (P < 0.0001), and groups B (P = 0.0002) and C (P = 0.0308) also differed significantly from group D. There were no significant intergroup differences in the CB and ST results. CONCLUSIONS: An age-related decrease in reflex-tear secretion and ocular-surface sensation was revealed by the SOLF test but could not be detected by either CB or the ST.

Continuous infusion of pantoprazole versus ranitidine for prevention of ulcer rebleeding: a U.S. multicenter randomized, double-blind study.

OBJECTIVES: No North American randomized study has compared ulcer rebleeding rates after endoscopic hemostasis in high-risk patients treated with high-dose intravenous (IV) proton pump inhibitors (PPIs) or IV histamine-2 receptor antagonists. Our hypothesis was that ulcer rebleeding with IV pantoprazole (PAN) would be lower than with IV ranitidine (RAN). METHODS: This was a multicenter, randomized, double-blind, U.S. study. Patients with bleeding peptic ulcers and major stigmata of hemorrhage had endoscopic hemostasis with thermal probes with or without epinephrine injection, then were randomly assigned to IV PAN 80 mg plus 8 mg/h or IV RAN 50 mg plus 6.25 mg/h for 72 h, and subsequently had an oral PPI (1/day). Patients with signs of rebleeding had repeat endoscopy. Rebleeding rates up to 30 days were compared in an intention-to-treat analysis. RESULTS: The study was stopped early because of slow enrollment (total N = 149, PAN 72, RAN 77). Demographics, APACHE II scores, ulcer type/location, stigmata, and hemostasis used were similar. The 7- and 30-day rebleeding rate was 6.9% (5 of 72 patients) with PAN and 14.3% (11 of 77) for RAN (p= 0.19). Rebleeds occurred within 72 h in 56% and between 4 and 7 days in 44% of patients. The 30-day mortality rate was 4%. Nonbleeding severe adverse events were more common in the RAN than in the PAN group (14 [18.1%]vs 7 [9.7%], p= 0.16). CONCLUSIONS: Because of the small sample size of this study, there was an arithmetic but not significant difference in ulcer rebleeding rates.

Pantoprazole infusion as adjuvant therapy to endoscopic treatment in patients with peptic ulcer bleeding: prospective randomized controlled trial.

BACKGROUND AND AIM: Following successful endoscopic therapy in patients with peptic ulcer bleeding, rebleeding occurs in 20% of patients. Rebleeding remains the most important determinant of poor prognosis. We investigated whether or not administration of pantoprazole infusion would improve the outcome in ulcer bleeding following successful endoscopic therapy. METHODS: In this double-blind, placebo-controlled, prospective trial, patients who had gastric or duodenal ulcers with active bleeding or non-bleeding visible vessel received combined endoscopy therapy with injection of epinephrine and heater probe application. Patients who achieved hemostasis were randomly assigned to receive pantoprazole (80 mg intravenous bolus followed by an infusion at a rate of 8 mg per hour) or placebo for 72 h. The primary end-point was the rate of rebleeding. RESULTS: Rebleeding was lower in the pantoprazole group (8 of 102 patients, 7.8%) than in the placebo group (20 of 101 patients, 19.8%; P = 0.01). Patients in the pantoprazole group required significantly fewer transfusions (1 +/- 2.5 vs 2 +/- 3.3; P = 0.003) and days of hospitalization (5.6 +/- 5.3 vs 7.7 +/- 7.3; P = 0.0003). Rescue therapies were needed more frequently in the placebo group (7.8% vs 19.8%; P = 0.01). Three (2.9%) patients in the pantoprazole group and eight (7.9%) in the placebo group required surgery to control their bleeding (P = 0.12). Two patients in the pantoprazole group and four in the placebo group died (P = 0.45). CONCLUSION: In patients with bleeding peptic ulcers, the use of high dose pantoprazole infusion following successful endoscopic therapy is effective in reducing rebleeding, transfusion requirements and hospital stay.

Efficacy and safety of rifabutin-containing 'rescue therapy' for resistant Helicobacter pylori infection.

BACKGROUND: Current 'rescue' therapies provide inadequate Helicobacter pylori eradication rates because of antibiotic resistance. AIM: To test the efficacy of a modified triple regimen combining rifabutin, pantoprazole and amoxicillin as rescue therapy for patients in whom eradication of H. pylori had failed standard clarithromycin-based triple therapy. METHODS: One hundred and thirty patients (mean age 51.7 +/- 14.8 years) who had failed one or more eradication attempts with omeprazole, clarithromycin and amoxicillin were treated for 12 days with rifabutin 150 mg daily, amoxicillin 1 g or 1.5 g t.d.s, and pantoprazole 80 mg t.d.s. RESULTS: The intention-to-treat and per-protocol eradication rates were 90.8/90.8%. Metronidazole or/and clarithromycin resistance had no significant impact on H. pylori eradication rates. A higher overall eradication rate of 96.6% (95% CI: 92.1-101%) was obtained in patients treated with a regimen containing 1.5 g amoxicillin t.d.s compared with 90.7% (95% CI: 82-98.6%) using a regimen with 1 g amoxicillin t.d.s but the difference was not significant. Side-effects reported in 40% of patients were mild. CONCLUSION: A 12-day course of low dose of rifabutin with an increased dose of amoxicillin and pantoprazole is well-tolerated and highly effective against dual-resistant H. pylori infection after failure of triple therapy.

Intravenous proton pump inhibitor therapy: a rationale for use.

Proton pump inhibitors (PPIs) are used widely in the management of acid-related disorders and, for the majority of patients, oral therapy is highly effective. Not all patients with acid-related disorders respond completely to standard, once-daily PPI therapy, but most nonresponders will generally respond to an increase in the dose or frequency of PPI therapy. At equivalent doses, oral and intravenous (IV) PPIs produce comparable acid suppression; thus there are very few clinical indications for IV PPI therapy. IV PPIs are an appropriate substitute for oral PPIs, at an equivalent dose, for patients with, for example, gastroesophageal reflux disease, peptic ulceration, or Zollinger-Ellison syndrome, who cannot take oral medication. For patients with nonvariceal, upper gastrointestinal hemorrhage, profound acid suppression (gastric pH . 6.0) optimizes clot stability and reduces the risk of rebleeding; this is achieved most effectively with an initial IV PPI bolus followed by a continuous infusion. High-dose, IV PPI therapy is beneficial and cost-effective in patients who have a high-risk lesion at endoscopy and it should be preceded by effective endoscopic hemostasis if possible. IV PPIs, preoperatively and in the intensive care setting, effectively reduce gastric acidity, but there are no convincing data that this confers any significant clinical benefit compared with other therapeutic strategies.

Intravenous proton-pump inhibitors versus H2-antagonists for treatment of GI bleeding.

OBJECTIVE: To evaluate the evidence supporting the use of intravenous proton-pump inhibitors in the treatment of gastrointestinal (GI) hemorrhage in comparison with histamine(2) (H(2))-receptor antagonists. DATA SOURCES: Clinical literature was accessed through a MEDLINE search (1966-October 2002). Data from abstracts and fully published articles were retrieved for analysis. Key search terms included pantoprazole, omeprazole, proton-pump inhibitors, gastrointestinal hemorrhage, histamine(2)-receptor antagonists, ranitidine, and cimetidine. DATA SYNTHESIS: There are limited published clinical outcome data evaluating the use of intravenous pantoprazole in patients with upper GI hemorrhage. However, there are several gastric pH studies suggesting that intravenous pantoprazole is effective in quickly obtaining and maintaining a pH >6. When considering the results from studies of high-dose intravenous omeprazole, in addition to the pantoprazole data, the relative efficacy of intravenous proton-pump inhibitors appears to be superior to that of intravenous H(2)-receptor antagonists in providing a more predictable and sustained pH control. CONCLUSIONS: Intravenous proton-pump inhibitors are suitable, possibly superior, alternatives to intravenous H(2)-receptor antagonists in treatment of upper GI bleeding.

Fish oil (Eicosapen) is less effective than metronidazole, in combination with pantoprazole and clarithromycin, for Helicobacter pylori eradication.

BACKGROUND: In vitro omega-3-fatty acids (Eicosapen) are bacteriostatic to Helicobacter pylori and have a variety of immuno-modulating effects. AIM: To investigate the efficacy and tolerability of eicosapen (E) as an antibiotic-sparing component of a triple H. pylori eradication regimen in non-ulcer dyspepsia patients in a randomized, double-blind trial. METHODS: Non-ulcer dyspepsia patients (n=199), with a normal upper endoscopy and a positive (13)C-urea breath test (UBT) were randomly assigned to either pantoprazole, clarithromycin and metronidazole (PCM) or pantoprazole, clarithromycin and eicosapen (PCE) for 7 days. Four weeks after treatment, H. pylori eradication was determined by UBT. Symptoms were followed up to 16 months. RESULTS: In the intention-to-treat population, PCM eradicated infection in 78% but PCE was successful in only 34% (P < 0.001). Symptomatic improvement occurred in both groups, and was not related to H. pylori eradication. CONCLUSION: Eicosapen is unlikely to be useful in H. pylori eradication regimens.

Triple therapy for Helicobacter pylori eradication: a comparison of pantoprazole once versus twice daily.

BACKGROUND: Proton pump inhibitor-based triple therapy is recommended as treatment for Helicobacter pylori eradication. The proton pump inhibitor may be given once or twice daily. However, little information is available on how these two treatment strategies compare. METHODS: H. pylori-positive patients (two positive test results) with endoscopy-proven healed duodenal ulcer or non-ulcer dyspesia were randomly allocated to 1 week of double-blind treatment with pantoprazole 40 mg once or twice daily, plus clarithromycin 250 mg and metronidazole 400 mg twice daily. Eradication was defined as a negative 13C-urea breath test (13C-UBT) and histology, 4-5 weeks post-treatment. The follow-up phase comprised 12 months off therapy, with 13C-UBT at 6 and 12 months. RESULTS: Two hundred and four patients received treatment: pantoprazole once daily (x1), n=104; twice daily (x2), n=100. Eradication rates were 84% in both the pantoprazole x1 and pantoprazole x2 groups by modified intention-to-treat analysis and 89% and 87%, respectively, by per protocol analysis. Metronidazole resistance was found in 44% of pre-treatment cultures of H. pylori. Eradication rates were similar in susceptible (72%) and resistant (75%) strains. During follow-up, recrudescence of infection occurred in 3/118 patients. CONCLUSION: When using pantoprazole plus clarithromycin and metronidazole, the proton pump inhibitor can be used once daily without loss of efficacy.

Two-week course of pantoprazole combined with 1 week of amoxycillin and clarithromycin is effective in Helicobacter pylori eradication and duodenal ulcer healing.

BACKGROUND: Experience with proton pump inhibitor-based triple therapy is predominantly with omeprazole-containing regimens. AIM: To investigate the efficacy of a pantoprazole-based regimen, with either a 1 or 2-week course of antibiotic co-therapy, in eradicating H. pylori, healing duodenal ulcers and to assess the antibiotic sensitivity profiles of isolated H. pylori strains. METHODS: A single-blind, multicentre, parallel group comparison of patients with endoscopically proven, H. pylori associated, active duodenal ulceration. All patients received pantoprazole, 40 mg b.d. for 2 weeks. Patients were randomized to receive either 1 or 2 weeks of therapy with amoxycillin, 1 g b.d. and clarithromycin 500 mg b.d. Patients were endoscoped at entry, at 14 days and a minimum of 4 weeks after cessation of all therapy. H. pylori status was determined by urease reaction, histological assessment and culture from antral and body biopsies. Antibiotic sensitivity was determined using the agar dilution technique. RESULTS: Sixty-seven patients were randomized. One week co-therapy (n=33): eradication efficacy, ITT= 79% (95% CI: 61-91%); ulcer healing efficacy (at 6-week visit)=88% (95% CI: 72-97%). Two-week co-therapy (n=34): eradication efficacy, ITT=91% (95% CI: 76-98%: ulcer healing efficacy= 88% (95% CI: 73-97%). Both regimens were well tolerated and no primary antibiotic resistance was noted. CONCLUSION: Pantoprazole-based triple therapy, with either 1 or 2 weeks of co-therapy with amoxycillin and clarithromycin, is effective in eradicating H. pylori and healing duodenal ulceration.

Optimizing the intragastric pH as a supportive therapy in upper GI bleeding.

Acid inhibitory therapy has long been considered of no benefit for upper GI bleeding. The reason was that achlorhydria in the stomach could not be achieved with any single or combination of acid inhibitory drugs. The introduction of proton pump inhibitors has, for the first time, allowed the physician to temporarily achieve achlorhydria by large doses of intravenously applied proton pump inhibitors. The first placebo-controlled clinical trials have shown that, indeed, an intragastric pH of near 7 can significantly improve the clinical outcome of upper GI bleeding. Pharmacokinetic studies with proton pump inhibitors have shown that a bolus of 80 mg pantoprazole or omeprazole followed by immediate continuous infusion of eight mg per hour will result in an intragastric pH of 7 within 20 minutes. This intragastric pH optimizes the different steps of hemostasis in the stomach.